Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
Biochem Biophys Res Commun. 2014 May 2;447(2):263-70. doi: 10.1016/j.bbrc.2014.03.140. Epub 2014 Apr 4.
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.
胶原蛋白 I 型是细胞外基质（ECM）的主要成分。在血管平滑肌细胞（VSMCs）中，促炎细胞因子干扰素γ（IFN-γ）对胶原蛋白 I 型基因（COL1A2）转录的抑制是动脉粥样硬化形成过程中的关键步骤，导致动脉粥样硬化斑块的不稳定。IFN-γ 诱导的 COL1A2 抑制的表观遗传机制尚不清楚。我们在这里表明，Sin3B 是真核组蛋白去乙酰化酶（HDAC）复合物的一个组成部分，在 VSMCs 中，IFN-γ 处理后，Sin3B 被募集到 COL1A2 转录起始位点，与 COL1A2 抑制平行。短发夹 RNA（shRNA）介导的 Sin3B 沉默消除了 IFN-γ 引起的胶原抑制，并阻断了活性组蛋白标记的消除和抑制性组蛋白标记在 COL1A2 转录起始位点的积累，如染色质免疫沉淀（ChIP）试验所示。Sin3B 与组蛋白 H3K9 甲基转移酶 G9a 合作，在 IFN-γ 刺激下，在胶原基因转录起始位点周围诱导一种抑制性染色质结构。Sin3B 通过涉及 HDAC2 介导的 RFX5 去乙酰化的机制，通过调节因子 X 盒 5（RFX5）募集到胶原蛋白位点。总之，我们的数据表明，含有 RFX5、HDAC2、Sin3B 和 G9a 的抑制复合物负责 IFN-γ 诱导的 VSMCs 中 COL1A2 的抑制。针对该复合物的单个成分可能会为动脉粥样硬化提供潜在的治疗解决方案。
