title: The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration.
abstract: To investigate the role of enhancer of zeste homolog (EZH) 1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1(-/-) and EZH2(fl/fl) alleles and an Alb-Cre transgene. Only the combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global trimethylation on Lys 27 of histone H3 (H3K27me3) marks and the specific loss of over ∼1900 genes at 3 mo of age. Ezh1(-/-),Ezh2(fl/fl)Alb-Cre mice exhibited progressive liver abnormalities manifested by the development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration, and activation of A6-positive hepatic progenitor cells at 8 mo of age. In response to chronic treatment with carbon tetrachloride, all experimental mice, but none of the controls (n = 27 each), showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After two-thirds partial hepatectomy, mutant mice (n = 5) displayed increased liver injury and a blunted regenerative response. Genome-wide analyses at 3 mo of age identified 51 genes that had lost H3K27me3 marks, and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration.
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea drwookyun@chonnam.ac.kr lotharh@mail.nih.gov.
authors.forename: Woo Kyun
authors.initials: WK
authors.lastname: Bae
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Keunsoo
authors.initials: K
authors.lastname: Kang
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Yu
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Factor
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Matthias
authors.initials: M
authors.lastname: Matter
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Snorri
authors.initials: S
authors.lastname: Thorgeirsson
authors.affiliation: *Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea; Department of Microbiology, Dankook University, Cheonan, Korea; and New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea drwookyun@chonnam.ac.kr lotharh@mail.nih.gov.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D006657:Histones; D012333:RNA, Messenger; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: H3-K27 trimethylation; fibrosis; liver regeneration