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Silencing the enhancer of zeste homologue 2,EZH2,represses axon regeneration of dorsal root ganglion neurons

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Neural Regeneration Research 2022年第7期17卷 1518-1525页

作者： Ting-Ting Guo Ying Zhao Wei-Xiao Huang Tao Zhang Li-Li Zhao Xiao-Song Gu Song-Lin Zhou Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology ProductsJiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury RepairCo-Innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Model Animal Research Center and MOE Key Laboratory of Animal Models of Disease Nanjing UniversityNanjingJiangsu ProvinceChina

Recovery from injury to the peripheral nervous system is different from that of the central nervous system in that it can lead to gene reprogramming that can induce the expression of a series of regeneration-associated genes.This eventually leads to axonal regeneration of injured neurons.Although some regeneration-related genes have been identified,the regulatory network underlying axon regeneration remains largely unknown.To explore the regulator of axon regeneration,we performed RNA sequencing of lumbar L4 and L5 dorsal root ganglion(DRG)neurons at different time points(0,3,6,12 hours,1,3 and 7 days)after rat sciatic nerve crush.The isolation of neurons was carried out by laser capture microscopy combined with NeuN immunofluorescence staining.We found 1228 differentially expressed genes in the injured sciatic nerve tissue.The hub genes within these differentially expressed genes include Atf3,Jun,Myc,Ngf,Fgf2,EZH2,Gfap and Il6.We verified that the expression of the enhancer of zeste homologue 2 gene(EZH2)was up-regulated in DRG neurons after injury,and this up-regulation differed between large-and small-sized dorsal root ganglion neurons.To investigate whether the up-regulation of EZH2 impacts axonal regeneration,we silenced EZH2 with siRNA in cultured DRG neurons and found that the growth of the newborn axons was repressed.In our investigation into the regulatory network of EZH2 by interpretive phenomenal analysis,we found some regulators of EZH2(including Erk,Il6 and Hif1a)and targets(including Atf3,Cdkn1a and Smad1).Our findings suggest that EZH2,as a nerve regeneration-related gene,participates in the repair of the injured DRG neurons,and knocking down the EZH2 in vitro inhibits the axonal growth of DRG neurons.All the experimental procedures approved by the Administration Committee of Experimental Animals of Jiangsu Province of China(approval No.S20191201-201)on March 21,2019.

关键词： axon regeneration dorsal root ganglion neurons EZH2 IB4 laser capture microscopy NF160/200 quantitative reverse transcription-polymerase chain reaction sciatic nerve crush scRNA-seq siRNA

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

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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

Are BCL6 and EZH2 novel therapeutic targets for systemic lupus erythematosus?

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Cellular & Molecular Immunology 2022年第7期19卷 863-865页

作者： Shu Ding Yu Rao Qianjin Lu Department of Dermatology The Third Xiangya Hospital of Central South University#138 Tongzipo RoadChangsha 410013 HunanChina Institute of Dermatology Chinese Academy of Medical Sciences and Peking Union Medical College#12 Jiangwangmiao StreetXuanwuNanjing 210042 JiangsuChina Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases Chinese Academy of Medical SciencesNanjing 210042China

As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact pathogenesis of SLE remains to be explored.However,there is increasing evidence that T-cell−Bcell interactions promote the development of SLE,resulting in the generation of high-affinity antibodies[1].Tfh cells,a subgroup of T cells,can promote the formation of germinal centers,the maturation of B cells,and the differentiation of plasma cells[2].It has been found that multiple transcription factors(TFs)can regulate the generation of Tfh cells.For instance,B-cell lymphoma-6(BCL-6),an evolutionarily conserved zinc-finger protein,is an important positive transcription factor responsible for the differentiation and maturation of Tfh cells.In addition to maintaining the phenotype and GC response of Tfh cells,BCL-6 can also regulate the dynamics of T-cell−B-cell interactions and improve the efficiency of delivering help to B cells[3].

关键词： EZH2 erythematosus lupus organs

Essential role of MALAT1 in reducing traumatic brain injury

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Neural Regeneration Research 2022年第8期17卷 1776-1784页

作者： Na Wu Chong-Jie Cheng Jian-Jun Zhong Jun-Chi He Zhao-Si Zhang Zhi-Gang Wang Xiao-Chuan Sun Han Liu Department of Neurosurgery the First Affiliated Hospital of Chongqing Medical UniversityChongqingChina Department of Neurosurgery Qilu Hospital of Shandong University(Qingdao Campus)QingdaoShandong ProvinceChina

As a highly evolutionary conserved long non-coding RNA,metastasis associated lung adenocarcinoma transcript 1(MALAT1)was first demonstrated to be related to lung tumor metastasis by promoting angiogenesis.To investigate the role of MALAT1 in traumatic brain injury,we established mouse models of controlled cortical impact and cell models of oxygen-glucose deprivation to mimic traumatic brain injury in vitro and in vivo.The results revealed that MALAT1 silencing in vitro inhibited endothelial cell viability and tube formation but increased migration.In MALAT1-deficient mice,endothelial cell proliferation in the injured cortex,functional vessel density and cerebral blood flow were reduced.Bioinformatic analyses and RNA pull-down assays validated enhancer of zeste homolog 2(EZH2)as a downstream factor of MALAT1 in endothelial cells.Jagged-1,the Notch homolog 1(NOTCH1)agonist,reversed the MALAT1 deficiency-mediated impairment of angiogenesis.Taken together,our results suggest that MALAT1 controls the key processes of angiogenesis following traumatic brain injury in an EZH2/NOTCH1-dependent manner.

关键词： angiogenesis controlled cortical impact EZH2 Jagged-1 LncRNA MALAT1 NOTCH1 oxygen-glucose deprivation traumatic brain injury vascular remodeling

Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2880-2899页

作者： Qi Lv Yao Xing Jian Liu Dong Dong Yue Liu Hongzhi Qiao Yinan Zhang Lihong Hu Jiangsu Key Laboratory for Functional Substance of Chinese Medicine Stake Key Laboratory Cultivation Base for TCM Quality and EfficacySchool of PharmacyNanjing University of Chinese MedicineNanjing 210023China

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potential therapy,the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial.By focusing on the flavonoid lonicerin,one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb.,here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2(EZH2)histone methyltransferase.EZH2-mediated modification of H3 K27 me3 promotes the expression of autophagy-related protein 5,which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation.Mutations of EZH2 residues(His 129 and Arg685)indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin.More importantly,in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis,which is compromised by administration of EZH2 overexpression plasmid.Thus,these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.

关键词： Lonicerin Colitis NLRP3 inflammasome Autophagy EZH2

The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection

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Cellular & Molecular Immunology 2020年第3期17卷 247-260页

作者： Xiangyu Chen Guoshuai Cao Jialin Wu Xinxin Wang Zhiwei Pan Jianbao Gao Qin Tian Lifan Xu Zhirong Li Yaxing Hao Qizhao Huang Pengcheng Wang Minglu Xiao Luoyingzi Xie Shupei Tang Zhenyu Liu Li Hu Jianfang Tang Ran He Li Wang Xinyuan Zhou Yuzhang Wu Mengjie Chen Beicheng Sun Bo Zhu Jun Huang Lilin Ye Institute of Immunology PLAThird Military Medical University400038 ChongqingChina Institute for Molecular Engineering University of ChicagoChicagoIL 60637USA Institute of Cancer Xinqiao HospitalThird Military Medical University400038 ChongqingChina Cancer Center The General Hospital of Western Theater CommandChengduChina Section of Genetic Medicine Department of MedicineUniversity of ChicagoChicagoIL 60637USA Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210009 JiangsuChina

Epigenetic modifications to histones dictate the differentiation of naïve CD4^(+) T cells into different subsets of effector T helper(TH)cells.The histone methyltransferase enhancer of zeste homolog 2(EZH2)has been implicated in the mechanism regulating the differentiation of TH1,TH2 and regulatory T(Treg)cells.However,whether and how EZH2 regulates follicular helper T(TFH)cell differentiation remain unknown.Using a mouse model of acute lymphocytic choriomeningitis virus(LCMV)infection,we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells.Ablation of EZH2 in LCMV-specific CD4^(+) T cells leads to a selective impairment of early TFH cell fate commitment,but not late TFH differentiation or memory TFH maintenance.Mechanistically,EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment,particularly B cell lymphoma 6(Bcl6),and thus directs TFH cell commitment.Therefore,we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.

关键词： EZH2 infection acute

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

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Acta Pharmaceutica Sinica B 2021年第3期11卷 708-726页

作者： Tailin He Jialin Shang Chenglong Gao Xin Guan Yingyi Chen Liwen Zhu Luyong Zhang Cunjin Zhang Jian Zhang Tao Pang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Medicinal Bioinformatics Center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Neurology of Drum Tower Hospital Medical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjing 210008China

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.

关键词： SIRT6 activator Neuroinflammation Ischemic stroke Deacetylation Microglia Macrophage FOXC1 EZH2

EZH2 identifies the precursors of human natural killer cells with trained immunity

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Cancer Biology & Medicine 2021年第4期18卷 1021-1039页

作者： Chen Zhang Jie Yin Jian Zheng Jun Xiao Jiajian Hu Yudong Su Kaichen Zhou Yingchi Zhang Xuzhen Zhang Hong Zhang Qian Sun Yang Wang Wenwen Yu Feng Wei Qiang Zhao Long Li Xiubao Ren Department of Immunology and Biotherapy Key Laboratory of Cancer Immunology and BiotherapyTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China Department of Immunology Key Laboratory of Immune Microenvironment and Disease of the Ministry of EducationTianjin Medical UniversityTianjin 300070China Department of Pediatric Cancer Tianjin Medical University Cancer Institute and HospitalTianjin 300060China State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300000China Center for Stem Cell Medicine Chinese Academy of Medical SciencesBeijing 100730China Research Center of Basic Medicine Science Tianjin Medical UniversityTianjin 300070China

Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the in

关键词： Natural killer cells trained immunity precursor EZH2 cell cycle

Growth differentiation factor 6,a repressive target of EZH2,promotes the commitment of human embryonic stem cells to mesenchymal stem cells

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Bone Research 2020年第4期8卷 439-446页

作者： Pend Deng Yongxin Yu Christine Hong Cun-Yu Wang Laboratory of Molecular Signaling Division of Oral Biology and MedicineSchool of DentistryUniversity of California Los AngelesLos AngelesCA 90095USA Section of Orthodontics Division of Growth and DevelopmentSchool of DentistryUniversity of California Los AngelesLos AngelesCA 90095USA Jonsson Comprehensive Cancer Center Broad Stem Cell Research Institute and Department of BioengineeringHenry Samueli School of Engineering and Applied ScienceUniversity of California Los AngelesLos AngelesCA 90095USA

Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a key role in promoting the mesodermal differentiation of hESCs.In this study,an epigenome-wide analysis of hESCs and MSCs revealed that growth differentiation factor 6(GDF6),which is involved in bone formation,was the most upregulated gene associated with MSCs compared to hESCs.Furthermore,we identified GDF6 as a repressive target of EZH2 and found that ectopic GDF6 selectively promoted hESC differentiation towards the mesodermal lineage and enriched the MSC population.Our results provide molecular insights governing the mesenchymal commitment of hESCs and identify an inducing factor that offers strong promise for the future of regenerative medicine.

关键词： EZH2 mesenchymal inhibiting