A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells
A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells
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DOI：
10.1016/j.bbagrm.2015.03.001
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发表时间：
2015-06-01
影响因子：
4.7
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Xia, Jun;Fang, Mingming;Xu, Yong
慢性炎症在动脉粥样硬化的发病机制中起主要作用。血管平滑肌细胞（VSMC）通过表达和提呈主要组织相容性复合体II（MHC II）分子，帮助募集T淋巴细胞并启动血管内的炎症反应。我们以前已经表明，从腺苷A2 b受体缺陷小鼠（A2 b-null）分离的VSMC表现出更高的表达类反式激活因子（CIITA），MHC II转录的主调节因子，与野生型同窝仔相比。在这里，我们报告，A2 b腺苷信号的激活抑制CIITA在人主动脉平滑肌细胞的表达。CIITA表达的下调主要归因于III型和IV型启动子的转录抑制。染色质免疫沉淀（ChIP）分析显示，A2 b信号抑制CIITA转录通过衰减特定组蛋白修饰CIITA启动子在STAT 1依赖的方式。STAT 1与PCAF/GCN 5、组蛋白H3 K9乙酰转移酶和哺乳动物H3 K4甲基转移酶复合物的关键组分WDR 5相互作用以激活CIITA转录。A2 b信号以STAT 1依赖性方式阻止PCAF/GCN 5和WDR 5募集到CIITA启动子。总之，我们的数据表明，腺苷A2 b信号抑制CIITA转录VSMCs通过操纵STAT 1和表观遗传机制之间的相互作用。(C)2015 Elsevier B. V.版权所有。
Chronic inflammation plays a major role in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMC), by expressing and presenting major histocompatibility complex II (MHC II) molecules, help recruit T lymphocyte and initiate the inflammatory response within the vasculature. We have previously shown that VSMCs isolated from mice with deficient adenosine A2b receptor (A2b-null) exhibit higher expression of class transactivator (CIITA), the master regulator of MHC II transcription, compared to wild type littermates. Here we report that activation of A2b adenosine signaling suppresses CIITA expression in human aortic smooth muscle cells. Down-regulation of CIITA expression was largely attributable to transcriptional repression of type III and IV promoters. Chromatin immunoprecipitation (ChIP) analyses revealed that A2b signaling repressed CIITA transcription by attenuating specific histone modifications on the CIITA promoters in a STAT1-dependent manner. STAT1 interacted with PCAF/GCN5, histone H3K9 acetyltransferases, and WDR5, a key component of the mammalian H3K4 methyltransferase complex, to activate CIITA transcription. A2b signaling prevented recruitment of PCAF/GCN5 and WDR5 to the CIITA promoters in a STAT1-dependent manner. In conclusion, our data suggest that adenosine A2b signaling represses CIITA transcription in VSMCs by manipulating the interaction between STAT1 and the epigenetic machinery. (C) 2015 Elsevier B.V. All rights reserved.