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histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury

Science China(Life Sciences) 2023年第6期66卷 1264-1279页

作者： Le Ni Bowen Lin Yanping Zhang Lingjie Hu Jianghua Lin Fengmei Fu Meiting Shen Can Li Lei Chen Jian Yang Dan Shi Yi-Han Chen Department of Cardiology Shanghai East HospitalTongji University School of MedicineShanghai200120China Key Laboratory of Arrhythmias of the Ministry of Education of China Shanghai East HospitalTongji University School of MedicineShanghai200120China Department of Vascular and Cardiology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025China Jinzhou Medical University Liaoning121000China Shanghai Frontiers Science Center of Nanocatalytic Medicine Shanghai200092China Department of Pathology and Pathophysiology Tongji University School of MedicineShanghai200092China Research Units of Origin and Regulation of Heart Rhythm Chinese Academy of Medical SciencesShanghai200092China

histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion(I/R)injury.However,a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established.Here,we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury.Disease-specific histone mark alterations were mainly found in H3K27me3-,H3K27ac-,and H3K4me1-marked regions 24 and 48 h after I/R.Genes differentially modified by H3K27ac,H3K4me1 and H3K27me3 were involved in immune response,heart conduction or contraction,cytoskeleton,and angiogenesis.H3K27me3 and its methyltransferase polycomb repressor complex 2(PRC2)were upregulated in myocardial tissues after I/R.Upon selective inhibition of EZH2(the catalytic core of PRC2),the mice manifest improved cardiac function,enhanced angiogenesis,and reduced fibrosis.Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro.This study delineates a landscape of histone modifications in myocardial I/R injury,and identifies H3K27me3 as a key epigenetic modifier in I/R process.The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.

关键词： histone modification myocardial ischemia/reperfusion EZH2 H3K27me3 angiogenesis

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histone modification regulates low-density lipoprotein receptor pre-mRNA alternative splicing

Histone modification regulates low-density lipoprotein recep...

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中国神经科学学会第十二届全国学术会议

作者： Ya-Na PANG Jin-Feng ZHAO Yuan-Kun DONG Ze-Ping HE Yang GAO Ce ZHANG Department of Physiology Shanxi Medical University Physical Education Institute of Shanxi University

Objective Low-density lipoprotein receptor(LDLR) is very important in lipid metabolism, which can clear most cholesterol in plasma,and abnormal lipid metabolism can cause diseases such as cerebral ischemia. Recent studies showed that alternative splicing(AS) of LDLR pre-mRNA can be altered by hypercholesteremia in vitro, LDLR-△Exon4 and LDLR-△Exon12 expressions were increased by cholesterol-inducible, but the mechanism is unknown. There is increasing evidence that epigenetic mechanisms, particularly histone modifications play an important role in AS. Currently, histone modification affects AS of pre-mRNA is mainly two mechanisms: kinetic model and recruitment model, one of important recruitment model regulating AS consists of trimethylation of histone H3 at lysine thirty-sixth(H3 K36 me3), chromatin binding protein(MRG15), and the polypyrimidine tract-binding protein(PTB). Studies have shown that LDLR is the target gene of PTB. The present study is to explore the mechanism of histone modification in LDLR pre-mRNA AS. Methods By establishing a high cholesterol model it was validated that LDLR-△Exon4 and LDLR-△Exon12 expressions were increased by cholesterol-inducible. The effect of cholesterol on H3 K36 me3 level of LDLR was identified by chromatin immunoprecipitation. By overexpression plasmid transfection, RNA interference(i RNA) and RT-PCR, it was measured that H3 K36 me3 and MRG15 both affect AS of LDLR. Results(1) LDLR-△Exon4 and LDLR-△Exon12 expressions were increased by cholesterol-inducible in Hep G2 cells.(2) The level of H3 K36 methylation around LDLR exon 4 or 12 was increased by cholesterol-inducible.(3) Over expression of MRG15 and H3 K36 me3 methyltransferase in cells causes LDLR-△Exon4 and LDLR-△Exon12 increased expression, the result is opposite when H3 K36 methyltransferase and MRG15 reduced expression by i RNA. Conclusion When the plasma cholesterol is high,H3 K36 me3 can be recognized and combined with MRG15 recruiting PTB,which binds to silencing elements around exon 4 or 12, to regulate altern

关键词： Hypercholesterolemia LDLR alternative splicing histone modification recruitment model

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

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Horticultural Plant Journal 2023年第3期9卷 496-508页

作者： Zhenfei Zhu Qingyun Li Duncan Kiragu Gichuki Yujun Hou Yuanshuang Liu Huimin Zhou Chen Xu Linchuan Fang Linzhong Gong Beibei Zheng Wei Duan Peige Fan Qingfeng Wang Haiping Xin Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture Core Botanical Gardens/Wuhan Botanical GardenChinese Academy of SciencesWuhanHubei430074China Sino-Africa Joint Research Center Chinese Academy of SciencesWuhanHubei430074China Key Laboratory of Plant Resources Institute of BotanyChinese Academy of ScienceBeijing100093China Institute of Fruit and Tea Hubei Academy of Agricultural SciencesWuhanHubei430064China University of Chinese Academy of Sciences Beijing100049China Wuhan Academy of Agricultural Sciences WuhanHubei430074China

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.

关键词： Vitis amurensis histone modification H3K27me3 Chilling stress

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Computational inference of mRNA stability from histone modification and transcriptome profiles

Computational inference of mRNA stability from histone modif...

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第五届全国生物信息学与系统生物学学术大会暨国际生物信息...

作者： Chengyang Wang Rui Tian Qian Zhao Han Xu Clifford A.Meyer Cheng Li Yong Zhang Xiaole Shirley Liu Department of Bioinformatics School of Life Science and TechnologyTongji University Department of Biostatistics and Computational Biology Dana-Farber Cancer InstituteHarvard school of Public Health450 Brookline AveBostonMA02215USA

histone modifications play important roles in regulating eukaryotic gene expression and have been used to model expression levels.Here,we present a regression model to systematically infer mRNA stability by comparing transcriptome profiles with ChlP-seq of H3K4me3,H3K27me3 and H3K36me3.The results from multiple human and mouse cell lines show that the inferred unstable mRNAs have significantly longer 3’Untranslated Regions (UTRs) and more microRNA binding sites within 3’UTR than the inferred stable mRNAs. Regression residuals derived from RNA-seq,but not from GRO-seq,are highly correlated with the half-lives measured by pulse-labeling experiments,supporting the rationale of our inference.Whereas,the functions enriched in the inferred stable and unstable mRNAs are consistent with those from pulse-labeling experiments,we found the unstable mRNAs have higher cell-type specificity under functional constraint.We conclude that the systematical use of histone modifications can differentiate non-expressed mRNAs from unstable mRNAs. In summary,we represent the first computational model of mRNA stability inference that compares transcriptome and epigenome profiles,and provides an alternative strategy for directing experimental measurements. Background:histone modifications are predictive of gene expression in multiple cell lines,so it may reflect steady-state transcription rate.However,the expression index, measured by either microarray or RNA-seq,represents the balance between transcript production and degradation.Our study is aimed to illuminate the biological meaning of the difference between mRNA level and histone modifications level. Methods:Using the information from histone modifications-H3K4me3,H3K27me3 and H3K36me3,we derive regression model to fit mRNA level in multiple cell lines.The mRNAs, whose expression levels(true values) are significantly lower than histone modifications level (prediction value),are inferred as unstable mRNAs(faster degraded),and vice versa. Results:Inferred unstable mRNAs harbor sequence

关键词： histone modification mRNA level mRNA stability

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

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Journal of Genetics and Genomics 2019年第10期46卷 467-476页

作者： Ting Zhao Zhenping Zhan Danhua Jiang State Key Laboratory of Plant Genomics Institute of Genetics and Developmental BiologyThe Innovative Academy of Seed DesignChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100101China

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.

关键词： histone modification Transcription Germination Flowering Plant-environmental response Environmental memory

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Development of rabbit monoclonal and polyclonal antibodies for detection of site-specific histone modifications and their application in analyzing overall modification levels

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Cell Research 2006年第5期16卷 519-527页

作者： Lan Guo~(1,2,*) Benliang Yin~(1,*) Junli Zhou~(1,3) Xueyong Li~3 Xing Wang Deng~(1,2,3) ~1National Institute of Biological Science,Zhongguancun Life Science Park,Beijing 102206,China ~2Peking-Yale Joint Center of Plant Molecular Genetics and Agrobiotechnology,College of Life Sciences,Peking University,Beijing 100871,China ~3Department of Molecular,Cellular,and Developmental Biology,Yale University,New Haven,Connecticut 06520-8104,USA 2Peking-Yale Joint Center of Plant Molecular Genetics and Agrobiotechnology College of Life Sciences Peking University Beijing 100871 China 1National Institute of Biological Science Zhongguancun Life Science Park Beijing 102206 China 3Department of Molecular Cellular and Developmental Biology Yale University New Haven Connecticut 06520-8104 USA 3Department of Molecular Cellular and Developmental Biology Yale University New Haven Connecticut 06520-8104 USA 3Department of Molecular Cellular and Developmental Biology Yale University New Haven Connecticut 06520-8104 USA

In addition to DNA sequence information,site-specific histone modifications are another important determinant ofgene expression in a eukaryotic organism.We selected four modification sites in common histones that are known tosignificantly impact chromatin function and generated monoclonal or polyclonal antibodies that recognize each of thosesite-specific modifications.We used these antibodies to demonstrate that the site-specific histone modification levelsremain relatively constant in different organs of the same organism.We also compared the levels of selected histonemodifications among several representative organisms and found that site-specific modifications are highly variable amongdifferent organisms,providing new insight into the evolutionary divergence of specific histone modifications.

关键词： histone modification site-specific antibody chromatin

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

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Plant Diversity 2024年第3期46卷 386-394页

作者： Yunzhen Li Liujie Jin Xinyu Liu Chao He Siteng Bi Sulaiman Saeed Wenhao Yan National Key Laboratory of Crop Genetic Improvement Hubei Hongshan LaboratoryHuazhong Agricultural UniversityWuhan 430070China

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.

关键词： Wheat Vernalization VRN1 histone modification Regulate network

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Epigenetic regulation of plant immunity:from chromatin codes to plant disease resistance

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aBIOTECH 2023年第2期4卷 124-139页

作者： Si-Si Xie Cheng-Guo Duan Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences Chinese Academy of SciencesShanghai 200032China University of the Chinese Academy of Sciences Beijing 100049China

Facing a deteriorating natural environment and an increasing serious food crisis,bioengineering-based breeding is increasing in importance.To defend against pathogen infection,plants have evolved multiple defense mechanisms,including pathogen-associated molecular pattern(PAMP)-triggered immunity(PTI)and effector-triggered immunity(ETI).A complex regulatory network acts downstream of these PTI and ETI pathways,including hormone signal transduction and transcriptional reprogramming.In recent years,increasing lines of evidence show that epigenetic factors act,as key regulators involved in the transcriptional reprogramming,to modulate plant immune responses.Here,we summarize current progress on the regulatory mechanism of DNA methylation and histone modifications in plant defense responses.In addition,we also discuss the application of epigenetic mechanism-based resistance strategies in plant disease breeding.

关键词： histone modification DNA methylation Transcriptional reprogramming Plant immunity Disease resistance

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

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Zoological Research 2024年第1期45卷 138-151页

作者： Tao Jiang Zhi-Min Zhou Zi-Qi Ling Qing Zhang Zhong-Zi Wu Jia-Wen Yang Si-Yu Yang Bin Yang Lu-Sheng Huang National Key Laboratory of Pig Genetic Improvement and Germplasm Innovation Jiangxi Agricultural UniversityNanchangJiangxi 330045China

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.

关键词： Transposable elements Porcine histone modification Alternative promoter TE-containing transcript

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

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Neural Regeneration Research 2023年第7期18卷 1441-1449页

作者： Dan-Dan Liu Chao-Yang Zhang Jing-Ting Zhang Li-Min Gu Guo-Tong Xu Jing-Fa Zhang Department of Ophthalmology of Tongji Hospital Tongji Eye InstituteDepartment of Regenerative Medicineand Department of PharmacologyTongji University School of MedicineShanghaiChina Department of Ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong UniversityShanghaiChina National Clinical Research Center for Eye Diseases Shanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina Department of Ophthalmology Shanghai Aier Eye HospitalShanghaiChina

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.

关键词： diabetic retinopathy DNA methylation epigenetics histone modification metabolic memory M6A modification non-coding RNAs review

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