DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis

Jing-Jing Yang; Hui Tao; Cheng Huang; Kai-hu Shi; Tao-Tao Ma; Er-Bao Bian; Lei Zhang; Li-Ping Liu; Wei Hu; Xiong-Wen Lv; Jun Li

doi:10.1016/j.cellsig.2013.01.005

DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis

Cell Signal. 2013 May;25(5):1202-11. doi: 10.1016/j.cellsig.2013.01.005. Epub 2013 Jan 16.

Authors

Jing-Jing Yang¹, Hui Tao, Cheng Huang, Kai-hu Shi, Tao-Tao Ma, Er-Bao Bian, Lei Zhang, Li-Ping Liu, Wei Hu, Xiong-Wen Lv, Jun Li

Affiliation

¹ School of pharmacy, Anhui Medical University, and Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.

PMID: 23333245
DOI: 10.1016/j.cellsig.2013.01.005

Abstract

Hepatic stellate cell (HSC) activation plays an important role in liver fibrogenesis. Transdifferentiation of quiescent hepatic stellate cells into myofibroblastic-HSCs is a key event in liver fibrosis. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. MeCP2 binds to methylated CpG dinucleotides, which are abundant in the promoters of many genes. Treatment of HSCs with DNA methylation inhibitor 5-aza-2'- deoxycytidine (5-azadC) prevented proliferation and activation. Treatment with 5-azadC prevented loss of Patched (PTCH1) expression that occurred during HSCs activation. In a search for underlying molecular medchanisms, we investigated whether the targeting of epigenetic silencing mechanisms could be useful in the treatment of PTCH1-associated fibrogenesis. It was indicated that hypermethylation of PTCH1 is associated with the perpetuation of fibroblast activation and fibrosis in the liver. siRNA knockdown of MeCP2 increased the expressions of PTCH1 mRNA and protein in hepatic myofibroblasts. These data suggest that DNA methylation and MeCP2 may provide molecular mechanisms for silencing of PTCH1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azacitidine / analogs & derivatives
Azacitidine / pharmacology
Carbon Tetrachloride / toxicity
Cell Line
Cell Transdifferentiation
DNA Methylation*
Gene Expression / drug effects
Hepatic Stellate Cells / cytology
Hepatic Stellate Cells / drug effects
Immunohistochemistry
Kruppel-Like Transcription Factors / metabolism
Liver Cirrhosis / chemically induced
Liver Cirrhosis / metabolism*
Liver Cirrhosis / pathology
Male
Methyl-CpG-Binding Protein 2 / antagonists & inhibitors
Methyl-CpG-Binding Protein 2 / genetics
Methyl-CpG-Binding Protein 2 / metabolism*
Myofibroblasts / cytology
Myofibroblasts / metabolism
Patched Receptors
Patched-1 Receptor
Promoter Regions, Genetic
Protein Binding
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Zinc Finger Protein GLI1

Substances

Gli1 protein, rat
Kruppel-Like Transcription Factors
Methyl-CpG-Binding Protein 2
Patched Receptors
Patched-1 Receptor
Ptch1 protein, rat
RNA, Messenger
RNA, Small Interfering
Receptors, Cell Surface
Zinc Finger Protein GLI1
5-aza-2'-deoxycytidine-5'-monophosphate
Carbon Tetrachloride
Azacitidine