Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany.
Cell Rep. 2021 May 11;35(6):109100. doi: 10.1016/j.celrep.2021.109100.
RNA-binding proteins (RBPs) control critical aspects of cardiomyocyte function, but the repertoire of active RBPs in cardiomyocytes during the growth response is largely unknown. We define RBPs in healthy and diseased cardiomyocytes at a system-wide level by RNA interactome capture. This identifies 67 cardiomyocyte-specific RBPs, including several contractile proteins. Furthermore, we identify the cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) as a dynamic RBP, regulating cardiac growth both in vitro and in vivo. We identify mRNAs bound to and regulated by Cpeb4 in cardiomyocytes. Cpeb4 regulates cardiac remodeling by differential expression of transcription factors. Among Cpeb4 target mRNAs, two zinc finger transcription factors (Zeb1 and Zbtb20) are discovered. We show that Cpeb4 regulates the expression of these mRNAs and that Cpeb4 depletion increases their expression. Thus, Cpeb4 emerges as a critical regulator of cardiomyocyte function by differential binding to specific mRNAs in response to pathological growth stimulation.
RNA 结合蛋白（RBPs）控制着心肌细胞功能的关键方面，但在生长反应过程中心肌细胞中活跃的 RBP 谱在很大程度上是未知的。我们通过 RNA 互作捕获在系统水平上定义了健康和患病心肌细胞中的 RBPs。这确定了 67 种心肌细胞特异性 RBPs，包括几种收缩蛋白。此外，我们还确定了细胞质多聚腺苷酸化元件结合蛋白 4（Cpeb4）是一种动态的 RBP，可在体外和体内调节心脏生长。我们确定了与心肌细胞中 Cpeb4 结合并受其调节的 mRNA。Cpeb4 通过差异表达转录因子来调节心脏重塑。在 Cpeb4 的靶 mRNA 中，发现了两个锌指转录因子（Zeb1 和 Zbtb20）。我们表明 Cpeb4 调节这些 mRNA 的表达，并且 Cpeb4 耗竭会增加它们的表达。因此，Cpeb4 通过响应病理生长刺激特异性结合特定 mRNA 来调节心肌细胞功能，成为关键的调节因子。
