title: Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ.
abstract: As a central event in liver fibrogenesis, hepatic stellate cell (HSC) transdifferentiation involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor γ; (PPARγ), which is epigenetically silenced during HSC activation. We hypothesized that JMJD1A, an H3K9 demethylase involved in adipogenic metabolism, could regulate PPARγ. In human HSC cell line, rat primary HSCs, and carbontetrachloride-induced mouse liver fibrogenesis model, we down-regulated the expression of JMJD1A using small interfering or short hairpin RNAs, and overexpressed its wild-type and mutant. We analyzed the effects of JMJD1A manipulation on the histone di-methyl-H3K9 (H3k9me2) status of PPARγ gene and the expression of PPARγ and fibrosis markers using chromatin immunoprecipitation, real-time quantitative RT-PCR and Western blot, and also investigated the in vitro and in vivo consequences on liver fibrosis and necrosis by Masson or hematoxylin-eosin staining, respectively. JMJD1A knockdown in HSCs correlated with reinforced H3K9me2 in the PPARγ gene promoter, and its down-regulation in both mRNA and protein led to increased expression of fibrosis markers, which could be consistently rescued by JMJD1A overexpression. Jmjd1a knockdown in situ resulted in significantly increased expression of α-smooth muscle actin (P = 0.005) and Col1a (P = 0.036), strengthened production of collagens (P = 0.028), and remarkably enhanced necrosis (P = 0.007) 4 weeks after treatment. This study suggests JMJD1A as a novel epigenetic regulator that modulates HSC activation and liver fibrosis through targeting PPARγ gene expression.
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Chengzhao
authors.initials: C
authors.lastname: Lin
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhong
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China hefc@nic.bmi.ac.cn haijianwang@fudan.edu.cn.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: *State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China; Department of Chemistry, Fudan University, Shanghai, China; and State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China hefc@nic.bmi.ac.cn haijianwang@fudan.edu.cn.
authors.forename: Haijian
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D057890:Epigenomics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006657:Histones; D047495:PPAR gamma; D012333:RNA, Messenger; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; C524220:KDM6B protein, human; C494424:KDM4A protein, human
keywords: HSC biology; PPARγ; adipogenic transcription factor; liver fibrogenesis