Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate
Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate
ABSTRACT During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.
Hetke Tanja、Ernst Alexander、Andr¨|s-Delgado Laura、Hlushchuk Ruslan、Osterwalder Marco、Vianin Andrej、Sanz-Morej¨?n Andr¨|s、Odriozola Adolfo、Langa Xavier、Mercader Nadia、Torroja Carlos、Arora Prateek、Haberth¨1r David、Naumann Uta、Zuber Beno?t、Marques Ines J.、Englert Christoph、Sim?es Filipa
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of BernCentro Nacional de Investigaciones Cardiovasculares CNIC||Department of Anatomy, Histology and Neuroscience, School of Medicine, Aut¨?noma University of MadridmicroCT group, Institute of Anatomy, University of BernDepartment of BioMedical Research (DBMR), University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern||Centro Nacional de Investigaciones Cardiovasculares CNIC||Molecular Neurobiology, German Cancer Research Center (DKFZ)Department of Microscopic Anatomy and Structural Biology, Institute of Anatomy, University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern||Centro Nacional de Investigaciones Cardiovasculares CNICCentro Nacional de Investigaciones Cardiovasculares CNICDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of BernmicroCT group, Institute of Anatomy, University of BernLeibniz Institute on Aging-Fritz Lipmann InstituteDepartment of Microscopic Anatomy and Structural Biology, Institute of Anatomy, University of BernDepartment of Developmental Biology and Regeneration, Institute of Anatomy, University of BernLeibniz Institute on Aging-Fritz Lipmann Institute||Institute of Biochemistry and Biophysics, Friedrich-Schiller-University JenaDepartment of Physiology, Anatomy and Genetics, Oxford University
基础医学分子生物学细胞生物学
wt1awt1bheart developmentcardiomyocyteepicardiumzebrafishcell fate
Hetke Tanja,Ernst Alexander,Andr¨|s-Delgado Laura,Hlushchuk Ruslan,Osterwalder Marco,Vianin Andrej,Sanz-Morej¨?n Andr¨|s,Odriozola Adolfo,Langa Xavier,Mercader Nadia,Torroja Carlos,Arora Prateek,Haberth¨1r David,Naumann Uta,Zuber Beno?t,Marques Ines J.,Englert Christoph,Sim?es Filipa.Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate[EB/OL].(2025-03-28)[2025-06-22].https://www.biorxiv.org/content/10.1101/2021.07.06.451274.点此复制
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