Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart
Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart
复制标题
DOI：
10.1073/pnas.0805491105
复制
发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Schwartz, Robert J.
中科院分区：
文献类型：
--
作者：
Niu, Zhiyv;Iyer, Dinakar;Schwartz, Robert J.
我们的条件性血清反应因子（SRF）敲除，Srf（CKO），在心脏形成区域阻止了有节奏的跳动的心肌细胞的出现，这是最早的心脏缺陷之一，由消融心脏富集的转录因子引起。在Srf（CKO）突变心脏中，Hand 1和Smyd 1（转录和染色质重塑因子）、Acta 1、Acta 2、Myl 3和Myom 1（肌原纤维蛋白）以及钙激活钾通道基因活性（KCNMB 1）（通道蛋白）的出现明显减弱。组合辅因子与SRF相互作用的必要作用，作为一个主要的决定因素，用于调节有组织的肌节的外观，显示了SRF-空ES细胞与SRIF点突变体，阻断辅因子相互作用的病毒救援。在不存在与生物矿化相关的SRIF基因的情况下，加塔-6、骨形态发生蛋白4（BMP 4）和骨膜蛋白被强烈上调，与许多SRIF依赖性microRNA（包括miR 1）的下调一致，miR 1在诱导加塔-6时发挥稳健的沉默物活性，导致BMP 4和骨膜蛋白的下调。
Our conditional serum response factor (SRF) knockout, Srf(CKO), in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand 1 and Smyd 1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom 1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the Srf(CKO) mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRIF point mutants that block cofactor interactions. In the absence of SRIF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRIF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.