Abstract：
RNA binding proteins have been shown to regulate heart development and cardiac diseases. However, the detailed molecular mechanisms is not known. In this study, we identified Wilms\' tumor 1-associating protein (WTAP, a key regulatory protein of the m6A RNA methyltransferase complex) as a key regulator of heart function and cardiac diseases. WTAP is associated with heart development, and its expression is downregulated in both human and mice with heart failure. Cardiomyocyte-specific knockout of Wtap (Wtap-CKO) induces dilated cardiomyopathy, heart failure and neonatal death. Although WTAP deficiency in the heart decreases METTL3 (methyltransferase-like 3) protein levels, cardiomyocyte-specific overexpression of Mettl3 in Wtap-CKO mice does not rescue the phenotypes of Wtap-CKO mice. Instead, WTAP deficiency in the heart decreases chromatin accessibility in the promoter regions of Mef2a (myocyte enhancer factor-2α) and Mef2c, leading to reduced mRNA and protein levels of these genes and lower expression of their target genes. Conversely, WTAP directly binds to the promoter of the Mef2c gene and increases its promoter luciferase activity and expression. These data demonstrate that WTAP plays a key role in heart development and cardiac function by maintaining the chromatin accessibility of cardiomyocyte specific genes.
摘要：
RNA结合蛋白已被证明可调节心脏发育和心脏疾病。然而,详细的分子机制是未知的。在这项研究中,我们鉴定了Wilms\'肿瘤1相关蛋白(WTAP，m6ARNA甲基转移酶复合物的关键调节蛋白）作为心脏功能和心脏疾病的关键调节因子。WTAP与心脏发育有关,其表达在人和心力衰竭小鼠中均下调。Wtap的心肌细胞特异性敲除（Wtap-CKO）诱导扩张型心肌病，心力衰竭和新生儿死亡。尽管心脏中的WTAP缺乏会降低METTL3（甲基转移酶样3）蛋白水平，在Wtap-CKO小鼠中Mettl3的心肌细胞特异性过表达不能挽救Wtap-CKO小鼠的表型。相反，心脏中的WTAP缺乏会降低Mef2a（肌细胞增强因子-2α）和Mef2c启动子区域的染色质可及性，导致这些基因的mRNA和蛋白质水平降低，并降低其靶基因的表达。相反，WTAP直接与Mef2c基因的启动子结合并增加其启动子荧光素酶活性和表达。这些数据表明WTAP通过维持心肌细胞特异性基因的染色质可及性在心脏发育和心脏功能中起关键作用。
