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Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping Liu Yajing Li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China School of Life Sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： Liver fibrosis Epigenetics regulation DNA methylation histone acetylation histone methylation mRNA methylation Non-coding RNA Drug development

Arabidopsis Trithorax histone methyltransferases are redundant in regulating development and DNA methylation

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Journal of Integrative Plant Biology 2022年第12期64卷 2438-2454页

作者： Ji-Yun Shang Xue-Wei Cai Yin-Na Su Zhao-Chen Zhang Xin Wang Nan Zhao Xin-Jian He National Institute of Biological Sciences Beijing 102206China Tsinghua Institute of Multidisciplinary Biomedical Research Tsinghua UniversityBeijing 100084China

Although the Trithorax histone methyltransferases ATX1-5 are known to regulate development and stress responses by catalyzing histone H3 K4 methylation in Arabidopsis thaliana,it is unknown whether and how these histone methyltransferases affect DNA methylation.Here,we found that the redundant ATX1-5 proteins are not only required for plant development and viability but also for the regulation of DNA methylation.The expression and H3 K4 me3 levels of both RNAdirected DNA methylation(RdDM)genes(NRPE1,DCL3,IDN2,and IDP2)and active DNA demethylation genes(ROS1,DML2,and DML3)were downregulated in the atx1/2/4/5 mutant.Consistent with the facts that the active DNA demethylation pathway mediates DNA demethylation mainly at CG and CHG sites,and that the RdDM pathway mediates DNA methylation mainly at CHH sites,whole-genome DNA methylation analyses showed that hyper-CG and CHG DMRs in atx1/2/4/5 significantly overlapped with those in the DNA demethylation pathway mutant ros1 dml2 dml3(rdd),and that hypo-CHH DMRs in atx1/2/4/5 significantly overlapped with those in the RdDM mutant nrpe1,suggesting that the ATX paralogues function redundantly to regulate DNA methylation by promoting H3 K4 me3 levels and expression levels of both RdDM genes and active DNA demethylation genes.Given that the ATX proteins function as catalytic subunits of COMPASS histone methyltransferase complexes,we also demonstrated that the COMPASS complex components function as a whole to regulate DNA methylation.This study reveals a previously uncharacterized mechanism underlying the regulation of DNA methylation.

关键词： development DNA demethylation DNA methylation histone methylation NRPE1 ROS1

The rice histone methylation regulates hub species of the root microbiota

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Journal of Genetics and Genomics 2021年第9期48卷 836-843页

作者： Zhiyao Lv Rui Dai Haoran Xu Yongxin Liu Bo Bai Ying Meng Haiyan Li Xiaofeng Cao Yang Bai Xianwei Song Jingying Zhang College of Life Sciences Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical DevelopmentJilin Agricultural UniversityChangchunJilin 130118China State Key Laboratory of Plant Genomics Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China CAS Center for Excellence in Biotic Interactions University of Chinese Academy of SciencesBeijing 100049China CAS-JIC Centre of Excellence for Plant and Microbial Science Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China College of Advanced Agricultural Sciences University of Chinese Academy of SciencesBeijing 100049China Shandong Rice Research Institute Shandong Academy of Agricultural SciencesJinan 250100China Institute of Farming and Cultivation Heilongjiang Provincial Academy of Agricultural SciencesHarbin 150086China Center for Excellence in Molecular Plant Sciences Chinese Academy of SciencesBeijing 100101China INASEED Chinese Academy of SciencesBeijing 100101China

Plants have a close relationship with their root microbiota,which comprises a complex microbial network.histone methylation is an important epigenetic modification influencing multiple plant traits;however,little is known about the role of plant histone methylation in the assembly and network structure of the root microbiota.In this study,we established that the rice(Oryza sativa)histone methylation regulates the structure and composition of the root microbiota,especially the hub species in the microbial network.DJjmj703(defective in histone H3K4 demethylation)and ZH11-sdg714(defective in H3K9 methylation)showed significant different root microbiota compared with the corresponding wild types at the phylum and family levels,with a consistent increase in the abundance of Betaproteobacteria and a decrease in the Firmicutes.In the root microbial network,35 of 44 hub species in the top 10 modules in the tested field were regulated by at least one histone methylation-related gene.These observations establish that the rice histone methylation plays a pivotal role in regulating the assembly of the root microbiota,providing insights into the links between plant epigenetic regulation and root microbiota.

关键词： histone methylation Root microbiota Hub species Co-occurrence network Rice Epigenetics

Regulation beyond genome sequences: DNA and histone methylation in embryonic stem cells

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Frontiers in Biology 2010年第1期5卷 41-47页

作者： Wei YANG Qi ZHOU Xiu-Jie WANG State Key Laboratory of Plant Genomics Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Graduate University of the Chinese Academy of Sciences Beijing 100101China

Embryonic stem(ES)cells distinct themselves from other cell type populations by their pluripotent ability.The unique features of ES cells are controlled by both genetic and epigenetic factors.Studies have shown that the methylation status of DNA and histones in ES cells is quite different from that of differentiated cells and somatic stem cells.Herein,we summarized recent advances in DNA and histone methylation studies of mammalian ES cells.The methylation status of several key pluripotent regulatory genes is also discussed.

关键词： Embryonic stem(ES)cells epigenetic DNA methylation histone methylation

The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications

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Protein & Cell 2023年第3期14卷 165-179页

作者： Yanjing Li Kexue Gei Tingting Li Run Cai Yong Chen State Key Laboratory of Molecular Biology National Center for Protein Science ShanghaiShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academyof Sciences320 Yue Yang RoadShanghai 200031China State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai Collaborative Innovation Center for Biomanufacturing(SCICB)Meilong Road 130Shanghai 200237China

histone lysine methyltransferases(HKMTs)deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression.The structures and functions of HKMTs have been extensively investigated in recent decades,significantly advancing our understanding of the dynamic regulation of histone methylation.Here,we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes(H3K4,H3K27,H3K36,H3K79,and H4K20 methyltransferases),with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs.These structural studies inform HKMTs'roles in tumorigenesis and provide the foundations for developing new therapeutic approachestargetingHKMTs incancers.

关键词： nucleosome cryo-EM structures histone methyltransferases epigenetics histone methylation tumorigenesis

Hedgehog pathway orchestrates the interplay of histone modifications and tailors combination epigenetic therapies in breast cancer

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药学学报:英文版 2023年第6期13卷 2601-2612页

作者： Xiaomin Wang Jun Xu Yiming Sun Siyuwei Cao Hanlin Zeng Nan Jin Matthew Shou Shuai Tang Yi Chen Min Huang Cancer Research Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Division of Diabetes Endocrinology and MetabolismDepartment of Molecular Physiology and BiophysicsVanderbilt University Medical CenterNashvilleTN 37232USA

Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

关键词： HDAC inhibitors Drug resistance histone methylation histone acetylation Epigenetic interplay Hedgehog pathway ZIC1 LIFR Combination therapy Breast cancer

Epigenetic regulation of mesenchymal stem cell aging through histone modifications

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Genes & Diseases 2023年第6期10卷 2443-2456页

作者： Yanping Sun Haoyu Zhang Tao Qiu Li Liao Xiaoxia Su State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&Department of Pediatrics&Engineering Research Center of Oral Translational Medicine Ministry of EducationWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

Stem cell senescence and exhaustion,a hallmark of aging,lead to declines in tissue repair and regeneration in aged individuals.Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew,lineage-commitment,survival,and function of stem cells.Moreover,epigenetic alterations are considered important drivers of stem cell dysfunction during aging.In this review,we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells(MSCs).The aberrant epigenetic modifications on histones,including methylation and acetylation,have been found in aging MSCs.By disturbing the expression of specific genes,these epigenetic modifications affect the self-renew,survival,and differentiation of MSCs.A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs.Furthermore,we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

关键词： Aging Epigenetic histone acetylation histone methylation Mesenchymal stem cell

Neuronal histone Methyltransferase EZH2 Regulates Neuronal Morphogenesis,Synaptic Plasticity,and Cognitive Behavior in Mice

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Neuroscience Bulletin 2023年第10期39卷 1512-1532页

作者： Mei Zhang Yong Zhang Qian Xu Joshua Crawford Cheng Qian Guo-Hua Wang Jiang Qian Xin-Zhong Dong Mikhail V.Pletnikov Chang-Mei Liu Feng-Quan Zhou Department of Orthopaedic Surgery Johns Hopkins University School of MedicineBaltimore 21205USA The Solomon H.Snyder Department of Neuroscience Johns Hopkins University School of MedicineBaltimore 21205USA Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of MedicineBaltimore 21205USA Department of Ophthalmology Johns Hopkins University School of MedicineBaltimore 21205USA School of Life Sciences Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230026China State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100190China Sir Run Run Shaw Hospital Zhejiang University School of MedicineHangzhou 310016China

The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit(EZH2)-mediated trimethylation of histone H3 lysine 27(H3K27me3)regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system.Here,we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line.The results showed that a lack of neuronal EZH2 led to delayed neuronal migration,more complex dendritic arborization,and increased dendritic spine density.Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis.In particular,the gene encoding p21-activated kinase 3(Pak3)was identified as a target gene suppressed by EZH2 and H3K27me3,and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density.Finally,the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice.Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development,and has long-lasting effects on cognitive function in adult mice.

关键词： Neural development Dendritic branching Dendritic spine Cognitive function Epigenetics histone methylation EZH2

SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas

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Biomedical and Environmental Sciences 2022年第3期35卷 194-205页

作者： PAN Dong DU Ya Rong LI Rong SHEN Ai Hua LIU Xiao Dong LI Chuan Yuan HU Bu Rong Department of Radiological Health and Radiation Medicine School of Public Health and ManagementWenzhou Medical UniversityWenzhou 325035ZhejiangChina Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences&Key laboratory of Space Radiobiology of Gansu province Institute of Modern PhysicsChinese Academy of SciencesLanzhou 730000GansuChina Department of Dermatology Duke University Medical CenterDurhamNC27710USA

Objective SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase(KMT)that monomethylates lysine 20 of histone H4(H4 K20 me1).SET8 has been implicated in many essential cellular processes,including cell cycle regulation,DNA replication,DNA damage response,and carcinogenesis.There is no conclusive evidence,however,regarding the effect of SET8 on radiotherapy.In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism.Methods First,we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data.Then,we measured a series of biological endpoints,including the xenograft tumor growth in mice and apoptosis,frequency of micronuclei,and foci of 53 BP1 andγ-H2 AX in cells to detect the SET8 effects on radiosensitivity.RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy.Results Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma(LUAD)and invasive breast carcinoma(BRCA)patients.Furthermore,genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model,and A549 and MCF7 cells;SET8 overexpression decreased the radiosensitivity.SET8 inhibition induced more apoptosis,the frequency of micronuclei,and blocked the kinetics process of DNA damage repair as 53 BP1 andγ-H2 AX foci remained in cells.Moreover,RNF8 was positively correlated with the SET8 impact on DNA damage repair.Conclusion Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair,thus suggesting that SET8 potentiated radiotherapy of carcinomas.As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings,combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

关键词： SET8 histone methylation DNA repair Radiotherapy Carcinoma