Open access

The Role of an NFκB-STAT3 Signaling Axis in Regulating the Induction and Maintenance of the Pluripotent State

Written By

Jasmin Roya Agarwal and Elias T. Zambidis

Submitted: 13 September 2013 Published: 02 July 2014

DOI: 10.5772/57602

From the Edited Volume

Pluripotent Stem Cell Biology - Advances in Mechanisms, Methods and Models

Edited by Craig S. Atwood and Sivan Vadakkadath Meethal

Chapter metrics overview

1,964 Chapter Downloads

View Full Metrics

1. Introduction

Induced pluripotent stem cells (iPSC) are generated by reprogramming differentiated somatic cells to a pluripotent cell state that highly resembles embryonic stem cells (ESC) [1]. Fully reprogrammed iPSC can differentiate into any adult cell type [2-6]. Takahashi and Yamanaka generated the first iPSC in 2006 by transfecting fibroblasts with four defined factors: SOX2, OCT4, KLF4, c-MYC (SOKM; also referred to as Yamanaka factors) [7]. The clinical use of iPSC offers great potential for regenerative medicine as any cell type can be generated from true pluripotent cells [8-10]. However, human clinical iPSC applications are currently limited by inefficient methods of reprogramming that often generate incompletely reprogrammed pluripotent states that harbor potentially cancerous epigenetic signatures, and possess limited or skewed differentiation capacities [11-13]. Many standard iPSC lines do not fully resemble pluripotent ESC, and often retain an epigenetic memory of their cell of origin [14, 15]. Such incompletely reprogrammed iPSC also display limited differentiation potential to all three germ layers (e.g., endoderm, ectoderm, mesoderm) [16, 17].

To avoid integrating retroviral constructs that may carry mutagenic risks, many non-viral methods have been described for hiPSC derivation [18, 19]. For example, one successful approach is to transiently express reprogramming factors with EBNA1-based episomal vectors [20-22]. It was initially intuitive to reprogram skin fibroblasts due to their easy accessibility. However, standard episomal reprogramming in fibroblasts occurs at even lower efficiencies (< 0.001-0.1%) than reprogramming with retroviral vectors (0.1%–1%) [23-25]. Subsequent studies revealed that various cell types possess differential receptiveness for being reprogrammed to pluripotency [26-30]. One highly accessible human donor source is blood, which has been demonstrated to reprogram with significantly greater efficiency than fibroblasts [4, 20, 31-33].

The innate immune system possesses highly flexible cell types that are able to adapt quickly to various pathogens by eliciting defense responses that protect the host [34-36]. Innate immune cells derived from the myeloid lineage (eg, monocyte-macrophage, dendritic cells, neutrophils) are able to reactivate some unique features of pluripotent stem cells that may give them greater flexibility for being reprogrammed to a pluripotent cell state than other differentiated cells [37]. Additionally, the differentiation state of the cell seems to be of critical importance for its reprogramming efficiency [38].

Our group established a reprogramming method that solves many of the technical caveats cited above (Figure 1). We have generated high-fidelity human iPSC (hiPSC) from stromal-primed (sp) myeloid progenitors [20]. This system can reprogram >50% of episome-expressing myeloid cells to high-quality hiPSC characterized by minimal retention of hematopoietic-specific epigenetic memory and a molecular signature that is indistinguishable from bona fide human ESC (hESC). The use of bone marrow-, peripheral-or cord blood (CB)-derived myeloid progenitor cells instead of fibroblasts, and a brief priming step on human bone marrow stromal cells / mesenchymal stem cells (MSC) appeared to be critical for this augmented reprogramming efficiency. In this system, CD34+ - enriched cord blood cells (CB) are expanded with the growth factors (GF) FLT3L (FMS-like tyrosine kinase 3 ligand), SCF (stem cell factor) and TPO (thrombopoietin) for 3 days, subsequently nucleofected with non-integrating episomes expressing the Yamanaka factors (4F, SOX2, OCT4, KLF4, c-MYC), and then co-cultured on irradiated MSC for an additional 3 days. Cells are then harvested, and passaged onto MEF (mouse embryonic fibroblasts), and hiPSC are generated via standard methods and culture medium. The initial population of enriched CD34+ CB progenitors quickly differentiates to myeloid and monocytic cells in this system, and reprogrammed cells arise from CD34- myeloid cells. The first iPSC colonies appear around day 10, and stable mature iPSC colonies can be established after ~21-25 days. The episomal constructs are partitioned after relatively few cell divisions (e.g., 2-9 passages) to generate high quality non-integrated hiPSC.

Figure 1.

Schema of the stromal-primed myeloid reprogramming protocol for the generation of high quality human iPSC. 4F: four Yamanaka factors, GF: hematopoietic growth factors.

A proteomics and bioinformatics analysis of this reprogramming system implicated significant activation of MSC-induced inflammatory TLR-NFκB and STAT3 signaling [20]. A combination of cell contact-dependent and soluble factors mediate these effects. A recent study similarly implicated inflammatory TLR3 signaling as a novel trigger for enhanced fibroblast reprogramming, albeit at much lesser efficiencies than observed in our myeloid reprogramming system. TLR3 signaling leads to epigenetic modifications that favor an open chromatin state, which increases cell plasticity and the induction of pluripotency [39]. Lee et al. termed this novel link between inflammatory pathways and cell reprogramming ‘Transflammation’ [40].

In this chapter we will discuss hypotheses why inflammation-activated myeloid cells may be highly receptive to factor-mediated reprogramming. Specifically, we will explore the role of the NFκB-STAT3 signaling axis in mediating the unique susceptibility of myeloid cells to high-quality human iPSC derivation.


2. Overview of the canonical and non-canonical NFκB pathway

Multipotent myeloid progenitors are derived from hematopoietic stem cells and differentiate to monocytes macrophages, dendritic cells, and granulocytes, which elicit the initial innate immune response toward pathogens [41]. NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a central transcription factor that regulates these innate immune responses during microbial infections [42-44]. The NFκB system belongs to a group of early-acting transcription factors that are present in the cytoplasm in an inactive state but can be quickly activated by multiple inflammatory stimuli [45, 46].

2.1. The canonical NFκB signaling pathway

The NFκB family consists of 5 members; p65 (RelA), p50 and c-Rel are involved in canonical signaling, and p52 and RelB are involved in non-canonical signaling. Canonical NFκB signaling is characterized by activation of the IκB kinase complex (IKK), which contains two kinases, IKK1/α and IKK2/β along with a non-catalytic subunit called IKKγ (NEMO) [47, 48]. Unstimulated NFκB is sequestered in the cytoplasm by IκBα protein. In contrast, activation of the IKK complex (e.g., by TLRs) leads to IKKβ-mediated serine phosphorylation of IκBα triggering its proteasome-mediated degradation and its dissociation from NFκB [49, 50]. This activates the p65:p50 dimer through p65 phosphorylation and leads to NFκB translocation into the nucleus where it induces target gene expression. Subsequent acetylation keeps p65 in the nucleus [51]. This can be reverted by HDAC3 (histone deacetylase 3)-induced deacetylation of p65, which increases the affinity of NFκB proteins for IκBα and nuclear export [52, 53]. Canonical NFκB signaling is a fast and transient process that regulates complex inflammatory processes that includes the initial pro-inflammatory phase, the induction of apoptosis, and even tumorigenesis [54]. It can be activated by toll-like receptors (TLR), which recognize characteristic pathogenic molecules to activate innate immune responses [55-57].

2.2. The non-canonical NFκB signaling pathway

Non-canonical NFκB signaling is stimulated via the NFκB-inducing kinase (NIK), which leads to phosphorylation of the p100 precursor protein and generation of the p52:RelB dimer that translocates to the nucleus to activate gene transcription. This pathway is uniquely dependent on steady state levels of NIK expression, which are controlled under normal conditions through TRAF3-directed ubiquitination and proteasomal degradation. Non-canonical NFκB signaling is slow but persistent and requires de novo NIK protein synthesis and NIK stabilization [58]. It is activated by receptors that belong to the TNFR (tumor necrosis factor receptor) superfamily like BAFF (B-cell-activating factor), CD40 or lymphotoxin β-receptor (LTβR) [59-62].

The common feature of these receptors is the possession of a TRAF-binding motif, which recruits TRAF members (e.g., TRAF2 and TRAF3) during ligand ligation [63, 64]. Receptor recruitment of TRAF members triggers their degradation, and leads to NIK activation and p100 processing [65]. Additionally, BAFF is an important component of pluripotency-supporting growth media for the culture of ESC and a regulator of B-cell maturation [66]. It predominantly activates non-canonical NFκB signaling due to its possession of an atypical TRAF-binding sequence, which interacts only with TRAF3 but not with TRAF2 [67]. TRAF3 degradation is sufficient to trigger non-canonical NFκB signaling, whereby activation of the canonical NFκB pathway requires TRAF2 recruitment [68].

2.3. CD40 stimulates both NFκB pathway components

Another receptor associated with NFκB signaling is CD40, which is expressed on various cell types including B cells and monocytes. The CD40 receptor interacts with its ligand CD40L, which is primarily expressed on activated T cells. This signaling is majorly involved in B-cell activation, dendritic cell maturation, antigen presentation and acts as a co-stimulatory pathway of T-cells [69]. Upon ligation by CD40L, CD40 targets both the canonical and non-canonical NFκB pathways via proteolysis of TRAF2 and TRAF3 [70-72]. Non-canonical NFκB signaling regulates hematopoietic stem cell self-renewal via regulating their interactions with the microenvironment [73]. The deregulation of non-canonical hematopoietic NFκB signaling is associated with auto-immunity, inflammation and lymphoid malignancies [58, 74].

2.4. NFκB subunit functions

A third NFκB signaling pathway is activated following response to DNA damage that results in IκB degradation independent of IKK. This results in dimerization of free NFκB subunits that are mobilized similarly to canonical NFκB signaling [47]. Unlike RelA, RelB, and c-Rel, the p50 and p52 NFκB subunits do not contain transactivation domains in their C-terminus. Nevertheless, the p50 and p52 NFκB members play critical roles in modulating the specificity of NFκB functions and form heterodimers with RelA, RelB, or c-Rel [75]. Cell contact-dependent signals are crucial during immune responses and can be mediated through NFκB signaling [76]. This can be augmented by co-stimulatory signals like CD40 or CD28 that directly bind to NFκB proteins like p65 [77-81].


3. Functional role of NFκB signaling in stem cells

3.1. Differential roles of canonical and non-canonical NFκB signaling in embryonic stem cells

TLR activation is not only important for mediating innate immune responses, but also for stem cell differentiation. For example, hESC are characterized by the expression of pluripotency genes and markers such as OCT4, NANOG, alkaline phosphatase (AP) and telomerase [82-86]. NFκB signaling has been demonstrated to be crucial for maintaining ESC pluripotency and viability, and drives lineage-specific differentiation [87, 88]. A balance of canonical and non-canonical NFκB signaling regulates these opposing functions; non-canonical pathway signaling maintains hESC pluripotency, and canonical pathway signaling regulates hESC viability and differentiation [89, 90]. For example, non-canonical NFκB signaling has to be silenced during cell differentiation, which allows this pathway to act like a switch between hESC self-renewal and differentiation. RelB positively regulates several key pluripotency markers and represses lineage markers by direct binding to their regulatory units. RelB down-regulation reduces the expression of pluripotency genes like SOX2 and induces differentiation-associated genes like BRACHYURY (mesodermal marker), CDX2 (trophoectodermal marker) and GATA6 (endodermal marker) [89].

3.2. Canonical NFκB signaling in hematopoietic stem cells

RelB/p52 signaling also positively regulates hematopoietic stem-progenitor cell (HSPC) self-renewal in response to cytokines (e.g., TPO and SCF) and maintains osteoblast niches and the bone marrow stromal cell population. It negatively regulates HSPC lineage commitment through cytokine down-regulation in the bone marrow microenvironment, although it is able to direct early HSC commitment to the myeloid lineage [73, 91].

Canonical p65 signaling also regulates hematopoietic stem cell functions and lineage commitment by controlling key factors involved in hematopoietic cell fate [92-94]. Canonical NFκB signaling is positively regulated by Notch1, which facilitates nuclear retention of NFκB proteins and promotes self-renewal [95-98]. FGF2 (fibroblast growth factor 2) is important for hESC self-renewal and preserves the long-term repopulating ability of HSPC through NFκB activation [99-102]. Deletion of p65, p52 and RelB dramatically decreases HSC differentiation, function and leads to extramedullary hematopoiesis [103]. NFκB pathway components and FGF4 are highly expressed in CD34+HSPC from cord blood, where they regulate clonogenicity. Nuclear p65 can be detected in 90% CB-derived CD34+ cells but only in 50% BM-derived CD34+ cells [104]. The important role of NFκB in regulating myeloid cell lineage development has been most potently revealed via genetic deletion of IKKβ, IκBα, and RelB, which resulted in granulocytosis, splenomegaly and impaired immune responses [73, 103].

3.3. Canonical NFκB signaling during ESC differentiation

Canonical NFκB signaling is very low in the undifferentiated pluripotent state, where it maintains hESC viability. However, it strongly increases during lineage-specific differentiation of pluripotent stem cells. p65 binds to the regulatory regions of similar differentiation genes as RelB with opposing effects on their activation or silencing. It regulates cell proliferation by direct binding to the CYCLIN D1 promoter [89]. There are different levels of inhibiting canonical NFκB signaling: first, p65 translational repression by the microRNA cluster miR-290 to maintain low p65 protein amounts and second, the inhibition of translated p65 by physical interaction with NANOG. Similarly, OCT4 expression is reversely correlated with canonical NFκB signaling [105]. In contrast to most observations in mouse ESC, NFκB probably plays a more important role in the maintenance of human ESC pluripotency [106]. Finally, active TLRs are expressed on embryonic, hematopoietic and mesenchymal stem cells (MSC), thus implicating their roles in a variety of stem cell types [107-110].


4. Role of NFκB signaling during reprogramming to pluripotency

Undifferentiated human iPSC have elevated NFκB activities, which play important roles in maintaining OCT4 and NANOG expression in pluripotent hiPSC [111]. Innate immune TLR signaling was recently shown to enhance nuclear reprogramming probably through the induction of an open chromatin state, and global changes of epigenetic modifiers [39]. This normally increases cell plasticity in response to a pathogen, but may also enhance the induction of pluripotency, transdifferentiation and even malignant transformation [112-116].

The EBNA (Epstein-Barr virus nuclear antigen) is a virus-derived protein that is not only a critical component of episomal reprogramming vectors, where it mediates extra-chromosomal self-replication, but it is also known to activate several TLRs [117-119]. These include TLR3, which is known to augment reprogramming efficiencies through the activation of inflammatory pathways [39, 120]. TLR3 recognizes double-stranded RNA from retroviruses and signals through TRAF6 and NFκB [121-123]. The TLR3 agonist poly I:C was shown to have the same effect as retroviral particles in enhancing Yamanaka factor-induced iPSC production. TLR3 causes widespread changes in the expression of epigenetic modifiers and facilitates nuclear reprogramming by inducing an open chromatin state through down-regulation of histone deacetylases (HDACs) and H3K4 (histone H3 at lysine 4) trimethylations [38, 39, 124]. These epigenetic modifications mark transcriptionally active genes, whereas the H3K9me3 (Histone H3 at lysine 9) modification marks transcriptionally silenced genes [125, 126]. Histone deacetylation is generally associated with a closed chromatin state and HDAC inhibitors were shown to enhance nuclear reprogramming [127, 128]. Histone acetylation favors an open chromatin state, and is maintained by proteins containing histone acetyltransferase (HAT) domains, such as p300 and CBP [129, 130]. Interestingly, p300/CBP is able to interact with NFκB [131, 132]. RelB directly interacts with the methyltransferase G9a to mediate gene silencing of differentiation genes [133]. Epigenetic changes that allow an open chromatin state are crucial for giving the Yamanaka factors access to promoter regions necessary for the induction of pluripotency. Epigenetic chromatin modifications by TLRs are normally involved in the expression of host defense genes during infections [134-136]. This capability can be deployed to enable nuclear reprogramming as TLR3 was shown to change the methylation status of the Oct4 and Sox2 promoters. Interestingly, changes in these methylation marks were not observed with TLR3 activation alone but only in the presence of the reprogramming factors. Although TLR3 by itself promotes an open chromatin configuration, the reprogramming proteins are likely necessary to direct the epigenetic modifiers to the appropriate promoter sequences [137]. Lee et al. described the potential of inflammatory pathways to facilitate the induction of pluripotency as ‘transflammation’ [40, 138].


5. Overview of the JAK/STAT pathway

The JAK/STAT pathway (Janus kinase/signal transducer and activator of transcription) integrates a complex network of exterior signals into the cell, and can be activated by a variety of ligands and their receptors [139]. These receptors are associated with a JAK tyrosine kinase at their cytoplasmic domain. The JAK family consists of the four members JAK1, JAK2, JAK3 and TYK2 [140, 141]. Many cytokines and growth factors signal through this pathway to regulate immune responses, cell proliferation, differentiation and apoptosis [142-146]. Ligand binding induces the multimerization of gp130 receptor subunits, which brings two JAKs close to each other inducing trans-phosphorylation. Such activated JAKs phosphorylate their receptor at the C-terminus and the transcription factor STAT at tyrosine residues. This allows STAT dimerization and their nuclear translocation to induce target gene transcription. [147, 148] STAT3 acetylation is critical for stable dimer formation and DNA binding [149]. From the 7 mammalian STATs, STAT3 and STAT5 are expressed in many cell types, are activated by a plethora of cytokines and growth factors, and integrate complex biological signals [150, 151]. The other STAT proteins mainly play specific roles in the immune response to bacterial and viral infections. STAT3 is an acute phase protein with important functions during immediate immune reactions [152-154]. STAT3 can be recruited by receptor tyrosine kinases that harbor a common STAT3 binding motif in their cytoplasmic domain (e.g., GCSF (granulocyte colony-stimulating factor), LIF (leukemia inhibitory factor), EGF (epidermal growth factor), PDGF (platelet-derived growth factor), interferons (IFNγ) and interleukins (IL-6, IL-10)) [155-158]. Many cytokines signal through IL-10/STAT3 to achieve an immunosuppressive function or anti-apoptotic effect [159, 160]. IL-10 is also required during terminal differentiation of immunoglobulins [161]. STAT3 can be phosphorylated at tyrosine or serine residues. The phosphorylation site can play distinct roles in the regulation of downstream gene transcription [162]. Stat3-deficient mice die during early embryogenesis due to Stat3 requirement for the self-renewal of ESC [163].

Negative feedback regulation of the JAK/STAT circuitry is mediated by the SOCS family of target genes (suppressors of cytokine signaling) in a way that activated STAT induces SOCS transcription [164, 165]. SOCS proteins can bind to phosphorylated JAKs as a pseudo-substrate to inhibit JAK kinase activity and turn off the pathway [166, 167]. SOCS are negative regulators of the immune response [168, 169]. A small peptide antagonist of SOCS1 was shown to bind to the activation loop of JAK2 leading to constitutive STAT activation and TLR3 induction. This boosts the immune system to exert broad antiviral activities [170]. The JAK/STAT pathway also interacts with many other signaling pathways in a complex manner to regulate cell homeostasis and immune reactions [149, 171].


6. Functional role of the JAK/STAT pathway in stem cells

6.1. Stat3 maintains naïve pluripotency in mouse embryonic stem cells

ESC pluripotency is regulated by transcriptional networks that maintain self-renewal and inhibit differentiation [172-174]. Stat3 and Myc are necessary to maintain mouse ESC (mESC) self-renewal and bind to many ESC-enriched genes [175]. Their target genes include pluripotency-related transcription factors, polycomb group repressive proteins, and histone modifiers [176, 177]. The transcription factor Stat3 is a key pluripotency factor required for ESC self-renewal [178, 179]. Mouse ESC require LIF-Stat3 (leukemia inhibitory factor) and Bmp4 (bone morphogenic protein 4) to remain pluripotent in in vitro cultures, whereas human ESC require FGF2/MAPK (fibroblast growth factor / mitogen-activated protein kinase) and TGFβ/Activin/Nodal (transforming growth factor β) [180-183]. Nevertheless, the core circuitry of pluripotency is conserved among species and includes OCT4, SOX2 and NANOG [174].

6.2. The LIF-IL6-STAT3 circuitry

LIF belongs to the IL-6 family of cytokines and acts in parallel through the Jak/Stat3 and PI3K/Akt (Phosphatidylinositide 3-kinase) pathways to maintain Oct4, Sox2 and Nanog expression via Kruppel-like factor 4 (Klf4) and T-box factor 3 [184, 185]. Lif and IL-6 are necessary for STAT3 phosphorylation mediated by Jak1 [186]. Stat3 phosphorylation positively regulates Klf4 and Nanog transcripts and facilitates Lif-dependent maintenance of pluripotency in a signaling loop [106]. Stat3 directly binds to genomic sites of Oct4 and Nanog, regulates the Oct4-Nanog circuitry and is necessary to maintain the self-renewal and pluripotency of mESC [187-189]. Overexpression of Stat3 maintains mESC self-renewal even in the absence of Lif [190]. Withdrawal of LIF up-regulates the NFκB pathway and results in ESC differentiation as well as STAT3 disruption [191-193]. The interleukin 6 (IL-6) response element (IRE) is activated by STAT3, vice versa IL-6 stimulation leads to STAT3 phosphorylation and transactivation of IRE- containing promoters providing a positively regulated STAT3-IL6 loop. STAT3 directly associates with c-Jun and c-Fos in response to IL-6 [194]. c-Jun and c-Fos are DNA binding proteins and components of the AP-1 (activation protein-1) transcription factor complex [195]. AP-1 can be activated by TLR2/4, IL-10 or STAT3 to regulate inflammatory responses or drive keratinocyte differentiation in interplay with STAT3 and c-MYC [196]. Tlr2 also plays an important role in the maintenance of mESC [107]. STAT3 is important to tune appropriate amounts of AP-1 proteins required for proper differentiation. DNA binding sites for both AP-1 and STAT3 have been found in many gene promoters [194, 197]. It is important to note that c-Jun is able to capture or release the NuRD (nucleosome remodeling and deacetylation) repressor complex, an important epigenetic modulator of gene silencing [198, 199]. STAT3 is able to bind to bivalent histone modifications enabling a quick switch between the activation of pluripotency genes during ESC maintenance and their inhibition during cell differentiation [193].

6.3. STAT3 signaling in immune cells

STAT3 also has complex functions during hematopoietic development, immune regulation, cell growth, and leukemic transformation [200-202]. It is critically important for the survival and differentiation of lymphocytes and myeloid progenitors [171]. STAT3 signaling can be activated in a cell contact-dependent way, which is distinct from its cytokine activation. Co-cultures of MSC (human mesenchymal stem cells) and APC (antigen-presenting cell) increase STAT3 signaling in both cell types in a cell contact-dependent way, which mediates the immune-modulatory effects of MSC to block APC maturation and induce T-cell tolerance [203]. MSC are high-proliferative non-hematopoietic stem cells with the ability to differentiate into multiple mesenchymal lineages [204-206]. They accumulate in tumor environments in response to NFκB signaling and produce cytokines [207]. MSCs are FDA-approved for the treatment of severe acute GVHD, due to their immunomodulatory properties [208]. STAT3 phosphorylation is induced by cell-cell contacts and inhibited in postconfluent cells that consequently become apoptotic. Therefore, STAT3 may represent a molecular junction that allows cell proliferation or growth arrest depending on the state of the cell. Increased STAT3 activity may promote cell survival during cell confluency [209].

6.4. Cell contact-dependent STAT3 signaling during cell transformation

Constitutive STAT3 activation can by itself result in cellular transformation [210-214]. For example, contact-dependent STAT3 activation is known to play a promoting role in the interactions between tumor cells and their environment [215-218]. Cell transformation and the induction of pluripotency may share very similar signaling processes, and it is possible that STAT3 may represent a common axis [219, 220]. During early tumor development, certain cells have to acquire stem cell-like features that allow them to self-renew (tumor-initiating cells) and to produce cell progeny (tumor bulk) [221-224]. These tumor-initiating cells are very difficult to eradicate during chemotherapies and often re-establish the tumor seen as clinical relapse [225-227]. Tumor-initiating cells display strong inflammatory gene signatures with elevated IL6-STAT3-NFκB signaling to sustain their self-renewal [228-231]. A better understanding of the mechanism by which STAT3 and NFκB regulates the acquisition of pluripotency and self-renewal might also give us crucial insight about tumor development, and may lead to future novel therapies [171, 232].


7. The role of STAT3 signaling during reprogramming

7.1. STAT3 is a master reprogramming factor

Activation of Stat3 is a limiting factor for the induction of pluripotency, and its over-expression eliminates the requirement for additional factors to establish pluripotency [233]. These key properties have positioned Stat3 signaling as one of the master reprogramming factors that dominantly instructs naïve pluripotency [175]. Elevated Stat3 activity overcomes the pre-iPSC reprogramming block and enhances the establishment of pluripotency induced by SOKM [234]. Stat3 and Klf4 co-occupy genomic sites of Oct4, Sox2 and Nanog. Klf4 and c-Myc are downstream targets of Stat3 signaling and part of the transcriptional network governing pluripotency. The Stat3 effect is combinatorial with other reprogramming factors, which implies that additional targets of Stat3 play a pivotal role [235].

7.2. STAT3 is an epigenetic regulator

Stat3 activation regulates major epigenetic events that induce an open-chromatin state during late-stage reprogramming to establish pluripotency [236-238]. For example, Stat3 signaling stimulates DNA methylations to silence lineage commitment genes and facilitates DNA demethylations to activate pluripotency-related genes [106, 239, 240]. Other chromatin modifications include histone acetylation and deacetylation, which are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activities. Histone acetylation is associated with an open chromatin state that allows active gene transcription. HDAC inhibitors are known to significantly improve the efficiency of iPSC generation by allowing promoter accessibility [128, 241, 242]. STAT3 suppresses HDAC expression and repressive chromatin regulators to establish an open-chromatin structure giving full access to transcriptional machineries. The key pluripotency factor Nanog cooperates with Stat3 to maintain ESC pluripotency [173]. Interestingly, HDAC inhibitors but not NANOG over-expression rescues complete reprogramming in the presence of STAT3 inhibition.

Finally, DNA demethylation is regulated in mammalian cells by Tet proteins (tet methylcytosine dioxygenase), which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 suppresses ESC differentiation and Tet1 knockdown leads to defects in ESC self-renewal. Tet1 up-regulation is positively regulated by Stat3 during the late-reprogramming stage [243-246].


8. Interactions between NFκB and STAT3 signaling

8.1. Synergistic NFκB and STAT3 signaling

The NFκB and STAT3 pathways are closely interconnected in regulating immune responses [247, 248]. STAT3 activation itself induces further STAT3 phosphorylation. Un-phosphorylated STAT3 that accumulates in the cell can bind to un-phosphorylated NFκB in competition with IκB. The resulting STAT3/NFκB dimer localizes to the nucleus to induce NFκB-dependent gene expression [249]. STAT3 associates with the p300/CBP (CREB-binding protein) co-activator enabling its histone acetyltranferase activity to open chromatin structures, which allows chromatin-modifying proteins to bind the DNA and activate gene transcription. [250, 251] Tyrosine-phosphorylated and acetylated STAT3 additionally binds to the NFκB precursor protein p100 and induces its processing to p52 by activation of IKKα. STAT3 then binds to the DNA-binding p52 complex to assist in the activation of target genes [252]. Both, the NFκB and STAT3 pathway synergize during terminal B-cell differentiation [253]. Phosho-p65/STAT3 dimers and phospho-STAT3/NFκB dimer complexes can bind to κB motifs. Also, phospho-STAT3 and phosho-p50 interact with each other. Soluble CD40L rapidly activates NFκB p65 and up-regulates IL10 receptors on the cell surface. This renders STAT3 more susceptible to IL-10 induced phosphorylation [161]. Macrophage activation is regulated by Toll-like receptors, JAK/STAT signaling and immunoreceptors that signal via ITAM motifs [254, 255]. These pathways have low activity levels under homeostatic conditions but are strongly activated during innate immune responses. ITAM-coupled receptors cooperate with TLRs in driving NFκB signaling and inflammation during infections, whereas extensive ITAM activation inhibits JAK/STAT signaling to limit the immune reaction [256, 257]. Pleiotropic cytokines like interferons and IL-6 regulate the balance of pro-and anti-inflammatory functions by activating variable levels of STAT1 and STAT3 [258].

8.2. NFκB and STAT3 synergies in stem cells

NFκB and STAT3 are also part of an important stem cell pathway axis [259, 260]. A functional link between NANOG, NFκB and LIF/STAT3 signaling was shown in the maintenance of pluripotency [228]. Non-canonical NFκB signaling is activated by STAT3 through activation of IKKα and p100 processing [58]. Conversely, STAT3 inhibits TLR-induced canonical NFκB activity probably through up-regulated SOCS3. C-terminal binding of NANOG inhibits the pro-differentiation activities of canonical NFκB signaling and directly cooperates with STAT3 to maintain ESC pluripotency. NANOG and STAT3 bind to each other and synergistically activate STAT3-dependent promoters [106, 261].

The STAT3 pathway also interacts with many signaling pathways that are critically involved in the reprogramming process. For example, STAT3 signaling activates the MYC transcriptome and signals in loop with LIN28 [229]. LIN28 is expressed in undifferentiated hESC and is able to enhance the reprogramming efficiency of fibroblasts. It is down-regulated upon ESC differentiation [262-265]. Proto-oncogene tyrosine-protein kinase Src activation triggers an inflammatory response mediated by NFκB that directly activates IL6 and Lin28B expression through a binding site in the first intron. IL6-mediated activation of STAT3 transcription is necessary for monocyte activation and tumorigenesis. IL6 itself further activates NFκB, thereby completing a positive NFκB-STAT3-IL6 feedback loop that links inflammation to cell transformation [229]. Constitutive STAT3 signaling maintains constitutive NFκB activity in tumors by inhibiting its nuclear export through p65 acetylation, although STAT3 signaling inhibits NFκB activation during normal immune responses [52].


9. The role of epigenetic regulators during the induction of pluripotency

9.1. The NuRD complex

A panoply of chromatin remodelers play active, regulatory roles during the reprogramming process [266, 267]. For example, the Mbd3/NuRD complex is an important epigenetic regulator that restricts the expression of key pluripotency genes [268]. MBD3 (Methyl-CpG-binding domain protein 3) is part of the NuRD (nucleosome remodeling and deacetylation) repressor complex, which mediates chromatin remodeling through histone deacetylation via HDAC1/2 and ATPase activities [269-271]. The NuRD complex interacts with methylated DNA to mediate heterochromatin formation and transcriptional silencing of ESC-specific genes. Whereas MBD2 recruits NuRD to methylated DNA, MBD3 fails to bind methylated DNA as it evolved from a methyl-CpG-binding domain to a protein–protein interaction module [272]. Mbd3 antagonizes the establishment of pluripotency and facilitates differentiation [273].

9.2. MBD3 suppression is a rate-limiting step in factor-mediated reprogramming

Recent evidence suggested that efficient reprogramming may require NuRD complex down-regulation [274]. The reprogramming factors OCT4, SOX2, KLF4 and MYC bind to MBD3, a critical component of the NURD complex. In the absence of MBD3, SOKM over-expression induces pluripotency with almost 100% efficiency [275]. Such reprogramming occurs within seven days in mouse cells. Once pluripotency is established, MBD3 does not appear to compromise its maintenance. The MBD3/NuRD repressor complex is probably the predominant molecular block that prevents the induction of ground-state pluripotency. Several reprogramming factors directly interact with the MBD3/NuRD complex to form a potent negative regulatory complex that restrains pluripotency gene reactivation. Thus, chromatin de-repression is of critical importance for the conversion of somatic cells into iPSC.

9.3. Bivalent histone modifications

Embryonic stem cells are not only able to maintain their undifferentiated state indefinitely, but also need to retain their ability to differentiate into various cell types [276]. The co-existence of these two features requires the combined action of signal transduction pathways, transcription factor networks, and epigenetic regulators [277]. Pluripotent gene expression has to be maintained in a way that it can be rapidly silenced upon receiving differentiation signals. The NuRD complex maintains this ESC flexibility by inducing variability in pluripotency factor expression that results in a low-expressing subpopulation of ESCs primed for differentiation [268, 278]. The control of gene expression by juxtaposition of antagonistic chromatin regulators is a common regulatory strategy in ESC, called bivalent histone modification [279, 280]. Individual promoters exhibit trimethylation of two different residues of histone H3: lysine 4 (H3K4me3) and lysine 27 (H3K27me3) [281, 282]. H3K27me3 is a repressive histone modification, whereas H3K4me3 is an activation-associated mark [283]. Both epigenetic markers have opposing effects and allow quick adjustments between ESC self-renewal and differentiation. Bivalent genes are generally transcriptionally silent in ESCs but are prone for rapid activation. MBD3 binding is enriched at bivalent genes characterized by 5hmC modifications. STAT3 binds to bivalent histone modifications and is able to switch between cellular pluripotency and differentiation [236, 284, 285].

9.4. MBD3 may prevent completion of the reprogramming process

MBD3 plays key roles in the biology of 5-hydroxy-methylcytosine (5hmC) [286]. 5hMC is an oxidation product of 5-methylcytosine (5mC) [287, 288]. MBD3 silences pluripotency genes like Oct4 and Nanog through 5-hydroxy-methylation of their promoters. MBD3 binds to 5hmC in cooperation with Tet1 to regulate 5hmC-marked genes, but does not interact with 5mC. Mbd3 interaction with 5hmC recruits NuRD to its targets resulting in gene repression. Knockdown of the MBD3/NuRD complex affects the expression of 5hmC-marked genes [289]. Mbd3 acts upstream of Nanog and may block the transition from partially to fully reprogrammed iPSC by silencing Nanog. Nanog overexpression was dominant over Mbd3 knockdown in the induction of efficient reprogramming and is in general sufficient to maintain mESC pluripotency. Mbd3 depletion facilitates the transcription of Oct4 and Nanog and leads to the generation of iPSC and chimeric mice even in the absence of Sox2 or c-Myc [290]. The depletion of Mbd3/NuRD does not replace Oct4 during iPSC formation as reprogramming did not occur with Klf4 and c-Myc alone. Mbd3-dependent silencing of pluripotency factors occurs during ESC differentiation. This involves NuRD-dependent deacetylation of H3K27 required for the binding of the polycomb repressive complex two. NuRD-dependent silencing of pluripotency genes prevents the de-differentiation of somatic cells. In the absence of Mbd3, NuRD disassembles, which lowers this epigenetic barrier and allows the activation of pluripotency genes. Drug-induced down-regulation of Mbd3/NuRD may greatly improve the efficiency and fidelity of reprogramming [291].

9.5. STAT3-MBD3 counteractions

Figure 2.

The master reprogramming factor STAT3 may overcome an unknown reprogramming block by inducing an open chromatin formation that facilitates the pluripotency factors SOKM to bind to ESC gene promoters. We hypothesize that upstream inflammatory signals mediated by NFκB signaling may facilitate STAT3 to de-repress the NuRD complex via c-Jun.

Stat3 promotes the expression of self-renewal transcription factors and opposes NURD-mediated repression of several hundred target genes in ESCs. The opposing functions of Stat3 and NuRD maintain variability in the levels of key self-renewal transcription factors. Stat3, but not NuRD, is the rate-limiting factor for pluripotency gene expression. Self-renewing ESC face a barrier that prohibits differentiation. NuRD constrains this barrier within a range that can be overcome when self-renewal signals are withdrawn [268, 278, 292]. Mbd3/NuRD-mediated gene silencing is a critical determinant of lineage commitment in embryonic stem cells and allows cells to exhibit pluripotency and self-renewal. Mbd3-deficient ESC show persistent self-renewal even in the absence of Lif. They are able to undergo the initial steps of differentiation, but their ability for lineage commitment is severely compromised. They fail to downregulate undifferentiated cell markers as well as upregulate differentiation markers [293]. Stat3 has many downstream effectors like the proto-oncogene c-Jun that is part of the AP-1 complex [194]. The transactivation domain of un-phosphorylated c-Jun recruits Mbd3/NuRD to AP-1 target genes to mediate gene repression. This repression is relieved by c-Jun N-terminal phosphorylation or Mbd3 depletion. Upon JNK activation, NuRD dissociates from c-Jun, which results in de-repression of target gene transcription. Termination of the JNK signal induces Mbd3/NuRD re-binding to un-phosphorylated c-Jun and cessation of target gene expression (Figure 2) [199].


10. Conclusions

In this review, we have discussed a potentially novel link between inflammatory pathways and efficient cell reprogramming. In this context, our group reported that bone marrow stromal-primed human myeloid cell progenitors are significantly more receptive to reprogramming stimuli than other cell types [20]. Myeloid cells harbor a unique epigenetic plasticity that allows them to quickly respond to a plethora of pathogens. They are innately equipped to transcriptionally and epigenetically activate key inflammatory pathways via an interconnected NFκB and STAT3 signaling machinery [294]. Both pathways act as epigenetic modifiers during normal inflammation stimulation, and both are also known to promote ESC pluripotency by inducing an open chromatin state that allows other transcription factors to regulate cell fates [236]. This epigenetic remodeling may prove crucial for efficient reprogramming, as well as the generation of high quality iPSC that resemble ESC without excessive epigenetic memory of their cell of origin [295].

Moreover, Stat3 is a master reprogramming factor that is able to dominantly instruct pluripotency, yet is also inherently interconnected with inflammatory signaling cascades (Figure 2). It binds to bivalent histone modifications, and allows rapid transitions between pluripotency and differentiation [193]. The NFκB pathway acts in synergy with downstream STAT3 signaling, whereby non-canonical NFκB signaling maintains pluripotency through epigenetic silencing of differentiation genes and canonical NFκB signaling promotes cell differentiation [296]. Finally, recent evidence suggests that strong chromatin repression by the NuRD complex is a key rate-limiting factor during reprogramming to pluripotency. This important complex may normally function to ensure that differentiated cells do not reactivate pluripotency genes, which might enable tumorigenesis [268]. We propose the hypothesis that NuRD complex silencing might be more easily achieved through the activation of inflammatory pathways in receptive cells such as those from the myeloid lineage.

It remains to be elucidated how all these processes are inter-regulated. It will be especially important to link reprogramming efficiency with the resulting quality of the pluripotent state achieved in hiPSC. We hypothesize that epigenetic plasticity in inflammatory cells that normally allows chromatin accessibility to the transcriptional machinery, could be manipulated to facilitate a complete erasure of the donor epigenetic memory during factor-mediated reprogramming. Additionally, preventing cancerous epigenetic patterns in iPSC via more accurate high-fidelity reprogramming methods will be the foundation for future clinical applications [13]. Finally, the basic understanding of pluripotency induction may also give us a better understanding of how tumor-initiating cells arise and how they can be eradicated to prevent tumor relapse, thus potentially opening a new era of cancer treatments.


JRA was supported by a fellowship from the German Research Foundation (DFG, DJ 71/1-1). ETZ was supported by grants from the NIH/NHLBI U01HL099775 and the Maryland Stem Cell Research Fund (2011-MSCRF-II-0008-00; 2007-MSCRF-II-0379-00). We would like to thank Dr. Alan Friedman for assistance in reading and editing the manuscript.


  1. 1. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell. 2009;5(1):111–23.
  2. 2. Choi K-D, Yu J, Smuga-Otto K, Salvagiotto G, Rehrauer W, Vodyanik M, et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells. 2009;27(3):559–67.
  3. 3. Feng Q, Lu S-J, Klimanskaya I, Gomes I, Kim D, Chung Y, et al. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells. 2010;28(4):704–12.
  4. 4. Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, et al. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PloS One. 2011;6(4):e18293.
  5. 5. Park TS, Zimmerlin L, Zambidis ET. Efficient and simultaneous generation of hematopoietic and vascular progenitors from human induced pluripotent stem cells. Cytometry A. 2012;38(1):114-26.
  6. 6. Park TS, Bhutto I, Zimmerlin L, Huo JS, Nagaria P, Miller D, et al. Vascular Progenitors from Cord Blood-Derived iPSC Possess Augmented Capacity for Regenerating Ischemic Retinal Vasculature. Circulation. 2013 Oct 25; Epub ahead of print.
  7. 7. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006;126(4):663–76.
  8. 8. Simara P, Motl JA, Kaufman DS. Pluripotent stem cells and gene therapy. Translational research. 2013;161(4):284–92.
  9. 9. Oh Y, Wei H, Ma D, Sun X, Liew R. Clinical applications of patient-specific induced pluripotent stem cells in cardiovascular medicine. Heart. 2012;98(6):443–9.
  10. 10. Kaufman DS. Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells. Blood. 2009;114(17):3513–23.
  11. 11. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471(7336):68–73.
  12. 12. Carey BW, Markoulaki S, Hanna JH, Faddah DA, Buganim Y, Kim J, et al. Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell. 2011;9(6):588–98.
  13. 13. Easwaran H, Johnstone SE, Van Neste L, Ohm J, Mosbruger T, Wang Q, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Research. 2012 May 1;22(5):837–49.
  14. 14. Ruiz S, Diep D, Gore A, Panopoulos AD, Montserrat N, Plongthongkum N, et al. Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells. Proceedings of the National Academy of Sciences. 2012;109(40):16196–201.
  15. 15. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467(7313):285–90.
  16. 16. Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nature Biotechnology. 2011;29(12):1117–9.
  17. 17. Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9(1):17–23.
  18. 18. Hu K, Yu J, Suknuntha K, Tian S, Montgomery K, Choi KD, et al. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood. 2011 Apr 7;117(14):e109–19.
  19. 19. Yu J, Chau KF, Vodyanik MA, Jiang J, Jiang Y. Efficient feeder-free episomal reprogramming with small molecules. PloS One. 2011;6(3):e17557.
  20. 20. Park TS, Huo JS, Peters A, Talbot CC, Verma K, Zimmerlin L, et al. Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors. PloS One. 2012;7(8):e42838.
  21. 21. Malik N, Rao MS. A review of the methods for human iPSC derivation. Methods Molecular Biology. 2013;997:23–33.
  22. 22. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nature Methods. 2011;8(5):409–12.
  23. 23. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology. 2008;26(1):101–6.
  24. 24. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797–801.
  25. 25. Huangfu D, Maehr RE, Guo W, Eijkelenboom A, Snitow M, Chen AE, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology. 2008;26(7):795–7.
  26. 26. Kleger A, Mahaddalkar PU, Katz S-F, Lechel AE, Joo JY, Loya K, et al. Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex. Gastroenterology. 2012;142(4):907–17.
  27. 27. Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, et al. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nature Cell Biology. 2013;15(10):1164–75.
  28. 28. Grande A, Sumiyoshi K, L o pez-Ju a rez A, Howard J, Sakthivel B, Aronow B, et al. Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nature Communications. 2013;4:2373.
  29. 29. Zou X-Y, Yang H-Y, Yu Z, Tan X-B, Yan X, Huang GT-J. Establishment of transgene-free induced pluripotent stem cells reprogrammed from human stem cells of apical papilla for neural differentiation. Stem Cell Research & Therapy. 2012;3(5):43.
  30. 30. Chen J, Lin M, Foxe JJ, Pedrosa E, Hrabovsky A, Carroll R, et al. Transcriptome comparison of human neurons generated using induced pluripotent stem cells derived from dental pulp and skin fibroblasts. PloS One. 2013;8(10):e75682.
  31. 31. Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA, et al. Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell. 2010;7(1):20–4.
  32. 32. Loh Y-H, Agarwal S, Park I-H, Urbach A, Huo H, Heffner GC, et al. Generation of induced pluripotent stem cells from human blood. Blood. 2009;113(22):5476–9.
  33. 33. Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C, et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell. 2009;5(4):434–41.
  34. 34. Springer TA. Adhesion receptors of the immune system. Nature. 1990;346(6283):425–34.
  35. 35. Medzhitov R, Janeway C. Innate Immunity. New England Journal Medicine. 2000;343(5):338-44.
  36. 36. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell, 5th edition. Taylor&Francis; 2007.
  37. 37. Lanzavecchia A, Bernasconi N, Traggiai E, Ruprecht CR, Corti D, Sallusto F. Understanding and making use of human memory B cells. Immunological Reviews. 2006;211:303–9.
  38. 38. Eminli S, Foudi A, Stadtfeld M, Maherali N, Ahfeldt T, Mostoslavski G, Hock H, Hochedlinger K. differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nature Genetics. 2009;41(9):970-976.
  39. 39. Gaspar-Maia A, Alajem A, Meshorer E, Ramalho-Santos M. Open chromatin in pluripotency and reprogramming. Nature reviews Molecular Cell Biology. 2011;12(1):36–47.
  40. 40. Lee J, Sayed N, Hunter A, Au KF, Wong WH, Mocarski ES, et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell. 2012;151(3):547–58.
  41. 41. Kawamoto H, Wada H, Katsura Y. A revised scheme for developmental pathways of hematopoietic cells: the myeloid-based model. International Immunology. 2010;22(2):65–70.
  42. 42. Zingarelli B. Nuclear factor-kappaB. Critical Care Medicine. 2005;33(12):414–6.
  43. 43. Abraham E. NF-kappaB activation. Critical Care Medicine. 2000;28(4):100–4.
  44. 44. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Research Reviews. 2008;7(2):83–105.
  45. 45. Luo J-L, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. The Journal of Clinical Investigation. 2005;115(10):2625–32.
  46. 46. Vanden Berghe W, Ndlovu MN, Hoya-Arias R, Dijsselbloem N, Gerlo S, Haegeman G. Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics. Biochemical Pharmacology. 2006;72(9):1114–31.
  47. 47. Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25(51):6680–4.
  48. 48. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. The Journal of Clinical Investigation. 2001;107(1):7–11.
  49. 49. Chen ZJ. Ubiquitin signalling in the NF-kappaB pathway. Nature Cell Biology. 2005;7(8):758–65.
  50. 50. Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends in Molecular Medicine. 2007;13(11):460–9.
  51. 51. Chen Lf, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. 2001;293(5535):1653–7.
  52. 52. Lee H, Herrmann A, Deng J-H, Kujawski M, Niu G, Li Z, et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009;15(4):283–93.
  53. 53. Dyson HJ, Komives EA. Role of disorder in IkappaB-NFkappaB interaction. IUBMB Life. 2012;64(6):499–505.
  54. 54. Panwalkar A, Verstovsek S, Giles F. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies. Cancer. 2004;100(8):1578–89.
  55. 55. Imani Fooladi AA, Mousavi SF, Seghatoleslami S, Yazdani S, Nourani MR. Toll-like receptors: role of inflammation and commensal bacteria. Inflammation & Allergy Drug Targets. 2011;10(3):198–207.
  56. 56. Li X, Jiang S, Tapping RI. Toll-like receptor signaling in cell proliferation and survival. Cytokine. 2010;49(1):1–9.
  57. 57. Carmody RIJ, Chen YH. Nuclear factor-kappaB: activation and regulation during toll-like receptor signaling. Cellular & Molecular Immunology. 2007;4(1):31–41.
  58. 58. Sun S-C. Non-canonical NF-kappaB signaling pathway. Cell Research. 2011;21(1):71–85.
  59. 59. Endo T, Nishio M, Enzler T, Cottam HB, Fukuda T, James DF, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007;109(2):703–10.
  60. 60. Meichle, Jurkat. Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor. J Biol Chem. 1990;265(14):8339–43.
  61. 61. Mordm u ller B, Krappmann D, Esen M, Wegener E, Scheidereit C. Lymphotoxin and lipopolysaccharide induce NF-kappaB-p52 generation by a co-translational mechanism. EMBO reports. 2003;4(1):82–7.
  62. 62. Moschonas A, Ioannou M, Eliopoulos AG. CD40 stimulates a “feed-forward” NF-kappaB-driven molecular pathway that regulates IFN-beta expression in carcinoma cells. Journal of Immunology. 2012;188(11):5521–7.
  63. 63. H a cker H, Tseng P-H, Karin M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nature Reviews Immunology. 2011;11(7):457–68.
  64. 64. Sinha SK, Zachariah S, Qui n ones HI, Shindo M, Chaudhary PM. Role of TRAF3 and-6 in the activation of the NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor. The Journal of Biological Chemistry. 2002;277(47):44953–61.
  65. 65. Morrison MD, Reiley W, Zhang M, Sun SC. An atypical TRAF-binding motif of BAFF receptor mediates induction of the noncanonical NF-kB signaling pathway. Journal of Biological Chemistry. 2005.
  66. 66. Lu J, Hou R, Booth CJ, Yang S-H, Snyder M. Defined culture conditions of human embryonic stem cells. Proceedings of the National Academy of Sciences. 2006;103(15):5688–93.
  67. 67. Ni C-Z, Oganesyan G, Welsh K, Zhu X, Reed JC, Satterthwait AC, et al. Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation. Journal of Immunology. 2004;173(12):7394–400.
  68. 68. Hu H, Brittain GC, Chang J-H, Puebla-Osorio N, Jin J, Zal A, et al. OTUD7B controls non-canonical NF-kappaB activation through deubiquitination of TRAF3. Nature. 2013;494(7437):371-4.
  69. 69. Kehry MR. CD40-mediated signaling in B cells. Balancing cell survival, growth, and death. Journal of Immunology. 1996;156(7):2345–8.
  70. 70. Gelbmann CM, Leeb SN, Vogl D, Maendel M, Herfarth H, Sch o lmerich J, et al. Inducible CD40 expression mediates NFkappaB activation and cytokine secretion in human colonic fibroblasts. Gut. 2003;52(10):1448–56.
  71. 71. Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor B activation pathways triggered by the cytoplasmic tail of CD40. Proceedings of the National Academy of Sciences. 1999;96(4):1234–9.
  72. 72. Zarnegar B, He JQ, Oganesyan G, Hoffmann A, Baltimore D, Cheng G. Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways. Proceedings of the National Academy of Sciences. 2004;101(21):8108–13.
  73. 73. Zhao C, Xiu Y, Ashton J, Xing L, Morita Y, Jordan CT, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells. 2012;30(4):709–18.
  74. 74. Jost PJ, Ruland JUR. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood. 2007;109(7):2700–7.
  75. 75. Senftleben U, Karin M. The IKK/NF-kappa B pathway. Critical Care Medicine. 2002;30(1 Suppl):S18–26.
  76. 76. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood. 1996;87(3):1104–12.
  77. 77. Takeda K, Harada Y, Watanabe R, Inutake Y, Ogawa S, Onuki K, et al. CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis. International Immunology. 2008;20(12):1507–15.
  78. 78. Coope HJ, Atkinson PGP, Huhse B, Belich M, Janzen J, Holman MJ, et al. CD40 regulates the processing of NF-kappaB2 p100 to p52. The EMBO Journal. 2002;21(20):5375–85.
  79. 79. Riha P, Rudd CE. CD28 co-signaling in the adaptive immune response. Self Nonself. 2010;1(3):231–40.
  80. 80. Muscolini, Jurkat. A novel association between filamin A and NF-kappaB inducing kinase couples CD28 to inhibitor of NF-kappaB kinase alpha and NF-kappaB activation. Immunology Letters. 2011;136(2):203–12.
  81. 81. Piccolella, CD28. Vav-1 and the IKK alpha subunit of I kappa B kinase functionally associate to induce NF-kappa B activation in response to CD28 engagement. Journal of Immunology. 2003;170(6):2895–903.
  82. 82. Wang Z, Oron E, Nelson B, Razis S, Ivanova N. Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells. Cell Stem Cell. 2012;10(4):440–54.
  83. 83. Chan KK-K, Zhang J, Chia N-Y, Chan Y-S, Sim HS, Tan KS, et al. KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cells. Stem Cells. 2009;27(9):2114–25.
  84. 84. Zeng X. Human embryonic stem cells: mechanisms to escape replicative senescence? Stem Cell Reviews. 2007;3(4):270–9.
  85. 85. Gourronc FA, Klingelhutz AJ. Therapeutic opportunities: telomere maintenance in inducible pluripotent stem cells. Mutation Research. 2012;730(1-2):98–105.
  86. 86. Klimanskaya I, Chung Y, Meisner L, Johnson J, West MD, Lanza R. Human embryonic stem cells derived without feeder cells. Lancet. 365(9471):1636–41.
  87. 87. Dutta D, Ray S, Home P, Larson M, Wolfe MW, Paul S. Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance. Stem Cells. 2011;29(4):618–28.
  88. 88. Molinero, CD28. High TCR stimuli prevent induced regulatory T cell differentiation in a NF-kappaB-dependent manner. Journal of Immunology. 2011;186(8):4609–17.
  89. 89. Yang C, Atkinson SP, Vilella F, Lloret M, Armstrong L, Mann DA, et al. Opposing putative roles for canonical and noncanonical NFkappaB signaling on the survival, proliferation, and differentiation potential of human embryonic stem cells. Stem Cells. 2010;28(11):1970–80.
  90. 90. Kang H-B, Kim Y-E, Kwon H-J, Sok D-E, Lee Y. Enhancement of NF-kappaB expression and activity upon differentiation of human embryonic stem cell line SNUhES3. Stem Cells and Development. 2007;16(4):615–23.
  91. 91. De Molfetta GA, Luciola Zanette D, Alexandre Panepucci R, Dos Santos ARD, da Silva WA, Antonio Zago M. Role of NFKB2 on the early myeloid differentiation of CD34+hematopoietic stem/progenitor cells. Differentiation. 2010;80(4-5):195–203.
  92. 92. Wang D, Paz-Priel I, Friedman AD. NF-kappa B p50 regulates C/EBP alpha expression and inflammatory cytokine-induced neutrophil production. Journal of Immunology. 2009;182(9):5757–62.
  93. 93. Nakata S, Matsumura I, Tanaka H, Ezoe S, Satoh Y, Ishikawa J, et al. NF-kappaB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species. The Journal of Biological Chemistry. 2004;279(53):55578–86.
  94. 94. Bottero V, Withoff S, Verma IM. NF-kappaB and the regulation of hematopoiesis. Cell Death and Differentiation. 2006;13(5):785–97.
  95. 95. Schwarzer R, Jundt F. Notch and NF-kappaB signaling pathways in the biology of classical Hodgkin lymphoma. Current Molecular Medicine. 2011;11(3):236–45.
  96. 96. Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, et al. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. The Journal of Clinical Investigation. 2011;121(12):4685–99.
  97. 97. Cheng P, Zlobin A, Volgina V, Gottipati S, Osborne B, Simel EJ, et al. Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells. Journal of Immunology. 2001;167(8):4458–67.
  98. 98. Wang J, Shelly L, Miele L, Boykins R, Norcross MA, Guan E. Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain. Journal of Immunology. 2001;167(1):289–95.
  99. 99. Lin G, Xu R-H. Progresses and challenges in optimization of human pluripotent stem cell culture. Current Stem Cell Research & therapy. 2010;5(3):207–14.
  100. 100. Darr H, Benvenisty N. Human embryonic stem cells: the battle between self-renewal and differentiation. Regenerative Medicine. 2006;1(3):317–25.
  101. 101. Dvorak P, Dvorakova D, Hampl A. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS letters. 2006;580(12):2869–74.
  102. 102. Byrd VM, Ballard DW, Miller GG, Thomas JW. Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. Journal of Immunology. 1999;162(10):5853–9.
  103. 103. Stein SJ, Baldwin AS. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood. 2013.
  104. 104. Panepucci RA, Calado RT, Rocha V, Proto-Siqueira R, Silva WA, Zago MA. Higher expression of transcription targets and components of the nuclear factor-kappaB pathway is a distinctive feature of umbilical cord blood CD34+precursors. Stem Cells. 2007;25(1):189–96.
  105. 105. Luningschror P, St o cker B, Kaltschmidt B, Kaltschmidt C. miR-290 cluster modulates pluripotency by repressing canonical NF-kappaB signaling. Stem Cells. 2012;30(4):655–64.
  106. 106. Torres J, Watt FM. Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3. Nature Cell Biology. 2008;10(2):194–201.
  107. 107. Taylor T, Kim Y-J, Ou X, Derbigny W, Broxmeyer HE. Toll-like receptor 2 mediates proliferation, survival, NF-kappaB translocation, and cytokine mRNA expression in LIF-maintained mouse embryonic stem cells. Stem Cells and Development. 2010;19(9):1333–41.
  108. 108. Chiffoleau E, Kobayashi T, Walsh MC, King CG, Walsh PT, Hancock WW, et al. TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease. Journal of Immunology. 2003;171(11):5751–9.
  109. 109. Yaddanapudi K, De Miranda J, Hornig M, Lipkin WI. Toll-like receptor 3 regulates neural stem cell proliferation by modulating the Sonic Hedgehog pathway. PloS One. 2011;6(10):e26766.
  110. 110. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2012. The Journal of Allergy and Clinical Immunology. 2013;131(3):675–82.
  111. 111. Takase O, Yoshikawa M, Idei M, Hirahashi J, Fujita T, Takato T, et al. The Role of NF-kappaB Signaling in the Maintenance of Pluripotency of Human Induced Pluripotent Stem Cells. PloS One. 2013;8(2):e56399.
  112. 112. Georgopoulos K. Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature Reviews Immunology. 2002;2(3):162–74.
  113. 113. Smale ST, Fisher AG. Chromatin structure and gene regulation in the immune system. Annual Review of Immunology. 2002;20:427–62.
  114. 114. Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Reviews. 2006;20(1):1–13.
  115. 115. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27–36.
  116. 116. Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nature Reviews Molecular Cell Biology. 2006;7(7):540–6.
  117. 117. Wirtz S, Becker C, Fantini MC, Nieuwenhuis EE, Tubbe I, Galle PR, et al. EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation. Journal of Immunology. 2005;174(5):2814–24.
  118. 118. Gaudreault E, Fiola SEP, Olivier M, Gosselin J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. Journal of Virology. 2007;81(15):8016–24.
  119. 119. Severa M, Giacomini E, Gafa V, Anastasiadou E, Rizzo F, Corazzari M, et al. EBV stimulates TLR-and autophagy-dependent pathways and impairs maturation in plasmacytoid dendritic cells: Implications for viral immune escape. European Journal of Immunology. 2013;43(1):147-58.
  120. 120. Martin HJ, Lee JM, Walls D, Hayward SD. Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus. Journal of Virology. 2007;81(18):9748–58.
  121. 121. Shimada M, Ishimoto T, Lee PY, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, et al. Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-kappaB-dependent pathway. Nephrology Dialysis Transplantation. 2012;27(1):81–9.
  122. 122. Salaun B, Coste I, Rissoan M-C, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. Journal of Immunology. 2006;176(8):4894–901.
  123. 123. Gohda J, Matsumura T, Inoue J-I. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. Journal of Immunology. 2004;173(5):2913–7.
  124. 124. Biran A, Meshorer E. Concise review: chromatin and genome organization in reprogramming. Stem Cells. 2012;30(9):1793–9.
  125. 125. Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 2010;6(5):479–91.
  126. 126. Org TON, Chignola F, Het e nyi C, Gaetani M, Rebane A, Liiv I, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Reports. 2008;9(4):370–6.
  127. 127. Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis. 2007;28(3):560–71.
  128. 128. Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8(4):376–88.
  129. 129. Dekker FJ, Haisma HJ. Histone acetyl transferases as emerging drug targets. Drug Discovery Today. 2009;14(19-20):942–8.
  130. 130. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H. Acetylation of general transcription factors by histone acetyltransferases. Current Biology. 1997;7(9):689–92.
  131. 131. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science. 1997;275(5299):523–7.
  132. 132. Sheppard KA, Rose DW, Haque ZK, Kurokawa R, McInerney E, Westin S, et al. Transcriptional activation by NF-kappaB requires multiple coactivators. Molecular and Cellular Biology. 1999;19(9):6367–78.
  133. 133. Chen X, Gazzar El M, Yoza BK, McCall CE. The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. The Journal of Biological Chemistry. 2009 Oct 9;284(41):27857–65.
  134. 134. Roger T, Lugrin JEROM, Le Roy D, Goy GEV, Mombelli M, Koessler T, et al. Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection. Blood. 2011;117(4):1205–17.
  135. 135. Pearce EL, Shen H. Making sense of inflammation, epigenetics, and memory CD8+T-cell differentiation in the context of infection. Immunological Reviews. 2006;211:197–202.
  136. 136. McCall CE, Yoza B, Liu T, Gazzar El M. Gene-Specific Epigenetic Regulation in Serious Infections with Systemic Inflammation. J Innate Immun. 2010;2(5):395–405.
  137. 137. Niwa H. How is pluripotency determined and maintained? Development.; 2007 Feb;134(4):635–46.
  138. 138. O’Neill LAJ. “Transflammation”: When Innate Immunity Meets Induced Pluripotency. Cell. 2012 Oct;151(3):471–3.
  139. 139. Heinrich PC, Behrmann I, M u ller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical Journal. 1998;334 (Pt 2:297–314.
  140. 140. Imada K, Leonard WJ. The Jak-STAT pathway. Molecular Immunology. 37(1-2):1–11.
  141. 141. Takemoto S, Mulloy JC, Cereseto A, Migone TS, Patel BK, Matsuoka M, et al. Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. Proceedings of the National Academy of Sciences. 1997;94(25):13897–902.
  142. 142. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nature Reviews Immunology. 2003;3(11):900–11.
  143. 143. Sherry MM, Reeves A, Wu JK, Cochran BH. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem cells. 2009;27(10):2383–92.
  144. 144. Ram PT, Iyengar R. G protein coupled receptor signaling through the Src and Stat3 pathway: role in proliferation and transformation. Oncogene. 2001;20(13):1601–6.
  145. 145. Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 2000;19(21):2548–56.
  146. 146. Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Research. 2008;18(2):254–67.
  147. 147. Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. The Journal of Biological Chemistry. 2007;282(28):20059–63.
  148. 148. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285(1-2):1–24.
  149. 149. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. Journal of Cell Science. 2004;117(Pt 8):1281–3.
  150. 150. Murray PJ. The JAK-STAT signaling pathway: input and output integration. Journal of Immunology. 2007;178(5):2623–9.
  151. 151. Darnell JE. STATs and gene regulation. Science. 1997;277(5332):1630–5.
  152. 152. Cheng F, Wang H-W, Cuenca A, Huang M, Ghansah T, Brayer J, et al. A critical role for Stat3 signaling in immune tolerance. Immunity. 2003;19(3):425–36.
  153. 153. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. The Journal of Biological Chemistry. 2007;282(13):9358–63.
  154. 154. Alonzi T, Maritano D, Gorgoni B, Rizzuto G, Libert C, Poli V. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Molecular and Cellular Biology. 2001;21(5):1621–32.
  155. 155. Tian SS, Lamb P, Seidel HM, Stein RB, Rosen J. Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Blood. 1994;84(6):1760–4.
  156. 156. Hansen ML, Woetmann A, Krejsgaard TOR, Kopp KLM, S o kilde R, Litman T, et al. IFN-alpha primes T-and NK-cells for IL-15-mediated signaling and cytotoxicity. Molecular Immunology. 2011;48(15-16):2087–93.
  157. 157. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415–21.
  158. 158. Ruff-Jamison S, Zhong Z, Wen Z, Chen K, Darnell JE, Cohen S. Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. The Journal of Biological Chemistry. 1994;269(35):21933–5.
  159. 159. Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JCR, Smith A. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell. 2010;7(3):319–28.
  160. 160. Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 2000;19(21):2607–11.
  161. 161. Lafarge S, Hamzeh-Cognasse H, Richard Y, Pozzetto B, Cogn e M, Cognasse F, et al. Complexes between nuclear factor-kappaB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells. Clinical and Experimental Immunology. 2011;166(2):171–83.
  162. 162. Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, et al. The STAT3 isoforms alpha and beta have unique and specific functions. Nature Immunology. 2004;5(4):401–9.
  163. 163. Akira S. IL-6-regulated transcription factors. The International Journal of Biochemistry & Cell Biology. 1997;29(12):1401–18.
  164. 164. Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. BioEssays : news and reviews in molecular, cellular and developmental biology. 1999;21(1):47–52.
  165. 165. Alexander WS. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Reviews Immunology. 2002 Jun;2(6):410–6.
  166. 166. Kershaw NJ, Murphy JM, Liau NPD, Varghese LN, Laktyushin A, Whitlock EL, et al. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nature Structural & Molecular Biology. 2013;20(4):469–76.
  167. 167. Waiboci LW, Ahmed CM, Mujtaba MG, Flowers LO, Martin JP, Haider MI, et al. Both the suppressor of cytokine signaling 1 (SOCS-1) kinase inhibitory region and SOCS-1 mimetic bind to JAK2 autophosphorylation site: implications for the development of a SOCS-1 antagonist. Journal of Immunology. 2007;178(8):5058–68.
  168. 168. Jo D, Liu D, Yao S, Collins RD, Hawiger J. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nature Medicine. 2005;11(8):892–8.
  169. 169. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nature Reviews Immunology. 2007;7(6):454–65.
  170. 170. Ahmed, PJAK2. Enhancement of antiviral immunity by small molecule antagonist of suppressor of cytokine signaling. Journal of Immunology. 2010;185(2):1103–13.
  171. 171. Hankey PA. Regulation of hematopoietic cell development and function by Stat3. Frontiers in Bioscience. 2009;14:5273–90.
  172. 172. Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006;444(7117):364–8.
  173. 173. Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Research. 2007;17(1):42–9.
  174. 174. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005;122(6):947–56.
  175. 175. Li Y-Q. Master stem cell transcription factors and signaling regulation. Cellular Reprogramming. 2010;12(1):3–13.
  176. 176. Neri F, Zippo A, Krepelova A, Cherubini A, Rocchigiani M, Oliviero S. Myc regulates the transcription of the PRC2 gene to control the expression of developmental genes in embryonic stem cells. Molecular and Cellular Biology. 2012;32(4):840–51.
  177. 177. Goodliffe JM, Cole MD, Wieschaus E. Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1. BMC Molecular Biology. 2007;8:40.
  178. 178. Liu S-P, Harn H-J, Chien Y-J, Chang C-H, Hsu C-Y, Fu R-H, et al. n-Butylidenephthalide (BP) Maintains Stem Cell Pluripotency by Activating Jak2/Stat3 Pathway and Increases the Efficiency of iPS Cells Generation. PloS One. 2012 Sep 7;7(9):e44024.
  179. 179. Niwa H, Burdon T, Chambers I, Smith A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes & Development. 1998;12(13):2048–60.
  180. 180. Wei CL, Miura T, Robson P, Lim S-K, Xu X-Q, Lee MY-C, et al. Transcriptome Profiling of Human and Murine ESCs Identifies Divergent Paths Required to Maintain the Stem Cell State. Stem Cells. 2005 Feb;23(2):166–85.
  181. 181. Vallier L. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. Journal of Cell Science. 2005 Sep 13;118(19):4495–509.
  182. 182. James D. TGF /activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development. 2005 Feb 9;132(6):1273–82.
  183. 183. Dahéron L, Opitz SL, Zaehres H, Lensch MW, Lensch WM, Andrews PW, et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004;22(5):770–8.
  184. 184. Niwa H, Ogawa K, Shimosato D, Adachi K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009;460(7251):118–22.
  185. 185. Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L, et al. Oct4 and LIF/Stat3 Additively Induce Krüppel Factors to Sustain Embryonic Stem Cell Self-Renewal. Cell Stem Cell. 2009 Dec;5(6):597–609.
  186. 186. Ying Q-L, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003 Oct 31;115(3):281–92.
  187. 187. Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, et al. The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Human Molecular Genetics. 2006;15(11):1894–913.
  188. 188. Lee H, Herrmann A, Deng J-H, Kujawski M, Niu G, Li Z, et al. Persistently Activated Stat3 Maintains Constitutive NF-κB Activity in Tumors. Cancer Cell. 2009;15(4):283–93.
  189. 189. Cavaleri F, Sch o ler HR. Nanog: a new recruit to the embryonic stem cell orchestra. Cell. 2003;113(5):551–2.
  190. 190. Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, et al. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. The EMBO Journal. 1999;18(15):4261–9.
  191. 191. Hawkins K, Mohamet L, Ritson S, Merry CLR, Ward CM. E-cadherin and, in its absence, N-cadherin promotes Nanog expression in mouse embryonic stem cells via STAT3 phosphorylation. Stem Cells. 2012;30(9):1842–51.
  192. 192. Do DV, Ueda J, Messerschmidt DM, Lorthongpanich C, Zhou Y, Feng B, et al. A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes & Development. 2013;27(12):1378–90.
  193. 193. Kidder BL, Yang J, Palmer S. Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PloS One. 2008;3(12):e3932.
  194. 194. Schuringa JJ, Timmer H, Luttickhuizen D, Vellenga E, Kruijer W. c-Jun and c-Fos cooperate with STAT3 in IL-6-induced transactivation of the IL-6 respone element (IRE). Cytokine. 2001;14(2):78–87.
  195. 195. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nature Cell Biology. 2002;4(5):E131–6.
  196. 196. Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity. 2006;24(5):563–74.
  197. 197. Saeki Y, Nagashima T, Kimura S, Okada-Hatakeyama M. An ErbB receptor-mediated AP-1 regulatory network is modulated by STAT3 and c-MYC during calcium-dependent keratinocyte differentiation. Experimental Dermatology. 2012 Mar 15;21(4):293–8.
  198. 198. Hu G, Wade PA. NuRD and pluripotency: a complex balancing act. Cell Stem Cell. 2012;10(5):497–503.
  199. 199. Aguilera C, Nakagawa K, Sancho R, Chakraborty A, Hendrich B, Behrens A. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature. 2011;469(7329):231–5.
  200. 200. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Medicine. 2005;11(12):1314–21.
  201. 201. Welte T, Zhang SSM, Wang T, Zhang Z, Hesslein DGT, Yin Z, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proceedings of the National Academy of Sciences. 2003;100(4):1879–84.
  202. 202. Schuringa JJ, Wierenga AT, Kruijer W, Vellenga E. Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood. 2000;95(12):3765–70.
  203. 203. Gur-Wahnon D, Borovsky Z, Beyth S, Liebergall M, Rachmilewitz J. Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling. Experimental Hematology. 2007;35(3):426–33.
  204. 204. Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem cells. 2007;25(11):2896–902.
  205. 205. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25(11):2739–49.
  206. 206. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nature Reviews Immunology. 2008;8(9):726–36.
  207. 207. Martinez-Outschoorn UE, Balliet RM, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, et al. Hereditary ovarian cancer and two-compartment tumor metabolism: epithelial loss of BRCA1 induces hydrogen peroxide production, driving oxidative stress and NFkappaB activation in the tumor stroma. Cell Cycle. 2012;11(22):4152–66.
  208. 208. Uchibori R, Tsukahara T, Mizuguchi H, Saga Y, Urabe M, Mizukami H, et al. NF-kappaB activity regulates mesenchymal stem cell accumulation at tumor sites. Cancer Research. 2013;73(1):364–72.
  209. 209. Vultur A, Cao J, Arulanandam R, Turkson J, Jove R, Greer P, et al. Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells. Oncogene. 2004;23(15):2600–16.
  210. 210. Oellerich T, Oellerich MF, Engelke M, Munch S, Mohr S, Nimz M, et al. 2 integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis. Blood. 2013;121(19):3889–99.
  211. 211. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009;324(5935):1713–6.
  212. 212. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE. Stat3 activation is required for cellular transformation by v-src. Molecular and Cellular Biology. 1998;18(5):2553–8.
  213. 213. Bromberg J, Wang TC. Inflammation and Cancer:IL-6 and STAT3 Complete the Link. Cancer cell. 2009 Feb 3;15(2):79–80.
  214. 214. Grivennikov S, Karin M. Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell. 2008;13(1):7–9.
  215. 215. Gur-Wahnon D, Borovsky Z, Liebergall M, Rachmilewitz J. The Induction of APC with a Distinct Tolerogenic Phenotype via Contact-Dependent STAT3 Activation. PloS One. 2009;4(8):e6846.
  216. 216. Bournazou E, Bromberg J. Targeting the tumor microenvironment: JAK-STAT3 signaling. JAK-STAT. 2013;2(2):e23828.
  217. 217. Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA, et al. 1 Integrin Adhesion Enhances IL-6-Mediated STAT3 Signaling in Myeloma Cells: Implications for Microenvironment Influence on Tumor Survival and Proliferation. Cancer Research. 2009 Jan 20;69(3):1009–15.
  218. 218. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Rev Immunol. 2007 Jan;7(1):41–51.
  219. 219. Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Reviews. 2007;3(1):7–17.
  220. 220. Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, et al. A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs. Cell. 2010;143(2):313–24.
  221. 221. Huntly BJP, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Reviews Cancer. 2005;5(4):311–21.
  222. 222. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.
  223. 223. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nature Reviews Cancer. 2003;3(12):895–902.
  224. 224. Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJA. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nature Reviews Cancer. 2005;5(11):899–904.
  225. 225. Agarwal JR, Matsui W. Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis. Anti-cancer agents in medicinal chemistry. 2010;10(2):116–20.
  226. 226. Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. The Journal of clinical investigation. 2010;120(1):41–50.
  227. 227. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253–61.
  228. 228. Lin C, Wang L, Wang H, Yang L, Guo H, Wang X. Tanshinone IIA inhibits breast cancer stem cells growth in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways. J Cell Biochem. 2013 Jul 18;114(9):2061–70.
  229. 229. Iliopoulos D, Hirsch HA, Struhl K. An Epigenetic Switch Involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell Transformation. Cell. 2009;139(4):693–706.
  230. 230. Glinka Y, Mohammed N, Subramaniam V, Jothy S, Prud'homme GERJ. Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-kappaB activation and tumor sphere formation. Biochemical and Biophysical Research Communications. 2012;425(4):775–80.
  231. 231. Long H, Xie R, Xiang T, Zhao Z, Lin S, Liang Z, et al. Autocrine CCL5 signaling promotes invasion and migration of CD133+ovarian cancer stem-like cells via NF-kappaB-mediated MMP-9 upregulation. Stem Cells. 2012;30(10):2309–19.
  232. 232. Inoue J-I, Gohda J, Akiyama T, Semba K. NF-kappaB activation in development and progression of cancer. Cancer Science. 2007;98(3):268–74.
  233. 233. Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JCR, Smith A. Stat3 Activation Is Limiting for Reprogramming to Ground State Pluripotency. Cell Stem Cell. 2010;7(3):319–28.
  234. 234. van Oosten AL, Costa Y, Smith A, Silva JECR. JAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency. Nature Communications. 2012;3:817.
  235. 235. Nichols J, Silva J, Roode M, Smith A. Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development. 2009;136(19):3215–22.
  236. 236. Ura H, Usuda M, Kinoshita K, Sun C, Mori K, Akagi T, et al. STAT3 and Oct-3/4 Control Histone Modification through Induction of Eed in Embryonic Stem Cells. The Journal of Biological Chemistry. 2008;283(15):9713–23.
  237. 237. Kim J, Chu J, Shen X, Wang J, Orkin SH. An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells. Cell. 2008;132(6):1049–61.
  238. 238. Orkin SH, Hochedlinger K. Chromatin Connections to Pluripotency and Cellular Reprogramming. Cell. 2011;145(6):835–50.
  239. 239. Tang Y, Luo Y, Jiang Z, Ma Y, Lin C-J, Kim C, et al. Jak/Stat3 Signaling Promotes Somatic Cell Reprogramming by Epigenetic Regulation. Stem Cells. 2012;30(12):2645–56.
  240. 240. Icardi L, De Bosscher K, Tavernier J. Cytokine & Growth Factor Reviews. Cytokine & Growth Factor Reviews. 2012;23(6):283–91.
  241. 241. Huangfu D, Osafune K, Maehr RE, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology. 2008;26(11):1269–75.
  242. 242. Ang Y-S, Gaspar-Maia A, Lemischka IR, Bernstein E. Stem cells and reprogramming: breaking the epigenetic barrier? Trends in Pharmacological Sciences. 2011;32(7):394–401.
  243. 243. Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes & Development. 2011;25(23):2436–52.
  244. 244. Tan L, Shi YG. Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development. 2012;139(11):1895–902.
  245. 245. Branco MR, Ficz G, Reik W. Uncovering the role of 5‐hydroxymethylcytosine in the epigenome. Nature reviews Genetics. 2011 Nov 15;13(1):7–13.
  246. 246. Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell. 2011;9(3):193–204.
  247. 247. Fan Y, Mao R, Yang J. NF-kappaB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein & Cell. 2013;4(3):176–85.
  248. 248. Gough DJ, Levy DE, Johnstone RW, Clarke CJ. IFNγ signaling—Does it mean JAK–STAT? Cytokine & Growth Factor Reviews. 2008;19(5-6):383–94.
  249. 249. Grivennikov SI, Karin M. Cytokine & Growth Factor Reviews. Cytokine & Growth Factor Reviews. 2010;21(1):11–9.
  250. 250. Brasier AR. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovascular Research. 2010;86(2):211–8.
  251. 251. Wang R. Activation of Stat3 Sequence-specific DNA Binding and Transcription by p300/CREB-binding Protein-mediated Acetylation. The Journal of Biological Chemistry. 2005;280(12):11528–34.
  252. 252. Nadiminty N, Lou W, Lee SO, Lin X, Trump DL, Gao AC. Stat3 activation of NF-\kappa\B p100 processing involves CBP/p300-mediated acetylation. Proceedings of the National Academy of Sciences. 2006;103(19):7264–9.
  253. 253. Schmidlin H, Diehl SA, Blom B. New insights into the regulation of human B-cell differentiation. Trends in Immunology. 2009;30(6):277–85.
  254. 254. Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT, Sharfstein SE, et al. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nature Medicine. 2005;11(6):653–60.
  255. 255. Hu X, Herrero C, Li W-P, Antoniv TT, Falck-Pedersen E, Koch AE, et al. Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nature Immunology. 2002;3(9):859–66.
  256. 256. Ivashkiv LB. A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways. Nature Reviews Immunology. 2008;8(10):816–22.
  257. 257. Wang L, Gordon RA, Huynh L, Su X, Park Min K-H, Han J, et al. Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity. 2010;32(4):518–30.
  258. 258. Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. Journal of Leukocyte Biology. 2007;82(2):237–43.
  259. 259. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008;133(6):1106–17.
  260. 260. Schugar RC, Robbins PD, Deasy BM. Small molecules in stem cell self-renewal and differentiation. Gene Therapy. 2008;15(2):126–35.
  261. 261. Hirai H, Karian P, Kikyo N. Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor. Biochem J. 2011;438(1):11–23.
  262. 262. Richards M, Tan S-P, Tan J-H, Chan W-K, Bongso A. The transcriptome profile of human embryonic stem cells as defined by SAGE. Stem Cells. 2004;22(1):51–64.
  263. 263. Melton C, Judson RL, Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature. 2010;463(7281):621–6.
  264. 264. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.
  265. 265. Darr H, Benvenisty N. Genetic analysis of the role of the reprogramming gene LIN-28 in human embryonic stem cells. Stem Cells. 2009;27(2):352–62.
  266. 266. Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, et al. Reprogramming Factor Expression Initiates Widespread Targeted Chromatin Remodeling. Cell Stem Cell. 2011;8(1):96–105.
  267. 267. Papp B, Plath K. Epigenetics of Reprogramming to Induced Pluripotency. Cell. 2013;152(6):1324–43.
  268. 268. Reynolds N, Latos P, Hynes-Allen A, Loos R, Leaford D, O'Shaughnessy A, et al. NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment. Cell Stem Cell. 2012;10(5):583–94.
  269. 269. Zhu D, Fang J, Li Y, Zhang J. Mbd3, a Component of NuRD/Mi-2 Complex, Helps Maintain Pluripotency of Mouse Embryonic Stem Cells by Repressing Trophectoderm Differentiation. Zwaka T, editor. PloS One. 2009;4(11):e7684.
  270. 270. Morey L, Brenner C, Fazi F, Villa R, Gutierrez A, Buschbeck M, et al. MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks. Molecular and Cellular Biology. 2008 Sep;28(19):5912–23.
  271. 271. Sakai H. MBD3 and HDAC1, Two Components of the NuRD Complex, Are Localized at Aurora-A-positive Centrosomes in M Phase. Journal of Biological Chemistry. 2002;277(50):48714–23.
  272. 272. Gunther K, Rust M, Leers J, Boettger T, Scharfe M, Jarek M, et al. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Research. 2013;41(5):3010–21.
  273. 273. Kaji K, Nichols J, Hendrich B. Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development. 2007;134(6):1123–32.
  274. 274. Luo M, Ling T, Xie W, Sun H, Zhou Y, Zhu Q, et al. NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells. Stem Cells. 2013;31(7):1278–86.
  275. 275. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature. 2013;502(7469):65–70.
  276. 276. Silva J, Smith A. Capturing Pluripotency. Cell. 2008;132(4):532–6.
  277. 277. Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009;137(4):647–58.
  278. 278. Fazzio TG, Rando OJ. NURDs are required for diversity. The EMBO journal. 2012;31(14):3036–7.
  279. 279. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells. Cell. 2006;125(2):315–26.
  280. 280. Gan Q, Yoshida T, McDonald OG, Owens GK. Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells. 2007;25(1):2–9.
  281. 281. Novershtern N, Hanna JH. esBAF safeguards Stat3 binding to maintain pluripotency. Nature Cell Biology. 2011;13(8):886–8.
  282. 282. Liang G, Zhang Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Research. 2012;23(1):49–69.
  283. 283. Araki Y, Wang Z, Zang C, Wood WH III, Schones D, Cui K, et al. Genome-wide Analysis of Histone Methylation Reveals Chromatin State-Based Regulation of Gene Transcription and Function of Memory CD8. Immunity. 2009;30(6):912–25.
  284. 284. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genetics. 2008;4(10):e1000242.
  285. 285. Li M, Liu G-H, Izpisua Belmonte JC. Navigating the epigenetic landscape of pluripotent stem cells. Nature Reviews Molecular Cell Biology. 2012;13(8):524–35.
  286. 286. Cui Y, Cho I-H, Chowdhury B, Irudayaraj J. Real-time dynamics of methyl-CpG-binding domain protein 3 and its role in DNA demethylation by fluorescence correlation spectroscopy. Epigenetics. 2013;8(10):10–9.
  287. 287. Shen L, Zhang Y. 5-Hydroxymethylcytosine: generation, fate, and genomic distribution. Current Opinion in Cell Biology. 2013;25(3):289–96.
  288. 288. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, et al. Genome-wide Regulation of 5hmC, 5mC, and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells. Molecular cell. 2011;42(4):451–64.
  289. 289. Yildirim O, Li R, Hung J-H, Chen PB, Dong X, Ee L-S, et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell. 2011;147(7):1498–510.
  290. 290. Liang J, Wan M, Zhang Y, Gu P, Xin H, Jung SY, et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nature Cell Biology. 2008;10(6):731–9.
  291. 291. Luo M, Ling T, Xie W, Sun H, Zhou Y, Zhu Q, et al. NuRD blocks reprogramming of mouse somatic cells into pluripotent stem cells. Stem Cells. 2013;31(7):1278–86.
  292. 292. Hu G, Wade PA. NuRD and Pluripotency: A Complex Balancing Act. Cell Stem Cell. 2012;10(5):497–503.
  293. 293. Kaji K, Caballero IMIN, MacLeod R, Nichols J, Wilson VA, Hendrich B. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature Cell Biology. 2006;8(3):285–92.
  294. 294. Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein & Cell. 2013;4(3):176–85.
  295. 295. Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell. 2011;8(1):96–105.
  296. 296. Chen X, Gazzar El M, Yoza BK, McCall CE. The NF-B Factor RelB and Histone H3 Lysine Methyltransferase G9a Directly Interact to Generate Epigenetic Silencing in Endotoxin Tolerance. The Journal of Biological Chemistry. 2009;284(41):27857–65.

Written By

Jasmin Roya Agarwal and Elias T. Zambidis

Submitted: 13 September 2013 Published: 02 July 2014