Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes.
Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes.
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DOI：
10.1016/j.celrep.2021.109100
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发表时间：
2021-05
期刊：
影响因子：
8.8
通讯作者：
Eva Riechert;V. Kmietczyk;F. Stein;T. Schwarzl;T. Sekaran;L. Jürgensen;V. Kamuf-Schenk;E. Varma;C. Hofmann;Mandy Rettel;Kira Gür;Julie Ölschläger;Friederike Kühl;Judit Martin;Marta Ramirez-Pedraza;Mercedes Fernandez;Shirin Doroudgar;R. Méndez;H. Katus;M. Hentze;M. Völkers
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文献类型：
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作者：
Eva Riechert;V. Kmietczyk;F. Stein;T. Schwarzl;T. Sekaran;L. Jürgensen;V. Kamuf-Schenk;E. Varma;C. Hofmann;Mandy Rettel;Kira Gür;Julie Ölschläger;Friederike Kühl;Judit Martin;Marta Ramirez-Pedraza;Mercedes Fernandez;Shirin Doroudgar;R. Méndez;H. Katus;M. Hentze;M. Völkers
RNA结合蛋白（RBP）控制着心肌细胞功能的关键方面，但在生长反应期间心肌细胞中活性RBP的库在很大程度上是未知的。我们通过RNA相互作用组捕获在全系统水平上定义健康和患病心肌细胞中的RBP。这鉴定了67种心肌细胞特异性RBP，包括几种收缩蛋白。此外，我们确定胞质多聚腺苷酸化元件结合蛋白4（Cpeb4）作为一个动态的RBP，调节心脏生长在体外和体内。我们鉴定了心肌细胞中与Cpeb4结合并受其调控的mRNA。Cpeb4通过转录因子的差异表达调节心脏重塑。在Cpeb4靶mRNA中，发现了两个锌指转录因子（Zeb1和Zbtb20）。我们发现Cpeb4调节这些mRNA的表达，Cpeb4缺失会增加它们的表达。因此，Cpeb4通过响应病理性生长刺激与特异性mRNA的差异结合而成为心肌细胞功能的关键调节剂。
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 bothin vitroandin 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.