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Assessing Cardiomyocyte Subtypes Following Transcription Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts
Published on: March 22, 2017
Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological
Eva Riechert1, Vivien Kmietczyk1, Frank Stein2
1Department 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.
Insights
This study identifies 67 RNA-binding proteins (RBPs) in cardiomyocytes, revealing cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) as a key regulator of cardiac growth and remodeling by controlling specific mRNA targets.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Gene Regulation
Background:
- RNA-binding proteins (RBPs) are crucial for cardiomyocyte function.
- The specific RBPs involved in cardiac growth responses remain largely uncharacterized.
Purpose of the Study:
- To comprehensively identify RBPs in healthy and diseased cardiomyocytes.
- To investigate the role of cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) in cardiac growth and remodeling.
Main Methods:
- RNA interactome capture was employed to identify RBPs.
- In vitro and in vivo models were used to study Cpeb4 function.
- mRNA targets of Cpeb4 were identified and validated.
Main Results:
- 67 cardiomyocyte-specific RBPs were identified, including contractile proteins.
- Cpeb4 was identified as a dynamic RBP regulating cardiac growth.
- Cpeb4 regulates cardiac remodeling by controlling the expression of transcription factors Zeb1 and Zbtb20.
Conclusions:
- Cpeb4 is a critical regulator of cardiomyocyte function during pathological growth.
- Cpeb4 controls cardiac remodeling through differential mRNA binding and subsequent gene expression changes.
Abstract:
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.
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