Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.
Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.
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DOI：
10.1161/circulationaha.113.002887
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发表时间：
2013-10-29
期刊：
影响因子：
37.8
通讯作者：
Martin KA
中科院分区：
文献类型：
--
作者：
Liu R;Jin Y;Tang WH;Qin L;Zhang X;Tellides G;Hwa J;Yu J;Martin KA
平滑肌细胞（SMC）具有显著的可塑性。它们的可逆分化是生长和伤口愈合所需的，但也有助于病理学，包括动脉粥样硬化和再狭窄。虽然已经鉴定了SMC表型的关键调节因子，包括心肌蛋白（MYOCD）和KLF 4，但尚未报道赋予可逆SMC分化的统一表观遗传机制。使用人SMC，人动脉组织，和小鼠模型，我们报告，SMC可塑性是由DNA修饰酶10 - 11易位-2（TET 2）。TET 2及其5-羟甲基胞嘧啶（5-hmC）产物在收缩性SMC中富集，但在去分化SMC中减少。TET 2敲低抑制关键促收缩基因（包括MYOCD和SRF）的表达，并伴随KLF 4的转录上调。TET 2敲低阻止雷帕霉素诱导的SMC分化，而TET 2过表达足以诱导收缩表型。TET 2过表达还诱导成纤维细胞中SMC基因表达。染色质免疫沉淀表明，TET 2协调调节表型调制通过对染色质的可及性在促收缩与去分化相关基因的启动子的相反的影响。值得注意的是，我们发现TET 2结合，5-hmC富集，在活性SMC收缩启动子（MYOCD，SRF和MYH 11）的CArG丰富的区域。TET 2和5-hmC的丢失与血管损伤和人类动脉粥样硬化疾病的小鼠模型中的损伤程度呈正相关。重要的是，局部TET 2敲低加剧损伤反应，而局部TET 2过表达恢复5-hmC表观遗传景观，收缩基因表达，并大大减弱体内内膜增生。我们确定TET 2作为一种新的和必要的主SMC分化的表观遗传调节。
Smooth muscle cells (SMC) are remarkably plastic. Their reversible differentiation is required for growth and wound healing, but also contributes to pathologies including atherosclerosis and restenosis. While key regulators of the SMC phenotype including myocardin (MYOCD) and KLF4 have been identified, a unifying epigenetic mechanism that confers reversible SMC differentiation has not been reported. Using human SMC, human arterial tissue, and mouse models, we report that SMC plasticity is governed by the DNA modifying enzyme ten-eleven translocation-2 (TET2). TET2 and its 5-hydroxymethylcytosine (5-hmC) product are enriched in contractile SMC but reduced in dedifferentiated SMC. TET2 knockdown inhibits expression of key pro-contractile genes including MYOCD and SRF with concomitant transcriptional upregulation of KLF4. TET2 knockdown prevents rapamycin-induced SMC differentiation, while TET2 overexpression is sufficient to induce a contractile phenotype. TET2 overexpression also induces SMC gene expression in fibroblasts. Chromatin immunoprecipitation demonstrates that TET2 coordinately regulates phenotypic modulation through opposing effects on chromatin accessibility at the promoters of pro-contractile versus dedifferentiation-associated genes. Notably, we find that TET2 binds, and 5-hmC is enriched, in CArG-rich regions of active SMC contractile promoters (MYOCD, SRF, and MYH11). Loss of TET2 and 5-hmC positively correlates with the degree of injury in murine models of vascular injury and human atherosclerotic disease. Importantly, localized TET2 knockdown exacerbates injury response while local TET2 overexpression restores the 5-hmC epigenetic landscape, contractile gene expression, and greatly attenuates intimal hyperplasia in vivo. We identify TET2 as a novel and necessary master epigenetic regulator of SMC differentiation.