title: Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a.
abstract: Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Long
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Fengxin
authors.initials: F
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D015536:Down-Regulation; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D006710:Homocysteine; D008239:Lysine; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C445405:EHMT2 protein, human; C533711:G9a protein, mouse