A crucial role of a high mobility group protein HMGA2 in cardiogenesis
A crucial role of a high mobility group protein HMGA2 in cardiogenesis
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DOI：
10.1038/ncb1719
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
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作者：
Monzen, Koshiro;Ito, Yuzuru;Komuro, Issei
核蛋白的高迁移率族（HMG）通过染色质结构的结构重塑和启动子/增强子区域上的多蛋白复合物的形成来调节许多基因的表达。这导致其靶基因的活性转录（1-3）。在这里，我们表明，HMGA 2，HMG蛋白的HMGA亚家族的成员，在心脏发生中具有重要的功能。HMGA 2的过表达增强了胚胎癌细胞系P19 CL 6的心肌细胞分化，而siRNA介导的HMGA 2敲低阻断了胚胎癌细胞系P19 CL 6的心肌细胞分化。此外，显性负性HMGA 2的过度表达或吗啉介导的HMGA 2表达的敲低阻断了非洲爪蟾胚胎中的正常心脏形成，表明HMGA 2在体外和体内心脏发生中具有重要作用。从机制上讲，HMGA 2与Smad 1/4相关，并显示出心脏转录因子Nkx2.5基因的协同反式激活;在P19 CL 6细胞和转基因非洲爪蟾胚胎中，Nkx2.5基因的启动子活性都需要一个保守的HMGA 2结合位点。因此，HMGA 2是Nkx2.5基因表达的正调控因子，对正常心脏发育至关重要。
The high mobility group ( HMG) of nuclear proteins regulates expression of many genes through architectural remodelling of the chromatin structure, and formation of multiprotein complexes on promoter/enhancer regions. This leads to the active transcription of their target genes(1-3). Here we show that HMGA2, a member of the HMGA sub-family of HMG proteins, has a critical function in cardiogenesis. Overexpression of HMGA2 enhanced, whereas siRNA-mediated knockdown of HMGA2 blocked, cardiomyocyte differentiation of the embryonal carcinoma cell line P19CL6. Moreover, overexpression of a dominant-negative HMGA2 or morpholino-mediated knockdown of HMGA2 expression blocked normal heart formation in Xenopus laevis embryos, suggesting that HMGA2 has an important role in cardiogenesis both in vitro and in vivo. Mechanistically, HMGA2 associated with Smad1/4 and showed synergistic trans-activation of the gene for a cardiac transcription factor Nkx2.5; a conserved HMGA2 binding site was required for the promoter activity of Nkx2.5 gene, both in P19CL6 cells and in transgenic Xenopus embryos. Thus, HMGA2 is a positive regulator of Nkx2.5 gene expression and is essential for normal cardiac development.