Sin3B mediates collagen type I gene repression by interferon gamma in vascular smooth muscle cells.

Abstract

Collagen type I is the primary component of the extracellular matrix (ECM). Repression of collagen type I gene (COL1A2) transcription by the pro-inflammatory cytokine interferon gamma (IFN-γ) in vascular smooth muscle cells (VSMCs) is a key step during atherogenesis that leads to the destabilization of the atherosclerotic plaque. The epigenetic mechanism underlying IFN-γ induced COL1A2 repression is not clearly appreciated. We show here that Sin3B, a component of the eukaryotic histone deacetylase (HDAC) complex, was recruited to COL1A2 transcription start site in response to IFN-γ treatment in VSMCs paralleling COL1A2 repression. Short hairpin RNA (shRNA) mediated silencing of Sin3B abrogated collagen repression by IFN-γ and blocked the erasure of active histone marks and the accumulation of repressive histone marks on COL1A2 transcription start site as evidenced by chromatin immunoprecipitation (ChIP) assays. Sin3B cooperated with G9a, a histone H3K9 methyltransferase, to induce a repressive chromatin structure surrounding the collagen gene transcription start site in response to IFN-γ stimulation. Sin3B was recruited by regulatory factor for X-box 5 (RFX5) to the collagen site through a mechanism that involved HDAC2 mediated deacetylation of RFX5. Together, our data indicate that a repressor complex that contains RFX5, HDAC2, Sin3B, and G9a is responsible for IFN-γ induced COL1A2 repression in VSMCs. Targeting individual component of this complex will likely yield potential therapeutic solutions against atherosclerosis.

• Authors: Xinyu Weng, Xian Cheng, Xiaoyan Wu, Huihui Xu, Mingming Fang, Yong Xu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 447 Issue 2 Pg. 263-70 (May 02 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 24709079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Collagen Type I
• DNA-Binding Proteins
• Histocompatibility Antigens
• RFX5 protein, human
• Regulatory Factor X Transcription Factors
• Repressor Proteins
• SIN3B protein, human
• Interferon-gamma
• EHMT2 protein, human
• Histone-Lysine N-Methyltransferase

Topics

• Animals
• Atherosclerosis (enzymology, genetics)
• Cells, Cultured
• Chromatin (metabolism)
• Collagen Type I (genetics)
• DNA-Binding Proteins (metabolism)
• Epigenesis, Genetic
• Gene Expression (drug effects)
• HEK293 Cells
• Histocompatibility Antigens (metabolism)
• Histone-Lysine N-Methyltransferase (metabolism)
• Humans
• Interferon-gamma (immunology, pharmacology)
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (enzymology, metabolism)
• Rats
• Regulatory Factor X Transcription Factors
• Repressor Proteins (metabolism)
• Transcription Initiation Site