当前位置: X-MOL 学术J. Mol. Cell. Cardiol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Transcriptional control of a novel long noncoding RNA Mymsl in smooth muscle cells by a single Cis-element and its initial functional characterization in vessels.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2019-11-18 , DOI: 10.1016/j.yjmcc.2019.11.148
Mihyun Choi 1 , Yao Wei Lu 1 , Jinjing Zhao 1 , Mingfu Wu 1 , Wei Zhang 1 , Xiaochun Long 1
Affiliation  

Differentiated vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular homeostasis. While the coding transcriptome of the differentiated VSMC phenotype has been defined, we know little about its noncoding signature. Herein, we identified a Myocardin-induced muscle specific long noncoding RNA (lncRNA) (Mymsl) downregulated upon VSMC phenotypic modulation. We demonstrated an essential role of a proximal consensus CArG element in response to MYOCD/SRF in vitro. To validate the in vivo role of this CArG element, we generated CArG mutant mice via CRISPR-Cas9 genome editing. While the CArG mutation had no impact on the expression of surrounding genes, it abolished Mymsl expression in SMCs, but not skeletal and cardiac muscle. Chromatin immunoprecipitation assays (ChIPs) showed decreased SRF binding to CArG region in mutants whereas the enrichment of H3K79Me2 remained the same. RNA-seq analysis showed a downregulation of matrix genes in aortas from Mymsl knockout mice, which was further validated in injured carotid arteries. Our study defined the transcriptional control of a novel lncRNA in SMCs via a single transcription factor binding site, which may offer a new strategy for generating SMC-specific knockout mouse models. We also provided in vivo evidence supporting the potential importance of Mymsl in vascular pathophysiology.



中文翻译:

单个顺式元件在平滑肌细胞中对新型长非编码RNA Mymsl的转录控制及其在血管中的初始功能表征。

分化的血管平滑肌细胞(VSMC)在维持血管稳态方面至关重要。虽然已经定义了分化的VSMC表型的编码转录组,但我们对其非编码签名了解甚少。在本文中,我们确定了我的ocardin诱导uscle小号pecific翁非编码RNA(lncRNA)(Mymsl)在VSMC表型调制下调。我们展示了近端共识CArG元素在体外对MYOCD / SRF的响应中的重要作用。为了验证该CArG元件的体内作用,我们通过CRISPR-Cas9基因组编辑产生了CArG突变小鼠。虽然CArG突变对周围基因的表达没有影响,但它取消了Mymsl在SMC中表达,但在骨骼肌和心肌中不表达。染色质免疫沉淀试验(ChIPs)显示,突变体中SRF与CArG区的结合减少,而H3K79Me2的富集保持不变。RNA-seq分析显示Mymsl基因敲除小鼠的主动脉中的基质基因下调,这在颈动脉损伤中得到了进一步验证。我们的研究通过单个转录因子结合位点定义了SMC中新型lncRNA的转录控制,这可能为生成SMC特异性基因敲除小鼠模型提供了新的策略。我们还提供了支持Mymsl在血管病理生理中潜在重要性的体内证据。

更新日期:2019-11-18
down
wechat
bug