TY - JOUR
T1 - Myocardin related transcription factor A programs epigenetic activation of hepatic stellate cells
AU - Tian, Wenfang
AU - Hao, Chenzhi
AU - Fan, Zhiwen
AU - Weng, Xinyu
AU - Qin, Hao
AU - Wu, Xiaoyan
AU - Fang, Mingming
AU - Chen, Qi
AU - Shen, Aiguo
AU - Xu, Yong
N1 - Publisher Copyright:
© 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Background & Aims Activation of hepatic stellate cells (HSCs) represents a key process in liver injury and, in the absence of intervention, leads to irreversible cirrhosis contributing significantly to the mortality of patients with liver disease. A missing link in the current understanding of HSC activation is the involvement of the epigenetic machinery. We investigated the role of the myocardin related transcription factor A (MRTF-A) in HSC activation.Methods Liver fibrosis was induced in wild type (WT) and MRTF-A deficient (KO) mice by CCl4 injection. Expression of mRNA and protein was measured by real-time PCR, Western blotting, and immunohistochemistry. Protein binding to DNA was assayed by chromatin immunoprecipitation (ChIP). Knockdown of endogenous proteins was mediated by either small interfering RNA (siRNA) or short hairpin RNA (shRNA), carried by lentiviral particles.Results KO mice exhibited resistance to CCl4-induced liver fibrosis compared to WT littermates. The expression of activated HSC signature genes was suppressed in the absence of MRTF-A. ChIP assays revealed that MRTF-A deficiency led to the erasure of key histone modifications, associated with transcriptional activation, such as H3K4 di- and tri-methylation, on the promoter regions of fibrogenic genes. Mechanistically, MRTF-A recruited a histone methyltransferase complex (COMPASS) to the promoters of fibrogenic genes to activate transcription. Silencing of individual COMPASS components dampened transactivation of fibrogenic genes in vitro and blocked liver fibrosis in mice. Oestradiol suppressed HSC activation by dampening the expression and binding activity of COMPASS.Conclusions Our data illustrate a novel mechanism that connects MRTF-A dependent histone H3K4 methylation to HSC activation.
AB - Background & Aims Activation of hepatic stellate cells (HSCs) represents a key process in liver injury and, in the absence of intervention, leads to irreversible cirrhosis contributing significantly to the mortality of patients with liver disease. A missing link in the current understanding of HSC activation is the involvement of the epigenetic machinery. We investigated the role of the myocardin related transcription factor A (MRTF-A) in HSC activation.Methods Liver fibrosis was induced in wild type (WT) and MRTF-A deficient (KO) mice by CCl4 injection. Expression of mRNA and protein was measured by real-time PCR, Western blotting, and immunohistochemistry. Protein binding to DNA was assayed by chromatin immunoprecipitation (ChIP). Knockdown of endogenous proteins was mediated by either small interfering RNA (siRNA) or short hairpin RNA (shRNA), carried by lentiviral particles.Results KO mice exhibited resistance to CCl4-induced liver fibrosis compared to WT littermates. The expression of activated HSC signature genes was suppressed in the absence of MRTF-A. ChIP assays revealed that MRTF-A deficiency led to the erasure of key histone modifications, associated with transcriptional activation, such as H3K4 di- and tri-methylation, on the promoter regions of fibrogenic genes. Mechanistically, MRTF-A recruited a histone methyltransferase complex (COMPASS) to the promoters of fibrogenic genes to activate transcription. Silencing of individual COMPASS components dampened transactivation of fibrogenic genes in vitro and blocked liver fibrosis in mice. Oestradiol suppressed HSC activation by dampening the expression and binding activity of COMPASS.Conclusions Our data illustrate a novel mechanism that connects MRTF-A dependent histone H3K4 methylation to HSC activation.
KW - Epigenetics
KW - Hepatic stellate cell
KW - Liver fibrosis
KW - Transcriptional regulation
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U2 - 10.1016/j.jhep.2014.07.029
DO - 10.1016/j.jhep.2014.07.029
M3 - Article
C2 - 25109772
AN - SCOPUS:84918552100
SN - 0168-8278
VL - 62
SP - 165
EP - 174
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -