THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision.
THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision.
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THO 复合物依赖性转录后控制有助于血管平滑肌细胞的命运决定
DOI：
10.1161/circresaha.118.313527
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发表时间：
2018
影响因子：
20.1
通讯作者：
Wang Li
中科院分区：
文献类型：
--
作者：
Yuan Xinli;Zhang Tao;Yao Fang;Liao Yingnan;Liu Fei;Ren Zongna;Han Leng;Diao Lixia;Li Yankui;Zhou Bingying;He Fan;Wang Li
原理：血管平滑肌细胞（VSMC）表型的调节在血管发育和疾病中发挥着重要作用。虽然广泛的研究揭示了VSMC特异性基因表达中的转录调控作用，但转录后调控对VSMC命运决定的作用仍有待确定。目的：建立THO复合物依赖的VSMC基因表达调控机制。方法和结果：针对THOC 2和THOC 5（THO复合物的2种组分）的免疫组织化学染色显示，与正常的乳房内动脉相比，接受颈动脉内膜切除术的人动脉中其表达显著降低。沉默THOC 2或THOC 5导致体外VSMC去分化，其特征在于VSMC标记基因表达降低，迁移和增殖增加。此外，RNA高通量测序（Seq）显示，TH 0 C5沉默与培养的VSMC中PDGF（血小板衍生生长因子）-BB/PDGF-DD处理诱导的基因表达变化非常相似。从机制上讲，THOC 2和THOC 5在物理上相互作用并在功能上相互依赖，以结合VSMC标记基因mRNA上的特定基序。有趣的是，在VSMC去分化过程中失去THOC 2或THOC 5结合的mRNA富含对分化的VSMC表型重要的基因。最后，THOC 5在大鼠颈动脉损伤中的过度表达显著抑制了VSMC标记基因表达的丧失和新生内膜的形成。结论：我们的数据介绍了THO与VSMC标记基因mRNA的动态结合作为一种新的机制，有助于VSMC表型转换，并暗示THOC 5作为血管疾病的潜在干预节点。
Rationale: Modulation of vascular smooth muscle cell (VSMC) phenotype plays a fundamental role in vascular development and diseases. Although extensive studies uncovered the roles of transcriptional regulation in VSMC-specific gene expression, how posttranscriptional regulation contributes to VSMC fate decisions remains to be determined. Objective: To establish THO complex-dependent VSMC gene expression as a novel regulatory basis controlling VSMC phenotypes. Methods and Results: Immunohistochemical staining against THOC2 and THOC5, 2 components of the THO complex, revealed a dramatic reduction in their expression in human arteries undergoing carotid endarterectomy compared with normal internal mammary arteries. Silencing of THOC2 or THOC5 led to dedifferentiation of VSMCs in vitro, characterized by decreased VSMC marker gene expression and increased migration and proliferation. Furthermore, RNA high-throughput sequencing (Seq) revealed that THOC5 silencing closely resembled the gene expression changes induced on PDGF (platelet-derived growth factor)-BB/PDGF-DD treatments in cultured VSMCs. Mechanistically, THOC2 and THOC5 physically interacted with and functionally relied on each other to bind to specific motifs on VSMC marker gene mRNAs. Interestingly, mRNAs that lost THOC2 or THOC5 binding during VSMC dedifferentiation were enriched for genes important for the differentiated VSMC phenotype. Last, THOC5 overexpression in injured rat carotid arteries significantly repressed loss of VSMC marker gene expression and neointima formation. Conclusions: Our data introduce dynamic binding of THO to VSMC marker gene mRNAs as a novel mechanism contributing to VSMC phenotypic switching and imply THOC5 as a potential intervention node for vascular diseases.