Bivalent histone modifications during tooth development

Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4trimethylation（H3K4me3） and histone H3 lysine 27 trimethylation（H3K27me3） epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5 B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction（qP CR） analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial–temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5 B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.

Histone modifications dictate specific biological readouts

The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-35 residues in length and rich in basic amino acids. These tails extending from the surface of nucleosome play an important role in folding of nucleosomal arrays into higher order chromatin structure, which plays an important role in eukaryotic gene regulation. The amino terminal tails protruding from the nuclesomes get modified by the addition of small groups such as methyl, acetyl and phosphoryl groups. In this review, we focus on these complex modi- fication patterns and their biological functions. Moreover, these modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a ＂histone code＂ read by other proteins to control the structure and/or function of the chromatin fiber. Errors in this histone code may be involved in many human diseases especially cancer, the nature of which could be therapeutically exploited. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences.

H2A.Z Represses Gene Expression by Modulating Promoter Nucleosome Structure and Enhancer Histone Modifications in Arabidopsis

Deposition of the histone variant H2A.Z at gene bodies regulates transcription by modifying chromatin accessibility in plants. However, the role of H2A.Z enrichment at the promoter and enhancer regions is unclear, and how H2A.Z interacts with other mechanisms of chromatin modification to regulate gene expression remains obscure. Here, we mapped genome-wide H2A.Z, H3K4me3, H3K27me3, Pol II, and nucleosome occupancy in Arabidopsis inflorescence. We showed that H2A.Z preferentially associated with H3K4me3 at promoters, while it was found with H3K27me3 at enhancers, and that H2A.Z deposition negatively correlated with gene expression. In addition, we demonstrated that H2A.Z represses gene expression by establishing low gene accessibility at ＋1 nucleosome and maintaining high gene accessibility at -1 nucleosome. We further showed that the high measures of gene responsiveness correlate with the H2A.Z-associated closed ＋1 nucleosome structure. Moreover, we found that H2A.Z represses enhancer activity by promoting H3K27me3 and preventing H3K4me3 histone modifications. This study provides a framework for future studies of H2A.Z functions and opens up new aspects for decoding the interplay between chromatin modification and histone variants in transcrip- tional control.

Histone modifications and their regulatory roles in plant development and environmental memory

Plants grow in dynamic environments where they receive diverse environmental signals.Swift and precise control of gene expression is essential for plants to align their development and metabolism with fluctuating surroundings.Modifications on histones serve as histone code" to specify chromatin and gene activities.Different modifications execute distinct functions on the chromatin,promoting either active transcription or gene silencing.Histone writers,erasers,and readers mediate the regulation of histone modifications by catalyzing,removing,and recognizing modifications,respectively.Growing evidence indicates the important function of histone modifications in plant development and environmental responses.Histone modifications also serve as environmental memory for plants to adapt to environmental changes.Here we review recent progress on the regulation of histone modifications in plants,the impact of histone modifications on environment-controlled developmental transitions including germination and flowering,and the role of histone modifications in environmental memory.

Dynamic regulation of DNA methylation and histone modifications in response to abiotic stresses in plants

DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants.Dynamic changes in gene expression levels can result from changes in DNA methylation and histone modifications.In the last two decades,how epigenetic machinery regulates abiotic stress responses in plants has been extensively studied.Here,based on recent publications,we review how DNA methylation and histone modifications impact gene expression regulation in response to abiotic stresses such as drought,abscisic acid,high salt,extreme temperature,nutrient deficiency or toxicity,and ultraviolet B exposure.We also review the roles of epigenetic mechanisms in the formation of transgenerational stress memory.We posit that a better understanding of the epigenetic underpinnings of abiotic stress responses in plants may facilitate the design of more stress-resistant or-resilient crops,which is essential for coping with global warming and extreme environments.

Intracellular HSP70L1 inhibits human dendritic cell maturation by promoting suppressive H3K27me3 and H2AK119Ub1 histone modifications

Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.

Epigenetic modifications and metabolic memory in diabetic retinopathy:beyond the surface

Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.

Genome-wide profiling of histone H3 lysine 27 trimethylation and its modification in response to chilling stress in grapevine leaves

Histone H3 lysine 27 trimethylation(H3K27me3) is a histone modification associated with transcriptional repression. However, insights into the genome-wide pattern of H3K27me3 in grapevines are limited. Here, anti-H3K27 chromatin immunoprecipitation(ChIP), high-throughput sequencing, and transcriptome analysis were performed using leaves of Vitis amurensis. The leaves were treated at 4°C for 2 h and 24 h and used to investigate changes in H3K27me3 under chilling treatment. The results show that H3K27me3 is well-distributed both in gene regions(-50%) and in the intergenic region(-50%) in the grapevine genome(Vitis vinifera ‘Pinot Noir PN40024'). H3K27me3 was found to be localized in8 368 annotated gene regions in all detected samples(leaves at normal temperature and under chilling treatments) and mainly enriched in gene bodies with the adjacent promoter and downstream areas. The short-term chilling treatments(4°C for 2 h) induced 2 793 gains and 305losses in H3K27me3 modification. Subsequently, 97.3% of the alterations were restored to original levels after 24 h treatment. The ChIP-qPCR for five differential peaks showed similar results to the data for ChIP-seq, indicating that the chilling-induced H3K27me3 modification is reliable.Integrative analysis of transcriptome and ChIP-seq results showed that the expression of H3K27me3 target genes was significantly lower than those of non-target genes, indicating transcriptional repression of H3K27me3 in grapevine leaves. Furthermore, histone methylation alterations were detected in 82 genes and were related to either repression or activation of their expression during chilling stress. The findings provide the genome-wide H3K27me3 patterns in grapevines and shed light on uncovering its regulation in chilling stress responses.

Role of the histone methyltransferases Ezh2 and Suv4-20h1/Suv4-20h2 in neurogenesis

Mechanisms regulating neurogenesis involve broad and complex processes that represent intriguing therapeutic targets in the field of regenerative medicine.One influential factor guiding neural stem cell proliferation and cellular differentiation during neurogenesis are epigenetic mechanisms.We present an overview of epigenetic mechanisms including chromatin structure and histone modifications;and discuss novel roles of two histone modifiers,Ezh2 and Suv4-20h1/Suv4-20h2(collectively referred to as Suv4-20h),in neurodevelopment and neurogenesis.This review will focus on broadly reviewing epigenetic regulatory components,the roles of epigenetic components during neurogenesis,and potential applications in regenerative medicine.

Improving TRAIL-induced apoptosis in cancers by interfering with histone modifications

Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription.In this review,we provide an overview of recent studies on the role of histone modifications in carcinogenesis.Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)are well-considered as promising anti-tumour therapies,we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers.In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.

Targeting epigenetic mechanisms in amyloid-β-mediated Alzheimer’s pathophysiology:unveiling therapeutic potential

Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

Epigenetic control on transcription of vernalization genes and whole-genome gene expression profile induced by vernalization in common wheat

Vernalization is necessary for winter wheat to flower.However,it is unclear whether vernalization is also required for spring wheat,which is frequently sown in fall,and what molecular mechanisms underlie the vernalization response in wheat varieties.In this study,we examined the molecular mechanisms that regulate vernalization response in winter and spring wheat varieties.For this purpose,we determined how major vernalization genes(VRN1,VRN2,and VRN3)respond to vernalization in these varieties and whether modifications to histones play a role in changes in gene expression.We also identified genes that are differentially regulated in response to vernalization in winter and spring wheat varieties.We found that in winter wheat,but not in spring wheat,VRN1 expression decreases when returned to warm temperature following vernalization.This finding may be associated with differences between spring and winter wheat in the levels of tri-methylation of lysine 27 on histone H3(H3K27me3)and tri-methylation of lysine 4 on histone H3(H3K4me3)at the VRN1 gene.Analysis of winter wheat transcriptomes before and after vernalization revealed that vernalization influences the expression of several genes,including those involved in leucine catabolism,cysteine biosynthesis,and flavonoid biosynthesis.These findings provide new candidates for further study on the mechanism of vernalization regulation in wheat.

Pig H3K4me3,H3K27ac,and gene expression profiles reveal reproductive tissue-specific activity of transposable elements

Regulatory sequences and transposable elements(TEs)account for a large proportion of the genomic sequences of species;however,their roles in gene transcription,especially tissue-specific expression,remain largely unknown.Pigs serve as an excellent animal model for studying genomic sequence biology due to the extensive diversity among their wild and domesticated populations.Here,we conducted an integrated analysis using H3K27ac ChIP-seq,H3K4me3 ChIP-seq,and RNA-seq data from 10 different tissues of seven fetuses and eight closely related adult pigs.We aimed to annotate the regulatory elements and TEs to elucidate their associations with histone modifications and mRNA expression across different tissues and developmental stages.Based on correlation analysis between mRNA expression and H3K27ac and H3K4me3 peak activity,results indicated that H3K27ac exhibited stronger associations with gene expression than H3K4me3.Furthermore,1.45%of TEs overlapped with either the H3K27ac or H3K4me3 peaks,with the majority displaying tissue-specific activity.Notably,a TE subfamily(LTR4C_SS),containing binding motifs for SIX1 and SIX4,showed specific enrichment in the H3K27ac peaks of the adult and fetal ovaries.RNA-seq analysis also revealed widespread expression of TEs in the exons or promoters of genes,including 4688 TE-containing transcripts with distinct development stage-specific and tissue-specific expression.Of note,1967 TE-containing transcripts were enriched in the testes.We identified a long terminal repeat(LTR),MLT1F1,acting as a testis-specific alternative promoter in SRPK2(a cell cycle-related protein kinase)in our pig dataset.This element was also conserved in humans and mice,suggesting either an ancient integration of TEs in genes specifically expressed in the testes or parallel evolutionary patterns.Collectively,our findings demonstrate that TEs are deeply embedded in the genome and exhibit important tissue-specific biological functions,particularly in the reproductive organs.

Research Progress of Epigenetics in Liver Cancer

Epigenetic changes are changes in gene expression by regulating gene transcription and translation without changing the nucleotide sequence of the genome. Although the genome itself changes during the occurrence and development of most malignant tumors, recent studies have found that epigenetic changes also play an important role in the occurrence and development of tumors. Epigenetic modification mainly includes DNA methylation, histone modification and miRNA regulation. This review focuses on the role and mechanism of epigenetic modification in the occurrence, metastasis and invasion of hepatocellular carcinoma (HCC), and summarizes the latest methods for the treatment of HCC by restoring dysregulated epigenetic modification. It provides a theoretical basis for revealing the pathogenesis of liver cancer and developing new methods of diagnosis and treatment.

Histone methylation in pancreatic cancer and its clinical implications

Pancreatic cancer(PC)is an aggressive human cancer.Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level,thus making epigenetics a promising research path in studies of PC.Histone methylation is one of the most complicated types of epigenetic modifications and has proved crucial in the development of PC.Histone methylation is a reversible process regulated by readers,writers,and erasers.Some writers and erasers can be recognized as potential biomarkers and candidate therapeutic targets in PC because of their unusual expression in PC cells compared with normal pancreatic cells.Based on the impact that writers have on the development of PC,some inhibitors of writers have been developed.However,few inhibitors of erasers have been developed and put to clinical use.Meanwhile,there is not enough research on the reader domains.Therefore,the study of erasers and readers is still a promising area.This review focuses on the regulatory mechanism of histone methylation,and the diagnosis and chemotherapy of PC based on it.The future of epigenetic modification in PC research is also discussed.

Application of histone modification in the risk prediction of the biochemical recurrence after radical prostatectomy

The role of histone modifications in the development and progression of cancer remains unclear. Here,we gave an investigation of the relationship between the various histone modifications and the risk prediction of the biochemical recurrence after radical prostatectomy （RP）. Histone 3 lysine 4 dimethylation （H3K4diMe）,trimethylation （H3K4triMe）,lysine 36 trimethylation （H3K36triMe）,histone 4 lysine 20 trimethylation （H4K20triMe）and acetylation of histome 3 lysine 9 （H3K9Ac） were evaluated using immnuohistochemistry coupled with the tissue microarray technique in 169 primary prostatectomy tissue samples. Recursive partitioning analysis （RPA） was used to analyze the data. Through global histone modification analysis in patients who underwent radical prostatectomy,we found that H3K4triMe can predict the risk of the biochemical recurrence for the low grade prostate cancer （Gleason score≤6） after RP. In the case of high grade prostate cancer （Gleason score≥7）,H4K20triMe and H3K9Ac accompanying with the pre-operation prostate-specific antigen （PSA） level could also predict the risk of the biochemical recurrence after RP. In combination with the Gieason score and pre-operation PSA level,the acetylation and methylation of histones H3 and H4 can predict the biochemical recurrence of the prostate cancer following RP.

Brownian dynamics simulation of the cross-talking effect among modified histones on conformations of nucleosomes

Using Brownian dynamics simulation, we studied the effect of histone modifications On conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows the dynamic behaviour that its conformation can switch between a state with nearly all of the histones being wrapped by DNA and a state with nearly all of the histones being unwrapped by DNA, thus involving the ＂cross-talking＂ interactions among the histones. Each state can stay for a sufficiently long time. These conformational states are essential for gene expression or gene silence. The simulation also shows that these conformational states can be inherited by the daughter DNAs during DNA replication, giving a theoretical explanation of the epigenetic phenomenon.

Histone methylation and acethylation contribute to rifampin-mediated induction of CYP3A4 through the interactions between PXR and NCOA6/p300

OBJECTIVE CYP3A4 is one of the majordrug-metabolizing enzymes in humans and is responsible for the metabolism of over 50%of the clinically used drugs.Many drugs have been proved to induce the expression of CYP3A4,which usually causes drug-drug interactions and adverse reactions.The induction by numerous inducers shows significant interindividual differ ence but genetic factors can not totally explain or esti mate the difference.Recently,Epigenetic factors have been pointed out to contribute to that difference.Since histone methylation and acethylation are important parts of epigenetics,this study aimed to explore the role o active histone marks(H3K4me3,H3 acethylation)and inactive histone mark(H3K27me3)in rifampin-induced expression of CYP3A4 in LS174T cells.METHODS Chromatin immunoprecipitation(ChI P)assay was utilized to determine the levels of histone modifications in CYP3A4 promoter.RNA interference and Co-immunopre cipitation(Co-IP)assays were performed to determine the role of PXR and interactions between PXR and his tone methyltransferase/acetylase.RESULTS We found that the induction of CYP3A4 m RNA by rifampin treat ment(10μmol·L-1)in LS174T cells was accompanied by increased levels of H3K4me3 and H3 acethylation and decreased level H3K27me3 in CYP3A4 promoter Besides,enhanced recruitment of NCOA6,a coactivato of multiple nuclear receptors and transcription factors that is associated with H3K4 methyltransferase,and p300,a histone acetylase,were observed in CYP3A4promoter.To reveal the relationship between PXR activa tion and histone methylation/acethylation,gene silence was performed by sh RNA transfection.Knockdown o PXR expression not only removed the induction o CYP3A4,but also eliminated the recruitment of NCOA6and p300 and the decreased levels of H3K4me3 and H3acethylation in CYP3A4 promoter.Moreover,co-immuno cipitation(Co-IP)assay showed that interactions between PXR and NCOA6/p300 were occurred upon rifampin stimulation.CONCLUSION Histone methylation and acethylation contribute to rifampin-mediated induction of CYP3A4 through the interactions between PXR and histone methyltransferase/acetylase.

The circular RNA Rap1b promotes Hoxa5 transcription by recruiting Kat7 and leading to increased Fam3a expression,which inhibits neuronal apoptosis in acute ischemic stroke

Circular RNAs can regulate the development and progression of ischemic cerebral disease.However,it remains unclear whether they play a role in acute ischemic stroke.To investigate the role of the circular RNA Rap1b(circRap1b)in acute ischemic stroke,in this study we established an in vitro model of acute ischemia and hypoxia by subjecting HT22 cells to oxygen and glucose deprivation and a mouse model of acute ischemia and hypoxia by occluding the right carotid artery.We found that circRap1b expression was remarkably down-regulated in the hippocampal tissue of the mouse model and in the HT22 cell model.In addition,Hoxa5 expression was strongly up-regulated in response to circRap1b overexpression.Hoxa5 expression was low in the hippocampus of a mouse model of acute ischemia and in HT22-AIS cells,and inhibited HT22-AIS cell apoptosis.Importantly,we found that circRap1b promoted Hoxa5 transcription by recruiting the acetyltransferase Kat7 to induce H3K14ac modification in the Hoxa5 promoter region.Hoxa5 regulated neuronal apoptosis by activating transcription of Fam3a,a neuronal apoptosis-related protein.These results suggest that circRap1b regulates Hoxa5 transcription and expression,and subsequently Fam3a expression,ultimately inhibiting cell apoptosis.Lastly,we explored the potential clinical relevance of circRap1b and Hoxa5 in vivo.Taken together,these findings demonstrate the mechanism by which circRap1b inhibits neuronal apoptosis in acute ischemic stroke.

Epigenetics of gastroenteropancreatic neuroendocrine tumors:A clinicopathologic perspective

Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEPNET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microR NA and long non-coding RNA(lncR NA) differential expression profiles that are distinctive of GEPNETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.