LARP7 Suppresses Endothelial-to-Mesenchymal Transition by Coupling With TRIM28
LARP7 Suppresses Endothelial-to-Mesenchymal Transition by Coupling With TRIM28
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LARP7 通过与 TRIM28 偶联抑制内皮细胞向间质细胞的转变
DOI：
10.1161/circresaha.121.319590
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发表时间：
2021-09
影响因子：
20.1
通讯作者：
Zhang Bing
中科院分区：
文献类型：
--
作者：
Liang Xiaodong;Wu Shuo;Geng Zilong;Liu Li;Zhang Shasha;Wang Shiyan;Zhang Yan;Huang Yu;Zhang Bing
文本中提供了补充数字内容。基本原理：内皮细胞向间充质细胞转化（EndMT）是内皮细胞丧失其内皮细胞特性并获得间充质细胞特性的基本生物学过程。EndMT有助于生理器官发育，如瓣膜发生，并与许多有害的病理学，如器官纤维化有关。TGF-β（transforming growth factor β，转化生长因子β）、BMP（bone morphogenetic protein，骨形态发生蛋白）和炎症等多种信号通路参与了EndMT的调控。然而，转录和表观遗传程序管理EndMT仍然在很大程度上不清楚。目的：探讨EndMT及其相关的心脏瓣膜形成的转录或表观遗传学机制。方法和结果：我们鉴定了LARP 7（La ribonucleoprotein domain family member 7），一种RNAPII（RNA结合蛋白调节RNA聚合酶II）暂停，在2种奎宁诱导的EndMT模型中下调。用慢病毒介导的shRNA去除LARP 7将内皮细胞转化为间充质形态，并诱导EndMT关键调节因子SLUG的表达。在诱导型CDH 5CreERT 2; LARP 7 f/f小鼠中，内分泌细胞中LARP 7的特异性缺失增强了房室和流出道垫中的EndMT，如谱系追踪方法所揭示的。ChIP-seq分析显示LARP 7和TRIM 28（包含28的三部分基序）共定位于SLUG启动子。LARP 7与TRIM 28直接相互作用，促进TRIM 28加载到SLUG启动子上，并通过组蛋白去乙酰化抑制其转录。更重要的是，在内皮细胞中LARP 7或TRIM 28的诱导性敲除加速了EndMT，导致瓣膜增生，这两个基因的双重敲除进一步加剧了瓣膜增生。结论：本研究揭示了LARP 7与TRIM 28协同调控EndMT和瓣膜发生的转录和表观遗传机制。
Supplemental Digital Content is available in the text. Rationale: Endothelial-to-mesenchymal transition (EndMT) is a fundamental biological process in which endothelial cells lose their endothelial characteristics and acquire mesenchymal properties. EndMT contributes to physiological organ development such as valvulogenesis and is associated with a number of deleterious pathologies such as organ fibrosis. Several signaling pathways of TGF-β (transforming growth factor β), BMP (bone morphogenetic protein) and inflammation have been shown to regulate EndMT. However, the transcriptional and epigenetic programs governing EndMT remains largely unclarified. Objective: To identify the transcriptional or epigenetic mechanisms underlying EndMT and EndMT-associated formation of cardiac valves. Methods and Results: We identified the LARP7 (La ribonucleoprotein domain family member 7), a RNAPII (RNA-binding protein regulating RNA polymerase II) pausing, was downregulated in 2 cytokine-induced EndMT models. LARP7 depletion with lentivirus-mediated shRNA transformed endothelial cells to mesenchymal morphology and induced the expression of the EndMT key regulator, SLUG. Specific deletion of LARP7 in the endocardium in inducible CDH5CreERT2;LARP7f/f mouse enhanced EndMT in the atrioventricular and outflow tract cushion as revealed by lineage tracing approach. ChIP-seq analysis showed LARP7 and TRIM28 (tripartite motif containing 28) which is an epigenetic repressor were colocalized at SLUG promoter. LARP7 directly interacted with TRIM28 and facilitated it loading to SLUG promoter and repressed its transcription through deacetylating the histones. More importantly, inducible knockout of LARP7 or TRIM28 in the endocardium accelerated EndMT, leading to the valvular hyperplasia, which was further aggravated by the double knockout of these 2 genes. Conclusions: The present study uncovers an orchestrated transcriptional and epigenetic mechanism by which LARP7 cooperates with TRIM28 to govern the EndMT and valvulogenesis.
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影响因子：
14.9
作者：
Martino L;Pennell S;Kelly G;Busi B;Brown P;Atkinson RA;Salisbury NJ;Ooi ZH;See KW;Smerdon SJ;Alfano C;Bui TT;Conte MR
通讯作者：
Conte MR
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影响因子：
16.6
作者：
Chen J;Fu Y;Day DS;Sun Y;Wang S;Liang X;Gu F;Zhang F;Stevens SM;Zhou P;Li K;Zhang Y;Lin RZ;Smith LEH;Zhang J;Sun K;Melero-Martin JM;Han Z;Park PJ;Zhang B;Pu WT
通讯作者：
Pu WT
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.8
作者：
Yang, ZY;Zhu, QW;Zhou, Q
通讯作者：
Zhou, Q
影响因子：
20.1
作者：
Bischoff J;Casanovas G;Wylie-Sears J;Kim DH;Bartko PE;Guerrero JL;Dal-Bianco JP;Beaudoin J;Garcia ML;Sullivan SM;Seybolt MM;Morris BA;Keegan J;Irvin WS;Aikawa E;Levine RA
通讯作者：
Levine RA