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",isbn:"978-1-83969-467-7",printIsbn:"978-1-83969-466-0",pdfIsbn:"978-1-83969-468-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"a6f32d3f2227df637fffd969a0cb5ed7",bookSignature:"Dr. Peter A. Clark",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10878.jpg",keywords:"Preimplantation Genetic Diagnosis, Medical Futility, Definition of Death, Extraordinary/Ordinary Means, Need for New Antibiotics, Role of Big Pharma, Uterine Transplants, Face Transplants, Confidentiality, Ethical Decision Making, Harm Reduction Theory, Safe Injection Sites",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 8th 2021",dateEndSecondStepPublish:"March 8th 2021",dateEndThirdStepPublish:"May 7th 2021",dateEndFourthStepPublish:"July 26th 2021",dateEndFifthStepPublish:"September 24th 2021",remainingDaysToSecondStep:"3 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A faculty member for medical residents, medical students, and undergraduate students and a researcher in issues that challenge the national and global arenas. He is also the Bioethicist for over 20 health care facilities in the United States and Palestine.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"58889",title:"Dr.",name:"Peter A.",middleName:null,surname:"Clark",slug:"peter-a.-clark",fullName:"Peter A. Clark",profilePictureURL:"https://mts.intechopen.com/storage/users/58889/images/system/58889.jpg",biography:"Peter A. Clark, S.J., Ph.D. is the John McShain Chair in Ethics and Director of the Institute of Clinical Bioethics at Saint Joseph’s University in Philadelphia, Pennsylvania. He is also the Bioethicist for over 20 health care facilities in the United States and Palestine. He is the author of To Treat or Not To Treat and Death With Dignity and has published numerous peer-reviewed articles in national and international medical and ethical journals.",institutionString:"Saint Joseph's University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Saint Joseph's University",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"346794",firstName:"Mia",lastName:"Miskulin",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/346794/images/15795_n.png",email:"mia@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1743",title:"Contemporary Issues in Bioethics",subtitle:null,isOpenForSubmission:!1,hash:"978cee44b901ff59a20a088f7dcfdbc5",slug:"contemporary-issues-in-bioethics",bookSignature:"Peter A. Clark",coverURL:"https://cdn.intechopen.com/books/images_new/1743.jpg",editedByType:"Edited by",editors:[{id:"58889",title:"Dr.",name:"Peter A.",surname:"Clark",slug:"peter-a.-clark",fullName:"Peter A. Clark"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5418",title:"Bioethics",subtitle:"Medical, Ethical and Legal Perspectives",isOpenForSubmission:!1,hash:"767abdeb559d66387ad2a75b5d26e078",slug:"bioethics-medical-ethical-and-legal-perspectives",bookSignature:"Peter A. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"18411",title:"Epigenetic Chromatin Regulators as Mediators of Abiotic Stress Responses in Cereals",doi:"10.5772/36025",slug:"epigenetic-chromatin-regulators-as-mediators-of-abiotic-stress-responses-in-cereals",body:'\n\t\tPlants are constantly exposed to environmental changes and have to adapt to a multitude of abiotic and biotic stresses. Due to their sessile nature plants had to develop sophisticated ways to respond and adapt to a variety of external stress factors that would otherwise compromise proper development, reproductive success and ultimately survival.
\n\t\t\tYears of rigorous research have demonstrated that abiotic stress such as drought, high salinity, temperature extremes, UV irradiation and oxidative stress, affect various cellular processes in plants and induce alterations in gene expression programmes in order to activate the plants defense mechanisms to survival. Extensive studies based on forward genetic, reverse genetics, and biochemical investigations of individual loci as well as genome-wide approaches, especially in the model-plant Arabidopsis, have revealed a plethora of genes that are involved in abiotic stress response pathways and acquisition of stress tolerance. These include a wide range of stress-responsive genes encoding transcription factors and functional proteins whose transcription is altered during abiotic stress [1].
\n\t\t\tGrowing evidence from recent studies has indicated that regulation of expression of stress-responsive genes is often accomplished by epigenetic mechanisms which modulate chromatin structure or regulate the level of mRNA accumulation at the postranscriptional level [2; 3; 4].
\n\t\t\tIn eukaryotes nuclear DNA is organized in chromatin, a tightly packed higher order structure which permits genomic DNA to fit within the nucleus. The fundamental unit of chromatin is the nucleosome which is composed of 147 base pairs of DNA that is wrapped almost twice around an octamer of histone proteins. The octamer consists of two copies of each of histone H2A, H2B, H3 and H4. Chromatin higher-order structure switches between condensed and relaxed states and plays a crucial role in the epigenetic regulation of gene expression [\n\t\t\t\tKouzarides 2007]. Alterations in chromatin structure affect the accessibility of the transcriptional machinery (transcription factors, RNA polymerase) to nucleosomal DNA and determine the levels of gene expression in response to developmental and environmental stimuli.
\n\t\t\tChromatin modulation is achieved by a variety of mechanisms including: DNA methylation catalyzed by DNA cytosine methyltransferases, histone post-translational modifications catalyzed by a wide range of enzymes specific for each modification, alterations in histone-DNA interactions which facilitate nucleosome sliding and are catalyzed by chromatin remodeling complexes, histone variants, and small RNA related pathways (siRNAs and miRNAs) which act directly on chromatin and induce RNA-dependent DNA methylation (RdDM) [\n\t\t\t\tKouzarides et al, 2007; \n\t\t\t\tPfluger and Wagner, 2007; \n\t\t\t\tLaw and Jacobsen, 2010; \n\t\t\t\tChapman and Carrington, 2007; \n\t\t\t\tHenderson and Jacobsen, 2007; \n\t\t\t\tKasschau et al., 2007; \n\t\t\t\tChinnusamy and Zhu; 2009]. In addition, small RNAs also regulate gene expression at the posttranscriptional level through mRNA degradation and/or translational inhibition [\n\t\t\t\tVoinnet 2009; \n\t\t\t\tBartel 2009].
\n\t\t\tResearch on the epigenetic regulation during plant development and in response to abiotic stress has focused on exploration of chromatin modulation at specific loci and the characterization of chromatin modifiers during development and under stress conditions[2; 3]. In recent years the advancement of –omics technologies [transcriptomics- microarrays/whole-genome tilling arrays, next generation sequencing (NGS), chromatin immunoprecipitation (ChIP) assays combined with sequencing technology (ChIP-seq), and bioinformatics tools] contributed greatly to these efforts and led to the transition from epigenetics (study of individual locus /small-scale) to epigenomics (study of whole epigenomes/global-scale) [reviewed in Tsaftaris et al., in press]. Large-scale epigenomics studies have established the genome-wide profile of DNA methylations, histone modifications and small RNA patterns, in different developmental stages or under abiotic stress conditions, primarily in the model-plant Arabidopsis [\n\t\t\t\tCokus et al. 2008; \n\t\t\t\tLister et al., 2008; \n\t\t\t\tZhang et al., 2007; \n\t\t\t\tBernatavichute et al., 2008; \n\t\t\t\tZhang et al.,2009; \n\t\t\t\tYang et al., 2010; \n\t\t\t\tVan Dijk et al., 2010; \n\t\t\t\tRoudier et al., 2011] but also in the cereal model-plant Brachypodium [\n\t\t\t\tZhang et al., 2009b] and in agronomically important cereal crops like rice [\n\t\t\t\tLi et al., 2008, \n\t\t\t\tSunkar et al., 2008; \n\t\t\t\tHe et al., 2010] maize [\n\t\t\t\tWang et al.,2009; Wang et al., 2011] wheat [\n\t\t\t\tYao et al., 2010] and barley [\n\t\t\t\tSchreiber et al., 2011]. Together, epigenetics and epigenomics studies have provided a wealth of information about epigenetic regulation in response to developmental and environmental stimuli, mostly in Arabidopsis. Recently, the availability of the rice and maize genomes and epigenomes provided the opportunity for exploring this exciting area in monocots as well, and data on epigenetic regulation in response to abiotic stress in cereals have started to come into sight.
\n\t\t\tIn this review we summarize the current progress on epigenetic regulation in response to abiotic stresses such as drought, cold, and high salinity, in Arabidopsis, and present the emerging information on the epigenetic regulatory mechanisms induced upon abiotic stress in cereals such as rice, maize, wheat and barley. Expanding our understanding of the epigenetic regulation associated with abiotic stress responses in cereals of agronomic importance could have a significant impact in breeding for improved varieties with increased stress tolerance. In view of the global climate change where abiotic stresses are expected to increase dramatically, this undertaking would be of paramount importance.
\n\t\tHistone post-translational modifications usually take place on histone tails protruding from nucleosomes, and include methylation, acetylation, phosphorylation, ubiquitination, biotinylation, and sumoylation on specific lysine, arginine, serine and threonine residues [\n\t\t\t\tZhang et al., 2007a; \n\t\t\t\tBerger et al., 2007]. A complex pattern of site-specific combinations of histone modifications on different residues known as the ‘epigenetic histone code’ leads to specific chromatin states in response to intrinsic (developmental) and external (environmental signals) which regulate transcriptional activity and are inherited by daughter cells [\n\t\t\t\tStrahl and Allis 2000].
\n\t\t\tThe best characterized histone modifications associated with the response of plants to abiotic stress are the histone acetylation/deacetylation and histone methylation/demethylation reversible modulations at individual loci [2; 3\n\t\t\t\tChinnusamy et al. 2008; Chinnusamy and Zhu 2009]. Histone acetylation carried out by histone acetyltransferases (HATs) is associated with gene activation, whereas histone deacetylation, performed by histone deacetylases (HDACs) is associated with gene silencing [\n\t\t\t\tChen and Tien, 2007]. Histone methylation/demethylation is catalyzed by specific histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively. Tri-methylation of H3 at lysine 4 (H3K4me3) which is catalyzed by a specific histone methyltransferase of the Trithorax (TrxG) group leads to gene transcription, whereas trimethylation of H3 at lysine 27(H3K27me3) by a specific methyltransferase of the Polycomb group (PcG), which antagonizes TrxG, leads to gene repression [\n\t\t\t\tAvramova 2009; \n\t\t\t\tAlvarez et al., 2010; \n\t\t\t\tPontvianne et al., 2009; \n\t\t\t\tLiu et al., 2010; \n\t\t\t\tKapazoglou et al., in press].
\n\t\t\tAbiotic stress such as drought, cold, heat, high salinity, oxidative stress and UV irradiation, alter the histone acetylation and/or methylation pattern within the promoters or coding regions of genes, thereby causing gene activation or gene silencing. In addition, abiotic (and biotic) stress factors trigger the production of certain phytohormones such as abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), gibberellic acid (GA) and ethylene, which mediate the regulation of gene expression during the adaptive responses of plants to various abiotic stresses. It has been proposed that histone acetylation/deacetylation through the action of HATs and HDACs, and histone methylation/demethylation through the action of HMTs and HDMs, respectively, epigenetically regulates the responses to various stresses as well as the integration of hormonal signals controlling stress-responsive genes [\n\t\t\t\tChinnusamy et al. 2008; \n\t\t\t\tChinnusamy and Zhu 2009;\n\t\t\t\t\n\t\t\t\tChinnusamy and Zhu 2009].
\n\t\t\tMuch research has been conducted in Arabidopsis on the effects of abiotic stress on histone modifications at specific chromatin loci. For example, ChIP assays detected histone modifications on the N- terminal tails of H3 in four drought–stress responsive genes, namely, RESPONSIVE TO DEHYDRATION(RD)29A, RD29B, RD20 and AP2 DOMAIN-CONTAINING TRANSCRIPTION FACTOR, Atg20880. In particular, the histone activation marks H3K23ac and H3K27ac were enriched in the coding regions of RD29B, RD20 and Atg20880 in response to drought stress and these changes were associated with increased expression of these genes under dehydration conditions [\n\t\t\t\tKim et al., 2008]. Enrichment for H3K4me3 was also observed at RD29A and Atg20880 chromatin and it occurred after full activation of these genes under conditions of drought. In another study, histone modifications were detected in two cold-responsive genes COLD-REGULATED (COR)15A and ATGOLS3 (encoding galactinol synthase) during exposure to low temperature conditions [\n\t\t\t\tTaji et al., 2002]. H3K27me3, a gene silencing mark, was found to be decreased on the chromatin of both genes and this reduction was associated with reduced expression under cold stress. Another report revealed that phosphorylation of histone H3 at serine 10, phosphoacetylation of H3 at serine 10 and lysine 14, and acetylation of histone H4 were enriched as a response to cold, high salinity, and exogenous ABA application, in Arabidopsis and tobacco cells. The induction of these histone modifications correlated with up-regulation of stress-responsive genes [\n\t\t\t\tSokol et al., 2007].
\n\t\t\tHistone modification alterations were also reported in cereals exposed to abiotic stress. Submergence of rice seedlings induced H3K4me3 and H3 acetylation in the 5’ and 3’ regulatory regions and coding regions of the ALCOHOL DEHYDROGENASE 1 (ADH1) and PYRUVATE DECARBOXYLASE\n\t\t\t\t(PDC1) genes. These modifications correlated with upregulation of ADH1 and PDC1 and were restored to pre-stress levels after seedlings were reinstating to areation, underlying the dynamic nature of histone methylation and acetylation modifications [\n\t\t\t\tTsuji et al., 2006]. In maize, exposure to UV irradiation resulted in increased H3 and H4 acetylation within the promoter and coding regions of UV-B-induced genes in a maize-UV-B-tolerant line, whereas such enrichment was not detected in a UV-B-sensitive maize line [\n\t\t\t\tCasati et al., 2008].
\n\t\t\tFinally, genome-wide analysis using ChIP and deep sequencing (ChIP-Seq) unraveled the global epigenomic map of H3Kme1, H3K4me2 and H3K4me3 during drought stress and non-stress conditions, in Arabidopsis. The H3K4me1 and H3K4me2 were found to be more widely distributed than the H3K4me3 mark. Upon dehydration stress a substantial change in H3K4me3 abundance was observed, whereas there were only moderate changes in H3K4me1 and H3K4me2 levels. In addition, whereas for most transcribed genes the H3K4me3 mark was more prominent at the 5’-ends, for drought- and ABA-induced genes H3K4me3 had an atypically broader distribution profile [\n\t\t\t\tvan Dijk et al., 2010].
\n\t\t\n\t\t\t\tHistone acetyltransferases (HATs)\n\t\t\t
\n\t\t\tHistone acetyltransferases (HATs) transfer an acetyl moiety to the ε-amino group of highly conserved lysines in the N-terminal extensions of nucleosomal core histones, thereby neutralizing the positive charge of lysines and resulting in less affinity to the negatively charged DNA molecules. This results in relaxation of chromatin structure and subsequent transcriptional activation. HATs comprise a superfamily including the GNAT/MYST, CBP and TFII250 families and are often subunits of large protein complexes.
\n\t\t\tAtGCN5, a member of the GNAT/MYST subfamily, is the best studied HAT protein in Arabidopsis and plays a role in gene activation in response to environmental changes such as cold [\n\t\t\t\tVlachonasios et al., 2003]. AtGCN5 associates in vitro with the transcriptional co-activator proteins ADA2a and ADA2b. ada2b mutants were found to exhibit hypersensitivity to salt and abscisic acid and had altered responses to low temperature stress [\n\t\t\t\tHark et al., 2009]. Elongator, another histone acetyltransferase complex consisting of six subunits and highly conserved in eukaryotic organisms, was implicated in abiotic stress response. Mutations in the core subcomplex ABO1/ELP1 and ELP2, but not in the accessory subcomplex ELP4 and ELP6, increased ABA-induced stomatal closure. These mutants also displayed increased tolerance to oxidative stress [\n\t\t\t\tZhou et al., 2009]. A recent report showed that ADA2b positively regulates salt-induced gene expression by maintaining the locus-specific acetylation of histones H4 and H3b. ChIP assays demonstrated that the promoter and coding regions of COR6.6 (COLD RESPONSIVE 6.6), RAB18 (RESPONSIVE TO ABA 18), and RD29b genes had reduced levels of histone H3 and H4 acetylation in ada2b-1 mutants relative to wild-type plants [\n\t\t\t\tKaldis et al., 2011].
\n\t\t\tOur group has identified HAT gene homologues from barley. Representative members of the GNAT/MYST family, namely HvMYST, HvELP3 and HvGCN5, were isolated and gene expression was examined in different stages of seed development and in response to ABA treatment. Exposure of barley seedlings to exogenus ABA resulted in marked induction of all three HAT genes. HvELP3 was the one mostly affected by the application of the hormone and had expression levels four times as much in the ABA-treated tissue than the untreated controls. HvGCN5 and HvMYST were also up-regulated by approximately two-fold. These data implied possible ABA-dependent regulation of barley histone acetyltransferases during seed development and abiotic stress response [\n\t\t\t\tPapaefthimiou et al., 2010].
\n\t\t\t\n\t\t\t\tHistone deacetylases (HDACs).\n\t\t\t
\n\t\t\tHistone deacetylases (HDACs) reverse the effect of HATs by removing the acetyl group on histones resulting in condensed chromatin structure and gene silencing [\n\t\t\t\tChen and Tian, 2007]. Eukaryotic HDACs can be grouped into three major families based on their primary homology to the yeast HDACs: 1) the RPD3/HDA1 family, 2) the SIR2 family and 3) the plant specific family HD2 (\n\t\t\t\tPandey et al., 2002).
\n\t\t\tSequence and phylogenetic analysis of the rice genome identified the respective three HDAC families in rice [\n\t\t\t\tFu et al., 2007]. HDA1 is further subdivided in four classes Class I, Class II and Class III, and ClassIV, and HD2 in two classes HD2a and HD2b. In maize, 15 HDAC genes have been identified (10 HDA1, 1 SIR2, and 4 HD2-like and a number of HDA1 members have been biochemically characterized [\n\t\t\t\tLusser et al., 2001; \n\t\t\t\tRossi et al., 2003; \n\t\t\t\tVarotto et al., 2003].
\n\t\t\tFunctional analysis using silencing or overexpression transgenic lines in Arabidopsis has demonstrated that both HDA1 and HD2 genes are associated with the response to abiotic (as well as biotic stress). For example, AtHDAC19 was proposed to mediate jasmonic acid (JA) and ethylene signaling during pathogen defense (\n\t\t\t\tTian et al. 2005; \n\t\t\t\tZhou et al. 2005). Overexpression of AtHDA19 resulted in reduced histone acetylation levels and upregulation of the stress-related genes ERF1 (Ethylene Response Factor-1) and PR (Pathogenesis\n\t\t\t\tRelated). Conversely, silencing of AtHDA19 led to increased histone acetylation and downregulation of ERF1 and PR. AtHDA6, another HDA1-Class I, was shown to be required for jasmonate response, senescence, and flowering. AtHDA6 was induced by exogenous JA and ethylene [\n\t\t\t\tWu et al. 2008]. In addition, in hda6 mutants and in HDA6-RNAi plants the Arabidopsis JA-responsive genes PDF1.2, VSP2, JIN1, and ERF1 were downregulated, suggesting an indirect involvement of HDAC6 in JA-responsive gene regulation.
\n\t\t\tHistone modification changes that take place as a response to abiotic stresses are often found to be induced by phytohormones, such as ABA [\n\t\t\t\tChinnusamy et al., 2008]. ABA affects a wide range of processes in plants like germination, vegetative to reproductive transitions, seed development, seed dormancy and abiotic stress tolerance. For example, AtHD2C, belonging to the HD2 family was proposed to play a role in ABA signaling and abiotic stress, in Arabidopsis (\n\t\t\t\tSridha and Wu 2006). ABA treatment caused severe reduction in expression of AtHD2C, whereas overexpression of AtHD2C resulted in enhanced abiotic stress tolerance to salt and drought stress, as well as repression of several ABA-responsive genes and induction of others (Sridha and Wu 2006). AtHOS15 encoding a protein similar to human transducing-β-like protein (TBC), a component of a repressor protein complex involved in histone deacetylation, was reported to mediate ABA-dependent deacetylation in response to cold stress [\n\t\t\t\tZhu et al., 2008]. The expression of AtHOS15 is increased by cold, high salinity, and ABA treatment and hos15 mutants are hypersensitive to freezing stress. In addition hos15 mutants displayed increased H4 acetylation levels and concurrent increase of RD29A expression levels, suggesting a role for HOS15 in regulating chromatin acetylation levels and gene expression under abiotic stress.
\n\t\t\tFurthermore, in a recent report, AtHDA6 was shown to be involved in modulating the levels of H3K9, 14 ac and H3K4me3 (gene activating marks) and of H3K9me2 (histone deactivation mark) in response to ABA and salt-stress [\n\t\t\t\tChen et al., 2010]. The hdac6 mutant and RNAi HDAC6 lines were hypersensitive to ABA and salt stress, and the expression of ABA- and abiotic stress-inducible genes, ABI1, ABI2, KAT1, KAT2, DREB2A,\n\t\t\t\tRD29A,\n\t\t\t\tRD29B was decreased when these plants were subjected to ABA or salt stress as compared to wild-type plants. Moreover, both ABA application and salt stress increased the gene activation marks, H3K9,14 ac and H3K4me3, in the promoter and coding regions of some of the stress-inducible genes mentioned above. However, such increase was not observed in the hdac6 mutant lines. Together these observations indicate that HDAC6 is required for ABA and stress-induced histone acetylation, and most likely functions indirectly by suppressing a repressor of histone acetylation. Ultimately, this leads to gene activation of stress-responsive genes and stress tolerance [\n\t\t\t\tChen et al., 2010].
\n\t\t\tStudies on HDAC genes in relation to stress and stress-related hormones have been recently reported in cereals as well. Expression analyses of 18 rice HDAC genes from HDA1, SIR2 and HD2 families demonstrated distinct spatial expression patterns and differential responses to environmental stresses and hormones [\n\t\t\t\tFu et al., 2007]. Cold, osmotic and salt stresses, and external application of hormones such as JA, ABA, and SA, increased the expression of certain HDA1 genes, and reduce the expression of others (\n\t\t\t\tFu et al. 2007). For example two members of the rice HDA1-class I (HDA 702 and HDA705) and one member of class II (HDA 704) were induced by exogenous JA application. Conversely, the expression of a member of class IV (HDA 712) was reduced after JA treatment.
\n\t\t\tOur group has identified and characterized gene members of both HDA1 and HD2 families from barley and examined their expression during barley development and in response to stress-related hormones, such as ABA and JA [\n\t\t\t\tDemetriou et al., 2009; \n\t\t\t\tDemetriou et al., 2010]. Barley HDA1 genes (one of each class, I, II, III, and IV, respectively) were induced upon JA treatment, in agreement with the expression of their rice homologues. In addition, both HvHDAC2-1 and HvHDAC2-2 of the barley HD2 family, were significantly induced at 6 and 24 h after exogenous application of seedlings with JA. On the other hand, HvHDAC2-1 showed a marked induction at 24 h after ABA treatment, whereas HvHDAC2-2 transcript levels declined at 6 h after ABA treatment and showed no significant difference in 24 h after ABA treatment [\n\t\t\t\tDemetriou et al., 2009]. In rice, the two HD2 homologues (HDT701) and (HDT702) were also induced upon treatment with JA (\n\t\t\t\tFu et al., 2007) in accord to their barley homologues. On the contrary, whereas both rice HD2 homologues were repressed by ABA, barley HvHDAC2-1 and HvHDAC2-2 showed differential responses to ABA exposure. Interestingly, the HD2c gene of Arabidopsis is also repressed by ABA (\n\t\t\t\tSridha and Wu, 2006). Together these results suggest common functions for some HDAC homologues among species but also possible species-specific functional diversification, in response to stress.
\n\t\t\t\n\t\t\t\tHistone methyltransferases(HMTs)/Histone demethylases (HDMs)\n\t\t\t
\n\t\t\tThe best characterized histone methyltransferase (HMTs) genes are the ones coding for the enzymes that perform the deposition of the H3K4me3 activation mark and H3K27me3 silencing mark, respectively. These have been intensively studied both in monocots and dicots and the results of these studies have been discussed in a number of reviews [\n\t\t\t\tAvramova 2009; \n\t\t\t\tAlvarez et al., 2010; \n\t\t\t\tPontvianne et al., 2009; \n\t\t\t\tLiu et al., 2010; Kapazoglou et al., in press]. The Polycomb group (PcG) complex with H3K27me3 activity plays a crucial role in various stages of development, such as flowering and seed development and is composed of four subunits. Two WD40 proteins, FERTILIZATION INDEPENDENT ENDOSPERM (FIE), and MULTICOPY SUPPRESSOR OF IRA1 (MSI1) remain constant in all PcG complex variants. Depending on cell type and function the different PcG complexes contain one of the three homologues of the Drosophila E(Z) homologues, MEA, CURLY LEAF (CLF) or SWINGER (SWN), which possess the histone methyltransferase activity, and one of the three homologues of the Drosophila Su(z)12 protein, EMBRYONIC FLOWER 2 (EMF2), FERTILIZATION INDEPENDENT SEED 2 (FIS2), and VERNALIZATION2 (VRN2), respectively. It was shown that Arabidopsis msi1-cs co-suppressor lines displayed increased tolerance to drought stress. In addition, the expression of stress- and ABA-responsive genes was up-regulated in msi1-cs lines suggesting that MSI1 suppresses stress-related genes in an ABA-dependent manner [\n\t\t\t\tAlexandre et al., 2009]. A recent study implicated the Trithorax protein ATX1, performing trimethylation of H3 at lysine 4 (H3K4me3), in dehydration stress signaling both in an ABA-dependent and ABA-independent manner. atx1 plants exhibited larger stomatal apertures, increased transpiration rates and decreased tolerance to dehydration stress. ATX1 was shown to be required for induction of NCED (a gene encoding a key enzyme in ABA biosynthesis) and H3K4me3, in response to dehydration stress. By inducing NCED3 and consequently ABA synthesis, ATX1 exerted an effect on ABA-dependent gene expression, but it was also shown to regulated ABA-independent gene expression pathways [\n\t\t\t\tDing et al., 2011].
\n\t\t\tA recent study by our group characterized the PcG gene homologues from barley and examined their expression during seed development and in response to ABA treatment. The barley homologues, HvE(Z) and HvFIE were significantly induced at 24 hours after ABA exposure, about 4-fold and 10-fold, respectively, implying a role of PcG genes in ABA-mediated processes, such as seed development, seed dormancy, germination and abiotic stress response [\n\t\t\t\tKapazoglou et al., 2010]. Moreover, a gene encoding a trithorax-like H3K4 methyltransferase, HvTX, was also identified and characterized in barley by our group. HvTX transcript levels showed a marked increase by drought in a drought-tolerant barley cultivar [Papaefthimiou and Tsaftaris, in press].
\n\t\t\tHistone demethylases were only recently discovered and their molecular and functional characterization is an area of active research [Kapazoglou et al., in press]. In Arabidopsis, functional studies assigned a role for H3K4-specific demethylases as regulators of flowering time by deactivating the flowering repressor gene FLC and promoting flowering []. In rice, a jmjC domain-containing gene encoding a H3K9 demethylase, JMJ706, was found to be required for floral organ development[]. Reports describing a putative role of HDMs in abiotic stress are anticipated. In the cereal crop barley, one putative plant-specific PKDM7 subfamily histone demethylase was characterised and was shown to be significantly induced by drought stress [Papaefthimiou and Tsaftaris, in revision].
\n\t\tThe SWI/SNF (switch/sucrose non-fermenting) is a multisubunit assembly with DNA-dependent ATPase activity that is implicated in alteration of chromatin structure and subsequent changes in gene expression [\n\t\t\t\tSchwabish and Stuhl, 2007]. An SNF-type putative remodeling gene was shown to be expressed in a desiccation- and ABA-dependent manner in pea [\n\t\t\t\tRios et al., 2007]. AtCHR12, a SNF/Brahma (BRM)-type chromatin remodeling factor, has been implicated as a negative regulator in the temporary growth arrest caused by drought and heat stress, in Arabidopsis [\n\t\t\t\tMlynarova et al., 2007]. Overexpression of AtCHR12 resulted in growth arrest of primary buds and reduced growth of primary stems under drought and heat stress. On the contrary, in atchr12 knockout mutants growth arrest was decreased as compared to wild type plants under stress. In another report it was shown that SWI3B, a subunit of a SWI/SNF complex in Arabidopsis, interacts with HAB1, (a phosphatase 2C), which is a negative regulator of ABA signaling [\n\t\t\t\tSaez et al., 2008]. swi3b mutant seedlings exposed to external ABA exhibited reduced sensitivity to ABA-mediated inhibition of seed germination and growth and reduced expression of ABA-responsive genes like RD29B and RAB18 [\n\t\t\t\tSaez et al., 2008]. Furthermore, ChIP assays showed that the interaction of HAB1 with RD29B and RAB18 promoters was abolished by ABA, suggesting that HAB1 modulates the ABA response through regulation of a SWI/SNF complex.
\n\t\t\tMolecular and functional characterization of chromatin remodeling factors in cereals is scarce. In one study it was shown that ChIP assays conducted with maize leaf nuclei, detected an enrichment for SWI2/SNF2 at target genes after UV-B treatment of maize plants, implying involvement of chromatin remodelling factors in abiotic stress responses [\n\t\t\t\tCasati et al., 2008]. It is expected that by exploiting the data from the completed rice, maize and recently Brachypodium genomes, additional studies on chromatin remodeling and its association with abiotic stress in cereals will soon be reported.
\n\t\tDNA methylation is a critical epigenetic modification which is established and maintained by multiple interacting cellular mechanisms. Cytosine methylation in plants is found predominately in a symmetrical CG dinucleotide site. However unlike animals, it also occurs at CHG and asymmetric CHH sites (where H is A, C, or T). A dynamic interplay between methylation and demethylation accomplished through specific enzymes, is critical for proper cellular regulation during plant development. DNA methylation is carried out by “de novo” and “maintenance” DNA methyltransferases (MTases), and in most cases results in gene silencing although the opposite has been also observed [\n\t\t\t\tLaw and Jacobsen, 2010; \n\t\t\t\tMacarevich et al., 2008; \n\t\t\t\tShibuya 2009]. A number of reports have demonstrated that DNA methylation may be employed by plants to regulated gene expression as a response to abiotic stresses.
\n\t\t\tAn early study in maize had shown that cold stress induced the expression of the ZmMI1 gene (a retrotransposon-like gene) and this correlated with reduction in nucleosomal DNA methylation [\n\t\t\t\tSteward et al., 2002]. Studies of F1 hybrids and their parents in maize revealed that under dense planting (a stressful condition), parents accumulated more DNA methylation sites than their hybrids which resist to DNA methylation changes [\n\t\t\t\tKovacevic et al., 2005; \n\t\t\t\tTani et al., 2005; and reviewed in \n\t\t\t\tTsaftaris et al., 2008]. Another report in tobacco showed that a methyltransferase (met1) mutant, exhibited demethylation of genomic regions that were associated with the expression of a large number of drought-related genes [\n\t\t\t\tWada et al., 2004]. Moreover, tobacco plants exposed to high salt, cold and aluminum displayed changes in the methylation pattern of a gene encoding glycerophosphodiesterase-like protein (NtGPDL) and known to be induced in response to aluminum stress, as compared to nonstressed plants [\n\t\t\t\tChoi and Sano, 2007]. CG sites within the coding region were selectively demethylated suggesting that abiotic stress caused gene activation by changing the DNA methylation status of the particular genomic locus. A recent study exploring the genome-wide DNA methylation status of two rice cultivars with different tolerance to drought, revealed significant differences in the methylation patterns between the two genomes [\n\t\t\t\tWang et al., 2011]. In particular, a drought-tolerant line DK151 and its drought-sensitive parent, IR64, were anaadapatationlyzed by methylation-sensitive amplified polymorphism analysis (MSAP) under drought stress and no stress conditions. DNA methylation/demethylation changes were induced under drought conditions in a developmental and tissue specific manner and they accounted for 12.1% of the total site-specific methylation differences between the two lines. Notably 70% drought-induced methylation changes were reversed after recovery, and 29% remained unaltered. These observations suggest that DNA methylation changes play a role in the response of rice to dehydration conditions probably by activating or deactivating stress-responsive genes and leading to adaptation to drought conditions [\n\t\t\t\tWang et al., 2011]. MSAP was also used recently in wheat, to assess DNA methylation changes upon salt stress in two cultivars with different tolerance to salt. Upon high salinity conditions DNA methylation alterations were observed in both cultivars which might be associated with the response and adaptation of wheat to salt stress [\n\t\t\t\tZhong et al., 2009].
\n\t\t\tUnlike the well characterized histone modification enzymes HATs, HDACs and HMTs, little is known regarding DNA methyltransferases and demethylases in association to stress. Ten putative DNA methyltransferases were characterized in rice and their expression examined in different developmental stages and under abiotic stress. OsCMT2 was found to be induced by cold and high salinity but not by drought. Conversely, OsCMT3 showed approximately a six- and four-fold reduction in mRNA accumulation in rice seedlings subjected to high salt and dehydration conditions, respectively [\n\t\t\t\tSharma et al., 2009]. In a recent study, the gene encoding the Arabidopsis DNA glycosylase ROS1 (REPRESSOR OF SILENCING 1)-now known as DML3 (DEMETER-LIKE protein 3) and involved in DNA demethylation-was indirectly implicated in the response to abiotic stress, as it was shown to be the target of the stress-responsive miRNA402 [\n\t\t\t\tKim et al., 2010].
\n\t\tFour major types of small RNAs have been identified in plants, namely, micro RNAs (miRNAs), transacting small interfering RNAs (ta-siRNAs), natural-antisense siRNAs (nat-siRNAs), and heterochromatic (hc-RNAs) siRNAs. Hc-siRNAs direct methylation of DNA sequences complementary to the siRNAs in a process known as RNA-directed DNA methylation (RdDM) and lead to gene silencing [\n\t\t\t\tChapman and Carrington, 2007; \n\t\t\t\tHenderson and Jacobsen. 2007]. MiRNAs, ta-siRNAs, and nat-siRNas function predominately at the post-transcriptional level through mRNA degradation and/or translational inhibition resulting in gene silencing, and miRNAs have been shown to also regulate gene expression through DNA methylation [\n\t\t\t\tWu et al., 2009; \n\t\t\t\tKhraiwesh et al., 2010].
\n\t\t\tSmall RNAs have essential functions in many aspects of plant growth and development [Liu et al., 2005; \n\t\t\t\tJones-Rhoades et al, 2006; \n\t\t\t\tVoinnet 2009; Mallory and Vaucheret, 2006; \n\t\t\t\tChen, 2009]. Furthermore, small RNAs have been shown to play key roles in the regulation of phytohormone signaling and the response to a variety of abiotic stresses [\n\t\t\t\tSunkar and Zhu 2004; \n\t\t\t\tSunkar et al., 2007; \n\t\t\t\tVoinnet 2008; Liu and Chen, 2009; \n\t\t\t\tCovarrubias and Reyes, 2010].
\n\t\t\tLocus-specific studies as well as large-scale transcriptome analyses have revealed numerous miRNAs that are conserved across species and are responsive to a broad spectrum of stresses. In the last several years the development of high-throughput sequencing technology has allowed for the discovery of ever more miRNAs including very low abundance or species-specific miRNAs. In this way a growing number of small RNAs has been detected that respond to abiotic (as well as biotic) stress both in dicots and monocots.
\n\t\t\tIn Arabidopsis, stress-related miRNAs were first detected in a library generated from small RNAs from seedlings exposed to various stresses (\n\t\t\t\tSunkar and Zhu, 2004). For example miR393, miR397b, and miR402 were found to be induced upon cold, drought and high salinity conditions as well as by ABA treatment. Follow-up studies with miR402 showed that miR402 overexpressing plants displayed reduced transcripts of the DNA demethylase DML3, implying miRNA-guided control through down-regulation of a DNA demethylase [\n\t\t\t\tKim et al., 2010].
\n\t\t\tAn siRNA derived from a pair of natural cis-antisense transcript composed of PYRROLINE-5-CARBOXYLATE DEHYDROGENASE(P5CDH) (sense), a stress-related gene, and SRO5 (antisense), a gene of unknown function, generates two types of siRNAs, 24-nt siRNA and 21-nt siRNA. These were found to down-regulate P5CDH by sequential cleavage of P5CDH mRNA after salt treatment leading to accumulation of the osmoprotectant proline and increased tolerance to salt stress [\n\t\t\t\tBorsani et al., 2005]. Stress- or ABA-inducible sense and antisense transcripts were also detected in the stress-inducible gene loci, RD29A and CYP707A1 [\n\t\t\t\tMatsui et al., 2008]. Transcriptome microarray analysis revealed numerous other miRNAs involved in abiotic stress both in Arabidopsis and poplar [\n\t\t\t\tLiu et al., 2008; \n\t\t\t\tLu et al., 2008]. Conserved miRNAs, such as miR397 and miR169, were up-regulated in both species under cold conditions, and species-specific stress responsive miRNAs were also detected.
\n\t\t\tMiRNA responsiveness to various abiotic stress factors has been demonstrated in cereals such as rice, wheat, maize and the model-plant of cereals, Brachypodium. For example drought and high salinity stress were found to induce several miRNAs in rice as determined by microarray analysis [\n\t\t\t\tZhao et al., 2009]. MiR169g was shown to be up-regulated in rice roots and shoots upon dehydration. Interestingly, the promoter of the miR169g gene was found to contain two dehydration responsive elements (DRE). Similar to miR169g, the rice miR169n gene was found to be induced at conditions of high salinity. A cis-acting ABA responsive element (ABRE) resides within the promoter of rice miR169n implying an ABA-mediated response to stress [\n\t\t\t\tZhao et al., 2009]. Notably, both miRNAs target a transcription factor, NF-YA, that has been shown to be down-regulated upon drought conditions [\n\t\t\t\tStephenson et al., 2007]. Recently, genome-wide profiling of miRNAs in rice revealed 29 novel miRNAs that were differentially expressed (11 down-regulated miRNAs and eight up-regulated) under drought [\n\t\t\t\tSunkar et al., 2008; \n\t\t\t\tZhou et al., 2010].
\n\t\t\t\n\t\t\t\t\n\t\t\t\tKantar et al. (2010), identified 28 new miRNAs in barley, of which Hvu-MIR156, Hvu-MIR166, Hvu-MIR171, and Hvu-MIR408 were shown to be induced under dehydration conditions. Microarray analysis in maize demonstrated that 34 miRNAs from 13 plant miRNA families exhibited substantial changes in expression after drought treatment of seedlings [Wei et al., 2009103]. MiR474 which targets a gene encoding proline dehydrogenase (PDH), an enzyme involved in the degradation of proline, was found to be up-regulated upon dehydration conditions. Proline is known to accumulate in plants as a protective mechanism against drought stress. Upon drought stress miR474 transcripts were increased, whereas PDH accumulation was reduced, suggestive of a miR474-dependent mechanism in regulating proline content under drought conditions in maize. Conversely, the expression of other maize miRNAs such as miR168, miR528, and miR167 was decreased and this probably resulted in increased expression of their target genes MAPK (MITOGEN ACTIVATED PROTEIN KINASE), POD (PEROXIDASE), and PLD (PHOSPHOLIPASE D), respectively. Interestingly, these genes contain an ABA responsive element and are involved in the ABA-induced stomatal movement and antioxidant defense in maize [Wei et al., 2009\n\t\t\t\t].
\n\t\t\tCold stress has also been shown to have a significant effect in the expression of a number of different miRNAs in cereals. Microarray analysis identified 18 rice miRNAs that were differentially expressed upon cold treatment of rice seedlings [\n\t\t\t\tLv et al., 2010]. 12 miRNAs corresponding to 10 different families exhibited significant down-regulation and 6 miRNAs corresponding to five families exhibited substantial up-regulation under cold. Four down-regulated rice miRNAs (miR1435, miR1876, miR1320, miR1884) were not present in Arabidopsis implying species-specific miRNas functions in the response to cold-stress. Six conserved families (miR156, miR166, miR169, miR171, miR319, miR444) are known to target genes encoding transcriptional factors such as homeodomain-leucine zipper proteins, scarecrow-like proteins, TCP family transcription factors and MADS-box proteins [Lu et al., 2008; Zhao et al., 2009]. The targets of rice miR319a/b and miR171a, were predicted to be the genes Os01g59660 and Os04g46860, respectively. Os01g59660 and Os04g46860 were induced by cold, whereas their cognate miRNAs were found to be down-regulated by cold. This inverse correlation between the expression of the miRNAs and their targets and the fact that the targets were validated by 5’RACE assays, strongly suggests miRNA-regulated responsiveness to cold stress [\n\t\t\t\tLv et al., 2010]. Interestingly, rice miR444 which is also down-regulated by cold-stress, targets two MADS-box proteins, MADS57 and MADS27 [Lu et al., 2008] which have been shown previously to be up-regulated under cold conditions [\n\t\t\t\tArora et al., 2007]. Most cold-responsive miRNAs were found to harbor cis-acting hormone-responsive elements in their 5’upstream regions, such as ABRE, and GARE (Gibberellin responsive element). For example, an ABRE element and two GARE elements were detected within the miR319 promoter implying ABA-mediated regulation of gene expression. In support to this a recent study showed that miR319 is down-regulated by ABA and up-regulated by GA, and a large number of other rice miRNAs are either induced or down-regulated by ABA and GA [\n\t\t\t\tLiu et al., 2009].
\n\t\t\tHigh throughput sequencing technology using the Solexa platform, uncovered 129 putative novel miRNAs in the model plant Brachypodium. 25 of the novel miRNAs as well as 3 conserved miRNAs (miR169e, miR172b and miR397) displayed significant alterations in gene expression in response to cold stress [\n\t\t\t\tZhang et al., 2009]. A subset of the novel cold-responsive miRNAs was found to be monocot-specific and another subset Brachypodium-specific. MiR169e, miR172 and miR397 and six of the novel predicted miRNAs were up-regulated under cold, whereas 19 novel miRNAs were down-regulated. Interestingly, miR397 is predicted to target laccases, enzymes involved in lignin biosynthesis and cell wall structure maintenance.
\n\t\t\tA recent study described the identification of a set of miRNAs from wheat that responded to heat stress as well as to the biotic-stress conditions of powdery mildew infection [\n\t\t\t\tXin et al, 2010]. Furthermore, by interrogating the recently deep-sequenced small RNA transcriptome of bread wheat, Yao et al. 2010\n\t\t\t\t identified a set of small non-coding RNAs with differential responses in a variety of stress conditions. For example siRNA 002061_0636_3054.1 shows down-regulation under conditions of increased heat, salinity and dehydration, whereas siRNA 005047_0654_19041.1 is substantially induced by cold.
\n\t\t\tSiRNAs have been also implicated in abiotic stress response in rice [\n\t\t\t\tYan et al., 2011]. Rice siR441 and siR446 accumulation was down-regulated by cold, drought, high salinity and by ABA treatment. Functional analysis showed that siR441 and siR446 knockdown mutants were more sensitive to drought, cold or salt treatment than the wild type, suggesting a role for siRNAs in rice tolerance to abiotic stress. The validated target of siR441 and siR446, MAIF1(encoding an F-box protein), was previously shown to be up regulated under abiotic stress conditions. In addition, transgenic rice plants with decreased accumulation of siR441 and siR446 had the same phenotype as MAIF1 overexpressing plants [Yan et al., 2010]. Together these observations point to a role for rice siR441 and siR446 in abiotic stress response through regulation of MAIF1.
\n\t\t\tGenome-wide studies of intraspecific hybrids and their parents, in Arabidopsis, have revealed major differences in the 24-nt siRNA levels between the two genomes which resulted in alterations in global DNA methylation and gene expression [Groszman et al., 2011]. Hybrid vigor is characterized by the superior performance of a hybrid over its parents in various traits, including stress tolerance, and this suggests that siRNA pathways may be associated with abiotic stress response in this phenomenon.
\n\t\t\tFinally, a recent report showed that siRNA biogenesis is crucial for protection against transgenerational retrotransposition under heat stress, in Arabidopsis [\n\t\t\t\tIto et al., 2011]. It is likely that such stress-related siRNA/retrotransposon effects will be revealed for cereal genomes as well.
\n\t\tAdverse environmental conditions may induce changes in the epigenetic state of genes which can be inherited over successive generations and these could play a role in stress adaptation [Paszkowski and Grossniklaus, in press].
\n\t\t\tExposure to stress can result in changes in DNA methylation patterns and genome instability. Studies on Arabidopsis and Pinus silvestris growing in the vicinity of the Chernobyl reactor area suggested an association between increased global genome methylation with genome stability and stress tolerance in response to irradiation [\n\t\t\t\tKovalchuk et al., 2003; \n\t\t\t\t2004]. An association between transgenerational changes in DNA methylation and stress tolerance was also reported in the progeny of plants exposed to different abiotic stresses [\n\t\t\t\tBoyko et al. 2010]. Arabidopsis plants were exposed to a wide spectrum of abiotic stresses including high salinity, UV-C, cold and heat as well as biotic stress. This resulted in higher homologous recombination frequency, increased global DNA methylation and higher stress tolerance in the untreated progeny. Moreover, in mutants defective in DICER-like genes, important for siRNA biosynthesis pathways, stress-induced homologous recombination frequency, DNA methylation and stress tolerance were impaired. These results suggested that stress-induced transgenerational responses require DNA methylation and the function of siRNA silencing pathways.
\n\t\t\tThe significance of induced genome changes in adaptation was examined also in rice [\n\t\t\t\tAkimoto et al., 2007]. Rice seeds were treated with 5-aza-deoxycytidine (inhibitor of cytosine methylation) and progeny after ten generations was screened to identify changes in DNA methylation by the MSAP and bisulfite assays. In one of the tested lines, line-2, DNA methylation was completely abolished in the gene coding region for the Xa21G gene encoding the Xa21-like protein. In wild type plants the XA21G promoter was methylated and there was no detectable expression of Xa21G, whereas in the line-2, Xa21G was expressed constitutively and the line was resistant to the pathogen race Xanthomonas\n\t\t\t\toryzae pv. oryzae, race PR. These results suggested that DNA methylation can be stably inherited and maybe associated with the plants adaptation to stressful environments.
\n\t\t\tWith the rapid progress in epigenetic research it is expected that further studies will emerge on the association of epigenetic states and transgenerational stress memory in more crop species.
\n\t\tGreat progress in the research of epigenetic regulation in response to abiotic stress has been accomplished in the last several years, especially in the model plant Arabidopsis. Changes in histone modifications and changes in the expression of genes encoding histone modifying enzymes, as well as changes in DNA methylation patterns and the effect of small RNAs have been shown to play critical roles in the response to abiotic stress at a gene-specific and genome-wide level. Similar studies have been performed in cereals and a growing number of reports on the epigenetic regulation during cereal plant development and in response to abiotic stress have accumulated. However, plenty more efforts are still required in order to fully characterize and understand this process. The completion of the two cereal genomes, rice and maize, and of the cereal/grass-model plant Brachypodium, as well as the rapid progress in the sequencing of wheat and barley, will contribute significantly to this endeavor. The detailed study of both the genetic and epigenetic components of this complex process is necessary to comprehend the molecular aspects of the abiotic stress response. Furthermore, understanding the molecular mechanisms underlying the association of epigenetic regulation and transgenerational stress memory will help us in establishing the potential adaptive significance of this process and could have significant implications in agriculture. Considering that cereals represent approximately 50% of total caloric intake worldwide (www.fao.org) and in view of the upcoming adverse changes of the global climate it is vital to delineate the molecular mechanisms by which such agronomically important crops manage to cope under conditions of stress. This could have important ramifications for agriculture as it would enable the generation of improved varieties with increased stress tolerance.
\n\t\tPhysiopathological mechanisms responsible for myocardial cell death (necrosis, apoptosis, autophagy, etc.) caused by coronary artery disease have been abundantly discussed over the past several decades. Acute myocardial infarction is a leading cause of sudden cardiac death among urban dwellers in North America and Europe. Clinical treatment of patients with coronary artery disease is focused on limiting the deleterious consequences that follow coronary artery occlusion; however, to do so it is fundamental to understand the mechanisms, at the molecular and cellular level, that are involved in cell death and survival. Existing knowledge has progressed massively over the years and useful clinical interventions, both pharmacologic and non-pharmacologic, are currently available to limit, but not abrogate, effects of ischemia. An important question that remains concerns the existence of “reperfusion-induced injury”; many adhere to the notion that significant cellular death can occur once blood flow is restored to an infarct-related artery. While definitive proof is lacking myocardial stunning, vascular no-reflow (perfusion deficit) and ventricular arrhythmias are often attributed to this form of cardiomyocyte loss after ischemia. The objective of the present chapter is to update current thinking on the question of lethal reperfusion injury and to summarize current treatments used to limit overall effects.
\nMyocardial ischemia is defined as the condition where coronary blood flow across the ventricular wall is insufficient to conserve steady-state metabolism. Acute disruption of the blood supply to any region of the heart causes cardiomyocyte injury and eventually cellular death depending on the duration of perfusion deficit. Cardiac cell injury is characterized to be either reversible (if reperfusion of the infarct-related artery can be instituted rapidly, ≤15 minutes), or irreversible (poor, or no, cellular survival even if blood flow is restored). Cardiomyocyte necrosis progresses as a transmural gradient across the ventricular wall, from endocardium to epicardium, in most animal models studied [1, 2]. Early development of necrosis in the subendocardium is probably related to higher oxygen requirements (due to greater contribution to myocardial contraction) of that layer compared to the subepicardium [3, 4, 5]; myocardial perfusion is coupled to myocardial oxygen consumption. Although we agree that progression of coronary heart disease and symptom phenotypes may differ in relation to sex this subject is beyond the scope of this review.
\nMyocardial ischemia initiates multiple changes in cardiomyocyte structure including marked swelling, development of contraction bands, mitochondrial calcification and membrane disruption; the pathobiology of cellular changes produced by ischemia have been characterized in earlier studies [6, 7, 8]. Different modes (apoptosis, autophagy, oncosis, and necrosis) of cellular injury have been described [9] and are discussed elsewhere [10]. The cardiomyocyte cytoskeleton (i.e. structure needed to maintain cellular morphology and physiology) is markedly altered by biochemical changes caused by disruption of oxygen and nutrient supply [11]. Cardiomyocyte death occurs with disruption of the cellular membrane and subsequent leakage of intracellular components into the extracellular fluid [12, 13, 14]. Irreversibly injured cardiomyocytes display small breaks in the plasmalemma along with cellular swelling and sarcolemmal blebbing [1]. Necrosis in non-cardiac cells is not well described but it is clear that other cell types within the myocardium (i.e. vascular endothelial and smooth muscle cells, nervous system cells, etc.) are affected by ischemia.
\nRestoration of blood flow to the perfusion bed of the infarct-related artery can limit damage to cardiomyocyte as long as reperfusion is instituted within a reasonable period. Indeed, this is the basis for widespread use of percutaneous coronary interventions for relief of symptoms in patients with coronary artery disease and is responsible for manifest reduction in mortality. Thousands of studies have examined the physiopathology of ischemia-reperfusion injury over the past half-century with the aim to elucidate pathways leading to cellular necrosis; increased knowledge gained from these studies has led to the realization that this is a complex and multi-faceted scenario.
\nIt is clear that restoration of blood flow to ischemic myocardium is the most effective treatment against myocyte necrosis [15, 16]. Timely opening of an infarct-related artery is essential as the amount of myocardium salvaged rapidly decreases when reperfusion interventions are delayed. Furthermore, reperfusion may itself cause further cellular damage; thus it is often viewed in the context of being a “double-edged sword” [17]. Studies have confirmed that reperfusion triggers abrupt metabolic, electrophysiologic, morphologic and functional changes. The term “lethal reperfusion injury” designates damage to viable cardiomyocytes caused after successful restoration of blood flow to the ischemic perfusion bed. Several possible forms of reperfusion injury such as coronary artery no-reflow, myocardial hibernation, myocardial stunning, ventricular arrhythmias, etc. have been advanced [18, 19]; however, definitive proof that reperfusion injury exists remains to be established. With that in mind, we believe that reperfusion might accelerate expression of injury produced by ischemia but does not itself cause de novo cardiomyocyte injury.
\nPhysiopathological mechanisms that produce reperfusion injury are complex and multifactorial; no specific mechanism has been shown to take precedence over others. In experimental animal models, the release of an acute coronary occlusion produces a prolonged hyperemic response particularly in the deeper myocardial layers (subendocardium > subepicardium); hyperemic responses vary depending on the duration of ischemia [20, 21, 22]. Reperfusion of the ischemic myocardium depends on arterial driving pressure and extravascular compressive forces; this is particularly important for the function of coronary collateral vessels that supply much needed oxygen and nutrients to surviving cardiomyocytes post-ischemia. As such, restoration of coronary blood flow in the infarct-related artery does not guarantee homogeneous perfusion of blood across the ventricular wall. Indeed, areas where blood flow is less than normal (i.e. no-reflow) are mostly associated with myocardial regions where injury is irreversible.
\nNo-reflow is caused by injury at the structural level (i.e. cell swelling, membrane gaps, etc.) [23, 24]; microvessels might be more resistant to short periods of ischemia compared to cardiomyocytes because their endothelial oxygen requirements are modest and they are in close proximity to oxygen supply. No-reflow does not precede tissue damage but follows it; furthermore, it does not expand myocardial infarct size (role in pathogenesis of tissue damage is considered to be minor) [25, 26]. However, it has been suggested to contribute to infarct expansion, ventricular dilatation and remodeling by limiting access of inflammatory cells to the ischemic zone to initiate cardiac repair [27, 28]. Microvessel damage is also manifest as hemorrhage due to abnormalities in vessel permeability [29].
\nNo-reflow occurs in patients with cardiovascular disease [30, 31]; pharmacotherapy appears to normalize ischemic zone perfusion and reduce mortality.
\nReperfusion injury is associated with depletion of high-energy phosphate stores, cellular swelling, increases in capillary permeability and reduced microvessel reactivity [32, 33, 34]. Restoration of blood flow to the ischemic myocardium mitigates myocardial injury; however, restoration of contractile function is not necessarily immediate. When blood supply to the heart is limited, myocardial contraction is restricted as described for the “smart heart theory” [35]. In normal myocardium, increases in metabolic demand due to intensification of myocardial work are met by regional increases in blood flow as well as increases in oxygen extraction [36]. Post-ischemic myocardial stunning and myocardial hibernation have been described in animals [37, 38] and patients [35, 39] and designate viable but chronically dysfunctional states [40]. Myocardial stunning refers to persistent (but reversible) contractile dysfunction [41, 42] produced by a relatively brief ischemic period [43]. Myocardial hibernation, on the other hand, refers to viable but chronically dysfunctional myocardium that may be related to poor resting perfusion [35], or general absence of perfusion abnormalities [44, 45] but the latter has not been clearly established [46, 47]. Recent findings suggest that repetitive ischemia, chronic stunning and hibernation are linked as a continuum [40]; in other words, stunned myocardium can progressively transform into hibernating myocardium. For both dysfunctional myocardial states, downregulation of contractile function might be a cellular adaptive mechanism to facilitate preservation of myocardial integrity and viability [35]. Perfusion-contraction matching may be key to myocardial hibernation but this may not be so for myocardial stunning; a number of review articles on this subject are available [48, 49, 50]. Whether contractile dysfunction can be reversed by improved revascularization in stunned or hibernating myocardium is moot after the formation of scar [40].
\nDevelopment of life threatening ventricular arrhythmias, which range from ventricular premature beats with long coupling intervals to ventricular fibrillation early after onset of reperfusion, also represent a form of reperfusion injury [51, 52]. Although the physiopathology causing ventricular arrhythmias during reperfusion is ill understood they are known to be initiated by complex cellular changes with regard to electrophysiological, metabolic and structural properties [53]; potential chemical mediators of arrhythmogenesis have been presented [54, 55]. In rat hearts subject to brief coronary artery occlusion (~5 minutes) followed by reperfusion severe ventricular arrhythmias occur [56]. However, in larger animal species, incidence of lethal ventricular arrhythmias increases when reperfusion is instituted within 30 minutes after coronary occlusion [57]. The overall incidence of ventricular arrhythmias decreases significantly when reperfusion follows longer durations of ischemia [58, 59].
\nStrategies designed to protect against myocardial injury caused by ischemia, or reperfusion have been extensively studied. In animal models reduction of infarct size is reported with the use of single, or multiple pharmacologicals; however, translation of cardioprotection to patients remains disappointing. Efficacy of interventions is dependent on a host of factors that include time of administration of treatment (i.e. during ischemia, at reperfusion, late reperfusion), duration of occlusion, reperfusion status, species, cell types and end targets (i.e. molecular, biochemical, etc.). In patients, cellular protection is more difficult; however, multi-target studies continue to attempt to limit cardiomyocyte injury. The presence of comorbidities also affects the cardioprotective capability of different treatments. Development of reliable interventions (i.e. pharmacologic, non-pharmacologic) remains an ongoing challenge; findings from basic science and clinical studies on understanding of mechanisms involved in cellular injury and death have been significant but more work is necessary.
\nFor more than 50 years a host of pharmacologic interventions have been employed to limit the extent of myocardial necrosis in animal models and clinical studies. Some cardioprotection has been reported for different manifestations of ischemic injury but no long-lasting protection has yet been afforded by any drug. Many different exogenously administered compounds, which act at different levels (i.e. cell membrane receptors, intracellular signaling pathways, platelet aggregation pathways, inflammation, etc.), have been tested, but results are highly variable. In patients with coronary artery disease/acute myocardial infarction, a “golden window of opportunity” may exist after onset of symptoms to attenuate ischemic injury [60]; however, to date most pharmacologic strategies to delay progression of ischemic injury have not shown great promise with regard to clinical outcomes. Potential reasons include problems regarding timing of drug administration and drug dosage as well as the heterogeneity of comorbidities within patient populations [61]. Recent studies have focused on use of pharmaceuticals that target molecular mechanisms and signal transduction at different cellular levels (i.e. cell membrane, mitochondria, etc.); however, translation of protection with pharmaceuticals that act by stimulating intracellular signaling pathways remains a challenge [62, 63]. While numerous pharmacologic compounds have been tested in animal models and humans to date, none offers protection greater than that afforded by ischemic conditioning (cf. below).
\nCurrent pharmacologic interventions targeting ischemia-reperfusion injury include use of beta-blockers; these drugs were among the first reported to delay progression of ischemic injury more than 40 years ago [64, 65, 66, 67]. Infarct limiting properties were mostly attributed to reductions in myocardial energy and oxygen consumption. More recently, the selective β1-adrenergic receptor antagonist, metoprolol, administered before reperfusion has been shown to inhibit neutrophil-platelet interactions and protect ischemic myocardium in patients [68]; other elements (i.e. neutrophil trafficking, formation of neutrophil-platelet co-aggregates, etc.) associated with neutrophil dynamics might also be involved [69, 70]. The role of neutrophils in ischemia-reperfusion injury is well established. Protection by metoprolol could be due to reduced microvessel plugging, or microvascular obstruction, by neutrophil-platelet plugs, or other inflammatory cell aggregates. Additionally, metoprolol could directly affect platelet aggregation but this remains to be proven.
\nPlatelet aggregation is a crucial factor for post-ischemic vessel re-occlusion in patients with coronary artery disease even after successful percutaneous coronary interventions. Activated platelets release potent chemotactic factors that stimulate formation of thrombus and microaggregates, which can cause microvascular obstruction underperfusion of the ischemic myocardium [71, 72, 73]. Anti-platelet and anti-thrombotic interventions provide significant protection against ischemic injury; though poorly understood, protection is probably mediated through pathways that are similar to those activated by ischemic conditioning [74, 75]. In animal studies, platelet aggregation inhibitors such as ticagrelor (P2Y12 receptor blocker) markedly reduce myocardial infarct size that effectively translates to improved cardiac contractile function [76, 77, 78]. However, this is not necessarily true for drugs such as clopidogrel (thienopyridine—class of platelet aggregation blockers) which efficiently limits platelet aggregation but does not influence ischemic myocardial injury [75, 79]. Protection probably occurs through adenosine-related mechanisms more than anti-platelet aggregation actions [80, 81]. Other classes of platelet activation blockers (i.e. glycoprotein 2b/3a blockers, etc.) have also reported significant anti-necrosis and anti-arrhythmic effects [82, 83]; however, cardioprotective efficacy of these agents may be limited with extended ischemic durations [84].
\nMitochondria are considered an important target for reduction of ischemia-reperfusion injury [85]; mitochondria are responsible for generation of high-energy phosphates and contribute to ion homeostasis, formation of reactive oxygen species and Ca2+ handling. Myocardial ischemia-reperfusion markedly alters mitochondrial function that can ultimately lead to cell death. Recent studies have focused on a large conductance pore of the mitochondrial membrane—mitochondrial transition pore (mPTP) located in the inner mitochondrial membrane, which opens at onset of reperfusion leading to osmotic swelling and a decrease in oxidative phosphorylation. In the heart, mPTP inhibitors have been studied in animal models of ischemia-reperfusion injury; several have been reported to be cardioprotective [86, 87, 88]. In clinical studies, pharmacologicals that target mitochondrial function have not had positive results with respect to limiting ischemic injury [89, 90, 91, 92].
\nTo date, no single pharmacologic compound has achieved a level of cardioprotection greater than that obtained by ischemic conditioning. In an attempt to enhance protection, new initiatives have begun to examine the efficacy of combined treatments (i.e. drug plus ischemic conditioning) that target different cellular mechanisms (i.e. insulin signaling, energy metabolism, etc.) affected by ischemia and reperfusion. For instance, combined glucose-insulin-potassium-exenatide with remote conditioning reduced infarct size in a large animal model [93]. In a combined basic science and clinical study from Hauerslev’s laboratory, it was shown that treatment with glyceryl trinitrate (nitric oxide donor) in combination with remote conditioning abolished the individual protective effects obtained with either intervention alone [94]. Similar results have been reported in patients [95] but not all data are consistent [96]. In a canine study from our laboratory, we reported that ischemic conditioning (classic and delayed) significantly reduced ischemic injury; however, combined treatment with EMD 87580 (NHE1 blocker) and ischemic conditioning did not affect the level of cardioprotection [97]. These findings suggest that the level of protection possible with any intervention is limited (i.e. not additive). Underlying explanations for these controversial findings need to be resolved with further investigation.
\nIn the clinical setting, percutaneous coronary interventions (PCI) remain the benchmark to restore perfusion in the infarct related artery; however, efficacy of these interventions is variable. An unfortunate aspect of PCI that is often underestimated is the release of micro particulate debris and platelet micro-aggregates that can cause additional myocardial injury downstream at the level of the microvasculature [98, 99, 100]. As a result, mechanical thrombectomy (i.e. passive aspiration, active mechanical catheters, etc.) is being developed to limit untoward effects of distal embolization by atherothrombotic debris [101, 102, 103].
\nKeeping in mind that “time is muscle” it is clear that any delay in onset of treatment considerably influences overall success. Combined pharmacotherapy with mechanical reperfusion (i.e. facilitated PCI) is being tested to improve clinical outcomes [104, 105].
\nCardiac regeneration therapies (i.e. cardiomyocyte transplantation, biocompatible matrices, etc.) to repair damaged myocardium is another promising intervention to restore post-ischemic cardiac dysfunction (cf. recent review from Kingma [106]). Basic studies designed to better understand underlying mechanisms are ongoing; however, many limitations (i.e. rejection of transplanted cells, presence of scar, poor vascularization, tumor formation, myocardial location, etc.) underscore initial optimism afforded to these interventions for improvement of ventricular function.
\nCardiac conditioning (also organ conditioning) is a promising intervention that may eventually prove to be useful for protection of ischemic myocardium (or other organs) in patients; this intervention was first described as ischemic preconditioning more than 30 years ago [107]. Since then, more than 8000 studies have consistently reported protection against necrosis, ventricular dysrhythmias and myocardial contractile dysfunction in experimental animal and in clinical studies [108, 109, 110, 111]. At the moment, the clinical usefulness of ischemic conditioning as a preventive strategy for tissue protection remains controversial; the presence of multiple comorbidities may be important [112, 113] but their effect may be overcome depending on the scale of stimulus that is used to trigger cytoprotective pathways [114].
\nIn the original ischemic preconditioning study by Murry and colleagues, dog hearts were exposed in situ to brief, repetitive non-lethal cycles of ischemia-reperfusion prior to a prolonged ischemic event [107]. Development of myocardial necrosis was initially delayed and protection was transient depending on the duration of coronary occlusion. An essential requirement for protection against ischemic injury by this intervention is reperfusion of the ischemic region [18]. Publication of this landmark paper paved the way for numerous studies not only with respect to the heart on potential contributory endogenous cellular protection pathways. To date, anesthetic drugs, other pharmacologic or remote interventions, have all demonstrated ischemic conditioning (pre-, per-, post-conditioning) mediated protection. A cross-tolerance phenomenon could also be involved since many triggers for intracellular signaling pathway-mediated protection are similar [115, 116, 117]. Prospective contributory mechanisms to conditioning mediated protection have been reviewed elsewhere [109, 118, 119, 120].
\nThe principal difficulty with ischemic conditioning strategies is the inability to translate success in animal models to the clinical setting to improve overall outcomes. A major liability is the requirement to physically apply an ischemic conditioning intervention prior to onset of acute ischemia (incapacity to determine its occurrence). The observation that remote ischemic conditioning could provide robust protection against ischemic injury is promising [121]. In their initial canine cardiac ischemia-reperfusion injury study, Przyklenk and coworkers pretreated a region of the heart with brief non-lethal cycles of repetitive ischemia and reperfusion and showed marked protection (i.e. reduced infarct size) of a distant adjacent region in the same heart. Since the publication of this study, others have reported significant limitation of different manifestations of ischemic injury in various experimental models [122]. A crucial question concerns the mechanism(s) by which cytoprotective signals are transported from conditioned tissue to the distant target tissue. Blood or perfusate-borne humoral factors, neuronal stimulation and transmission as well as systemic alteration of circulating immune cells have all been proposed [123, 124, 125]. Findings, in animal models, from our laboratory tend to favor the humoral hypothesis; in dogs subject to acute ischemia-reperfusion injury, protection was not reversed after either pharmacologic or surgical decentralization of the intrinsic cardiac nervous system [126]. On this basis we hypothesized that inter-organ crosstalk did not require an intact autonomic nervous system. Stimulation of the nervous system, either locally or within cardiac ganglia could potentially stimulate release of cardioprotective substances (chemokines, leukotrienes, microRNA, etc.) into the bloodstream to initiate downstream effects [109, 127, 128, 129]. Interestingly, activation of the sympathetic nervous system is not required for classical ischemic conditioning, however, it is essential for second-window, or delayed, conditioning [130, 131].
\nA key element for protection by remote conditioning is restoration of blood flow to affected tissues [111, 132]; without it transfer of triggering mediators would be constrained. In humans, it is not clear that conditioning strategies afford significant protection (against endothelial dysfunction, increased permeability, structural alterations, etc.) at the level of the microcirculation in the deeper myocardial tissue layers [115, 133, 134]. Nonetheless, improved myocardial perfusion with remote conditioning may occur based on findings of higher TIMI (thrombosis in myocardial infarction) scores, myocardial blush grade and coronary reserve in cardiac patients. Restoration of blood flow to the deeper layers of the myocardial wall is a crucial risk factor for ventricular remodeling and major adverse cardiac events [135, 136, 137].
\nIn the clinical setting, results with this intervention (i.e. repeated arm or leg ischemia-reperfusion) are mixed; studies report either manifest cardioprotection [138, 139], no benefit [18, 140, 141] or exacerbation of injury [112, 142]. Failure to provide protection by remote conditioning in patients may be associated with the use of anesthetics such as propofol that abrogates protection [18]; volatile anesthetics are mostly recommended for at-risk cardiac patients [143, 144]. In proof-of-concept studies, other forms of remote conditioning, such as remote ischemic perconditioning (intervention performed during evolving myocardial infarction) have reported protection against tissue injury, ST-segment resolution and biomarker release in animal models and patients [145, 146, 147].
\nPathogenesis of lethal reperfusion injury remains to be established; the principle that reperfusion injury contributes to post-ischemic myocardial dysfunction is generally accepted but definitive evidence for its existence is lacking. While evaluation of the nature of cellular changes produced by ischemia and subsequent reperfusion has produced significant novel insights it is unclear that cardiomyocytes are the only cell types (within the myocardium) that are at risk of further injury. Of principle importance is that interventions to limit myocardial injury be instituted at the time of, or in conjunction with other reperfusion strategies. Pharmacologic compounds currently being used in the clinical setting delay, at best, short-term progression of cellular injury; long-term effects of these treatments in large animal ischemia-reperfusion injury models have not been properly investigated. The concept of a “magic bullet” intervention remains utopic, at present, considering the complexity of physiopathological mechanisms involved in cell death and myocardial remodeling. Utilization of exogenous interventions such as ischemic conditioning in combination with pharmacologic treatments remains a significant challenge. Further investigations into combination therapy, particularly in longer-term studies should be envisaged; consideration should also be paid to the existence of comorbidities within the patient population since overall efficacy of any treatment option will be affected.
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