Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo
Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo
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DOI：
10.1172/jci26505
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Owens, GK
中科院分区：
文献类型：
--
作者：
McDonald, OG;Wamhoff, BR;Owens, GK
SMC转录的精确控制在血管发育和病理生理学中起着重要作用。血清反应因子（SRF）通过与表现出SMC限制性表达的基因内发现的CArG盒DNA序列结合来控制SMC基因转录。然而，这些基因的天然染色质内调节SRF与CArG盒DNA结合的机制尚不清楚。在这里，我们报告说，SMC限制性结合SRF小鼠SMC基因CArG盒染色质与模式的翻译后组蛋白修饰在此染色质是特定的SMC谱系在文化和体内，包括甲基化和乙酰化组蛋白H3和H4残基。我们发现，在SMC基因表达激活过程中，原肌源性SRF辅激活因子myocardin增加了SRF与甲基化组蛋白和CArG盒染色质的结合。与此相反，肌源性阻遏物Kruppel样因子4招募组蛋白H4去乙酰化酶活性SMC基因，并阻止SRF协会与甲基化组蛋白和CArG盒染色质在SMC基因表达的阻遏。最后，我们观察到组蛋白H4的去乙酰化，再加上SRF结合的损失，在抑制SMC分化，血管损伤的反应。两者合计，这些研究结果提供了新的证据表明，SMC选择性表观遗传控制SRF结合染色质中起着关键作用，调节SMC基因的表达，在体内的病理生理刺激。
Precise control of SMC transcription plays a major role in vascular development and pathophysiology. Serum response factor (SRF) controls SMC gene transcription via binding to CArG box DNA sequences found within genes that exhibit SMC-restricted expression. However, the mechanisms that regulate SRF association with CArG box DNA within native chromatin of these genes are unknown. Here we report that SMC-restricted binding of SRF to murine SMC gene CArG box chromatin is associated with patterns of posttranslational histone modifications within this chromatin that are specific to the SMC lineage in culture and in vivo, including methylation and acetylation to histone H3 and H4 residues. We found that the promyogenic SRF coactivator myocardin increased SRF association with methylated histones and CArG box chromatin during activation of SMC gene expression. In contrast, the myogenic repressor Kruppel-like factor 4 recruited histone H4 deacetylase activity to SMC genes and blocked SRF association with methylated histones and CArG box chromatin during repression of SMC gene expression. Finally, we observed deacetylation of histone H4 coupled with loss of SRF binding during suppression of SMC differentiation in response to vascular injury. Taken together, these findings provide novel evidence that SMC-selective epigenetic control of SRF binding to chromatin plays a key role in regulation of SMC gene expression in response to pathophysiological stimuli in vivo.