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Dgcr8 缺失在原始心脏中揭示了调节心脏-血管基因程序平衡的新型 microRNA。

Dgcr8 deletion in the primitive heart uncovered novel microRNA regulating the balance of cardiac-vascular gene program.

机构信息

Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China.

Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, China.

出版信息

Protein Cell. 2019 May;10(5):327-346. doi: 10.1007/s13238-018-0572-1. Epub 2018 Aug 20.

DOI:10.1007/s13238-018-0572-1
PMID:30128894
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6468043/
Abstract

Primitive mammalian heart transforms from a single tube to a four-chambered muscular organ during a short developmental window. We found that knocking out global microRNA by deleting Dgcr8 microprocessor in Mesp1 cardiovascular progenitor cells lead to the formation of extremely dilated and enlarged heart due to defective cardiomyocyte (CM) differentiation. Transcriptome analysis revealed unusual upregulation of vascular gene expression in Dgcr8 cKO hearts. Single cell RNA sequencing study further confirmed the increase of angiogenesis genes in single Dgcr8 cKO CM. We also performed global microRNA profiling of E9.5 heart for the first time, and identified that miR-541 was transiently highly expressed in E9.5 hearts. Interestingly, introducing miR-541 back into microRNA-free CMs partially rescued their defects, downregulated angiogenesis genes and significantly upregulated cardiac genes. Moreover, miR-541 can target Ctgf and inhibit endothelial function. Our results suggest that microRNAs are required to suppress abnormal angiogenesis gene program to maintain CM differentiation.

摘要

原始哺乳动物心脏在短暂的发育窗口期内从单个管腔转变为具有四个腔室的肌肉器官。我们发现，通过在 Mesp1 心血管祖细胞中敲除 Dgcr8 微处理器来敲除全局 microRNA，会导致由于心肌细胞 (CM) 分化缺陷而形成极度扩张和增大的心脏。转录组分析显示，Dgcr8 cKO 心脏中血管基因的表达异常上调。单细胞 RNA 测序研究进一步证实了 Dgcr8 cKO CM 中血管生成基因的增加。我们还首次对 E9.5 心脏进行了全局 microRNA 分析，发现 miR-541 在 E9.5 心脏中短暂高表达。有趣的是，将 miR-541 重新引入无 microRNA 的 CM 中部分挽救了它们的缺陷，下调了血管生成基因并显著上调了心脏基因。此外，miR-541 可以靶向 Ctgf 并抑制内皮功能。我们的结果表明，microRNAs 是抑制异常血管生成基因程序以维持 CM 分化所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/cd4c8044c14d/13238_2018_572_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/fe941803aec5/13238_2018_572_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/7e2bdceabb83/13238_2018_572_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/e5e482319a9e/13238_2018_572_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/1e2693b1ecb5/13238_2018_572_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/f5d35fbd3cbd/13238_2018_572_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/9160ad29af14/13238_2018_572_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/7211ac078099/13238_2018_572_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/cd4c8044c14d/13238_2018_572_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/fe941803aec5/13238_2018_572_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/7e2bdceabb83/13238_2018_572_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/e5e482319a9e/13238_2018_572_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/1e2693b1ecb5/13238_2018_572_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/f5d35fbd3cbd/13238_2018_572_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/9160ad29af14/13238_2018_572_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/7211ac078099/13238_2018_572_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ba8/6468043/cd4c8044c14d/13238_2018_572_Fig8_HTML.jpg

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