Summary of the target genes of the GATA3 and Menin with functions of the encoded proteins (based on https://www.ncbi.nlm.nih.gov/gene).
Abstract
Functionally polarized CD4 T helper (Th) cells, such as Th1, Th2, and Th17 cells, are essential for the regulation of acquired immunity. Differentiation of naïve CD4 T cells into Th2 cells is characterized by chromatin remodeling and the induced expression of a set of Th2-specific genes, which include Th2 cytokine genes. In the first stage of this differentiation, a Th2-skewing cytokine environment, especially IL-4, induces STAT6 activation. Activated STAT6 increases the expression of GATA3, a master regulator of Th2 cell differentiation, via direct binding to the Gata3 gene locus. This transcriptional induction of Gata3 mRNA during Th2 cell differentiation is accompanied by dynamic changes in the binding patterns of two epigenetic modification proteins such as Polycomb and Trithorax complexes. Consequently, expressed GATA3 epigenetically modifies and upregulates Th2-specific genes to establish Th2 cell identity. This identity is maintained by high-level expression of the Gata3 gene controlled by Menin, which is a member of the Trithorax proteins, after cycles of cultivation in vitro and a long-term resting state in vivo. Thus, the Menin-GATA3 axis handles the Th2-specific gene regulatory network.
Keywords
- Th2
- GATA3
- STAT6
- Menin
1. Introduction
Naïve CD4-positive (CD4+) T cells can differentiate into several effector T cell subsets, mainly known as Th1, Th2, and Th17 cells [1]. Th1 cells perform the crucial function of protecting against viruses and intracellular pathogens. Th17 cells similarly work against extracellular bacteria or fungi. Th2 cells are required for the removal of extracellular parasites. Each effector subset exerts its protective functions through the secretion of unique cytokines. Th1 cells mainly produce IFN-γ, which activates macrophages and CD8 T cells. Th17 cells secrete IL-17A, which propagates cascades of events that lead to neutrophil recruitment, inflammation, and host defense [2]. Th2 cells activate B cells to induce immunoglobulin class switching through IL-4, and enhance mucus production from epithelial cells by IL-13. In addition, Th2 cells recruit eosinophils to induce an inflammatory response through IL-5. However, the responses caused by these subsets are sometimes excessive and result in immunological diseases. For example, an excess amount of Th2 cytokines is known to induce allergic disease, such as asthma [3].
Each subset-specific cytokine enhances differentiation toward the corresponding Th subset, and environmental cytokines decide the differentiation fate of CD4 T cells. For example, IL-12-induced STAT4 activation in Th1 cells and IL-4-induced STAT6 activation in Th2 cells are essential for their respective differentiation [4, 5]. These STAT signals are commonly used for CD4 T cell differentiation into each subset and induce the upregulation of master transcription factors, T-bet in Th1 and GATA3 in Th2 [6, 7]. The master transcription factors directly bind to DNA and regulate the expression of each subset-specific gene, causing epigenetic modification of the DNA, which stabilizes the differentiation program. Due to this epigenetic modification, fully differentiated effector T cells are rarely converted to other Th subsets and are able to maintain their identity during the transition from effector to memory cells.
The Th2 master transcription factor GATA3 collaborates with the epigenetic regulator Menin to induce and stabilize the complex gene regulatory network. Th2-specific genes, which have been identified by gene expression profiling [8, 9], participate in this regulatory network and are controlled by neither, either or both GATA3 and Menin [10]. In fact, GATA3 or Menin deletion results in the loss of Th2 identity [10, 11]. Clarifying the interplay between the transcription factors and epigenetic modifiers is required to comprehend the Th2 cell biology and to identify new therapeutic targets for Th2-mediated immunological diseases [3].
2. STAT6 and GATA3: important transcription factors for Th2 cells
2.1. STAT6 is activated by IL-4 signaling
The most essential pathway promoting the Th2 fate is the IL-4 signaling cascade, followed by activating the transcription factor STAT6 [12, 13, 14]. When IL-4 is recognized by its receptor (type-I IL-4R), which consists of IL-4 receptor alpha chain (IL-4Rα) and a common gamma chain (γc), IL-4 can transmit a signal into a cell. Binding of IL-4 induces dimerization of IL-4Rα and γc, resulting in the phosphorylation of tyrosine residues within the intracellular portion of IL-4Rα by Janus Kinases. This phosphorylated intracellular portion of IL-4Rα recruits and phosphorylates signal transducer and activator of transcription (STAT)6, which then forms a dimer and translocates into the nucleus where the dimerized STAT6 regulates the expression of IL-4 target genes. STAT6 recognizes the DNA sequence TTCNNNNGAA, whereas other STAT family proteins prefer the DNA sequence TTCNNNGAA [15].
Like other STAT proteins, a major role of STAT6 is to activate the expression of its target genes, which is how it received its name (“signal transducer and activator of transcription”). The best-known target gene of STAT6 is the
It has been proposed that the IL-4/STAT6 cascade is necessary for the Th2 phenotype. This fact is also demonstrated by a series of knockout studies. In these studies, IL-4 deficient mice showed impaired Th2 responses, attributed to a reduced Th2 effector cytokine production, loss of IgE class switching, and reduced eosinophilia upon infection with
2.2. GATA3 plays roles in various tissues as well as the immune system
The GATA family proteins (GATA1–6) are conserved transcription factors that contain one or two C2-C2-type zinc-finger motif that recognize the consensus DNA sequence WGATAR [25, 26, 27]. Each member of the GATA family has different expression patterns in the body and can be grouped into hematopoietic factors (GATA1–3) and endodermal factors (GATA4–6). Among hematopoietic cells, immune cells, particularly developing and mature T cells, natural killer (NK) cells, and CD1-restricted NKT cells, mainly express GATA-binding protein 3 (GATA3) [6, 28, 29]. Mature mast cells express GATA1 and GATA2 but not GATA3 [30]. Outside of the immune system, GATA3 is also expressed in many embryonic and adult tissues, including the adrenal glands, kidneys, central nervous system, inner ear, hair follicles and skin, and breast tissue [27].
In the immune system, GATA3 is predominantly expressed in T lymphocytes and is essential for the development of CD4 single-positive (SP) cells in the thymus [31, 32, 33]. GATA3 exerts an important function at the β-selection checkpoint, which is involved in the CD4 versus CD8 lineage choice in the thymus [34]. It is continuously expressed in peripheral naïve CD4 T cells at a basal level, where the activation of STAT6 induced by the IL-4/IL-4 receptor signaling pathway upregulates
3. Polycomb and Trithorax proteins: fundamental epigenetic regulators for cell differentiation
3.1. Polycomb and Trithorax proteins epigenetically modify chromatin in a different way
Huge numbers of genes involved in epigenetic regulation have been identified. Many of them encode histone-modifying enzymatic proteins and their interaction partners. Among them, members of the Polycomb group (PcG) and Trithorax group (TrxG) complexes have been recognized as key epigenetic regulators [3, 43, 44, 45, 46]. PcG and TrxG proteins were originally identified in
PcG complexes are classified into two canonical types such as Polycomb repressive complex 1 (PRC1) and PRC2. Both of them are involved in transcriptional repression. A sequential recruiting mechanism is proposed for the binding of PRC2 and PRC1 to genomic DNA. First, enhancer of zeste (EZH), the enzymatically active subunit of PRC2, methylates H3K27. Next, the PRC1 complex recognizes trimethylated H3K27, resulting in its co-localization with PRC2. In addition, the ring finger protein 1 (RING1), a subunit of PRC1, has a ubiquitin ligase activity for histone H2AK119 [49]. In CD4+ T cells, Ezh2 appeared to directly bind and facilitate the correct expression of the
In contrast, mixed lineage leukemia (MLL) family proteins, which are major subunits of the TrxG complex, have H3K4 methyltransferase activity that induces a change in the chromatin structure to a form permissive for transcription. In mammals, six H3K4 methylases (MLL1–4, SET1A, and SET1B) have been discovered [53]. The H3K4 methylase complexes containing MLL1 or MLL2 are associated with a unique subunit named Menin (encoded by the
3.2. Spatial interplay between Polycomb and Trithorax complexes
Although many studies have been performed on the nature of PcG proteins and TrxG proteins individually, few have successfully defined how transcriptional counter-regulation is organized by the PcG and TrxG complexes. One pioneering work demonstrated the dynamic transformations of histone modifications during T cell development [57]. In addition, in our previous study, we successfully analyzed how the global signature of PcG and TrxG co-occupied genes changed during the developmental process. This study showed that a binding pattern in which Ezh2 binds upstream and Menin binds downstream of the transcription start site was frequently found at highly expressed genes, and a binding pattern in which Ezh2 and Menin bind to opposite positions was frequently found at low-expressed genes in T lymphocytes. Interestingly, genes showing a binding pattern in which Ezh2 and Menin occupied the same position displayed greatly enhanced sensitivity to Ezh2 deletion [3, 58].
4. STAT6 induces dynamic changes in epigenetic states at the Gata3 gene locus
4.1. The Gata3 gene is epigenetically regulated during Th2 cell differentiation
Epigenetic changes at the
4.2. STAT6 directly modifies epigenetic states at the Gata3 gene locus
We identified two functional STAT6 binding sites within the intronic regions of the
4.3. PRC2 components prevent hyperactivation of the Gata3 gene
In contrast to TrxG proteins, PcG proteins are proposed to maintain their
5. GATA3-dependent epigenetic and transcriptional regulation in the Th2 cytokine gene loci
5.1. Chromatin remodeling induced by GATA3 at the Th2 cytokine gene loci
Induction of changes in histone modifications has been reported at the
5.2. Interaction between GATA3 and regulatory elements
It has been reported that GATA3 interacts with some regulatory elements at Th2 cytokine gene loci, including conserved non-coding sequence (CNS)-1, HSVa, the conserved GATA response element (CGRE), and HSII in intron 2 of the
HSVa is a TCR re-stimulation-dependent HS site, whose DNase I hypersensitiveness is induced in Th2 cells upon stimulation [72]. HSVa is located 5 kbp downstream of the 3′ end of the
As we reported in 2002, CGRE was originally identified as a region with a 71-bp sequence located 1.6 kbp upstream of the
Among several GATA3 binding sites found in the
5.3. GATA3-dependent transcriptional regulation of Th2 signature genes
In addition to regulating chromatin remodeling, GATA3 may induce
Interestingly, changes in GATA3 dependency are observed during transition from effector to memory cells. In a previous study [9], we compared the GATA3 dependency in Th2-specific genes between effector Th2 cells and
6. A gene regulatory network in fully developed Th2 cells: the interplay between GATA3 and Menin, a component of the Trithorax complex
As described in Section 4.2, although Menin deficiency had little effect on the ordinary induction of Th2 differentiation, ‘Th2 cells’ lost their Th2 identity after several cycles of cultivation in the absence of Menin. Our study also revealed that Menin directly bound and epigenetically regulated the
Since Th2 cells derived from Menin-deficient mice have defects in both Menin and GATA3 expression, whether the lack of Menin, decreased expression of GATA3, or both are responsible for the dysregulation of the Th2-specific gene expression in Menin-deficient cells remains unclear. In a recent study [52], we addressed this point using differentiated Th2 cells with two additional cycles of cultivation (Th2-3rd cells). Consequently, the gene expression profiles under three conditions (i.e. genetic deletion of Menin,
In our ChIP-seq analysis, the direct binding of Menin was observed in most of the 31 Th2-specific genes, except for
RefSeq ID | Gene symbol | Group | GO term (function, process, or component) |
---|---|---|---|
NM_008355 | Il13 | 1 | Cytokine activity |
NM_010558 | Il5 | 1 | Cytokine activity [88] |
NM_023049 | Asb2 | 1 | Contributes to ubiquitin protein ligase activity [89] |
NM_028006 | Tube1 | 1 | GTPase activity |
NM_013871 | Mapk12 | 1 | MAP kinase activity |
NM_010370 | Gzma | 1 | Serine-type peptidase activity [90] |
NM_053095 | Il24 | 1 | Cytokine activity [91] |
NM_007720 | Ccr8 | 1 | C-C chemokine receptor activity [92] |
NM_021283 | Il4 | 1 | Cytokine activity [93] |
NM_181071 | Tanc2 | 1 | In utero embryonic development [94] |
NM_017373 | Nflil3 | 2 | RNA polymerase II core promoter sequence-specific DNA binding [95] |
NM_013498 | Crem | 2 | Core promoter sequence-specific DNA binding [96] |
NM_008967 | Ptgir | 2 | G-protein coupled receptor activity |
NM_010169 | F2r | 2 | G-protein alpha-/beta-subunit binding [97] |
NM_019779 | Cyp11a1 | 2 | Cholesterol monooxygenase (side-chain-cleaving) activity [98] |
NM_177368 | Tmtc2 | 2 | Calcium ion homeostasis |
NM_023270 | Rnf128 | 2 | Ubiquitin protein ligase activity [99] |
NM_011309 | S100a1 | 3 | Protein binding [100] |
NM_011897 | Spry2 | 3 | Negative regulation of ERK1 and ERK2 cascade [101] |
NM_007899 | Ecm1 | 4 | Interleukin-2 receptor binding [102] |
NM_009401 | Tnfsf8 | 4 | Tumor necrosis factor-activated receptor activity |
NM_176933 | Dusp4 | 4 | MAP kinase tyrosine/serine/threonine phosphatase activity |
NM_016780 | Itgb3 | 4 | Alpha9-beta1 integrin-ADAM8 complex [103] |
NM_010555 | Il1r2 | 4 | Interleukin-1 receptor activity [104] |
NM_010137 | Epas1 | 4 | DNA binding transcription factor activity [105] |
NM_001045530 | Ccnjl | 4 | Nucleus component |
NM_019676 | Plcd1 | 4 | Phosphatidylinositol phosphate binding [106] |
NM_001002927 | Penk | 4 | Aggressive behavior [107] |
NM_030887 | Jdp2 | 4 | RNA polymerase II proximal promoter sequence-specific DNA binding [108] |
NM_025768 | Grtp1 | 4 | Rab GTPase binding |
7. Conclusions
Since the human genome project was completed in 2003, the human genomic DNA database has become accessible to researchers [109]. Open access to the reference genomes of humans, mice, and other organisms encourages scientists to develop elegant technologies, including ChIP-seq and high-throughput sequencing of RNA (RNA-seq) [110]. This technique enables us to analyze the epigenetic status of each population of cells on a genome-wide scale. Many scientists have tried to use this technique to clarify the functional roles of epigenetic modifications in gene expression, particularly in the fields of developmental biology and immunology [47].
Recently, we identified several important principles between the binding positions of PcG and TrxG proteins and the gene expression [52]; a binding pattern in which PcG binds upstream and TrxG binds downstream of the transcription start site is frequently found at highly expressed genes, and a binding pattern in which PcG and TrxG bind to opposite positions is frequently found at low-expressed genes in T lymphocytes. We hope that these findings will prove useful for understanding how CD4+ T cells acquire effector functions and identifying new therapeutic targets for treating allergic diseases, such as asthma, allergic rhinitis, food allergy, and atopic dermatitis. A recently developed epigenetic editing technique using the CRISPR/Cas9 system now allows us to modify epigenetic marks in a site-specific manner [111]. In the future, we may use this technique to treat various diseases cause by epigenetic alternations.
Abbreviations
ATAC-Seq | assay for transposase-accessible chromatin sequencing |
ChIP-Seq | chromatin immunoprecipitation followed by massively parallel sequencing |
CNS | conserved non-coding sequence |
H3K27me3 | trimethylated histone H3 lysine 27 |
H3K4me3 | trimethylated histone H3 lysine 4 |
HS | DNase I hypersensitive site |
IL | interleukin |
PcG | Polycomb group |
PRC | Polycomb repressive complex |
STAT | signal transducer and activator of transcription |
Th | helper T cell |
TrxG | Trithorax group |
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