Sin3B mediates collagen type I gene repression by interferon gamma in vascular smooth muscle cells.
Sin3B mediates collagen type I gene repression by interferon gamma in vascular smooth muscle cells.
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DOI：
10.1016/j.bbrc.2014.03.140
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发表时间：
2014-05
影响因子：
3.1
通讯作者：
X. Weng;Xian Cheng;Xiaoyan Wu;Huihui Xu;Mingming Fang;Yong Xu
中科院分区：
文献类型：
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作者：
X. Weng;Xian Cheng;Xiaoyan Wu;Huihui Xu;Mingming Fang;Yong Xu
I型胶原是细胞外基质(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I型胶原基因（COL1A2）转录的抑制是导致动脉粥样硬化斑块不稳定的关键步骤。IFN-γ诱导col1a2抑制的表观遗传机制尚不清楚。我们在这里发现Sin3B是真核组蛋白去乙酰化酶（HDAC）复合物的一个组成部分，在平行col1a2抑制的VSMCs中，IFN-γ处理后，Sin3B被募集到col1a2转录起始位点。染色质免疫沉淀（ChIP）实验证明，短发夹RNA （shRNA）介导的Sin3B沉默消除了IFN-γ对胶原的抑制，阻断了活性组蛋白标记的清除和抑制组蛋白标记在肿瘤1a2转录起始位点的积累。Sin3B与组蛋白H3K9甲基转移酶G9a合作，在IFN-γ刺激下诱导胶原基因转录起始位点周围的抑制性染色质结构。Sin3B通过HDAC2介导的RFX5去乙酰化的机制被X-box 5调控因子（RFX5）募集到胶原位点。总之，我们的数据表明，一个包含RFX5、HDAC2、Sin3B和G9a的抑制因子复合物负责IFN-γ诱导的vsmc中col1a2的抑制。针对这种复合物的单个成分可能会产生潜在的治疗动脉粥样硬化的解决方案。
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 inducedCOL1A2repression is not clearly appreciated. We show here that Sin3B, a component of the eukaryotic histone deacetylase (HDAC) complex, was recruited toCOL1A2transcription start site in response to IFN-γ treatment in VSMCs parallelingCOL1A2repression. 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 onCOL1A2transcription 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 inducedCOL1A2repression in VSMCs. Targeting individual component of this complex will likely yield potential therapeutic solutions against atherosclerosis.