The SWI/SNF complex subunit Smarce1/SMARCE1 is a key regulator in cardiomyocyte proliferation during heart development and regeneration

D.-D. Park (Ulm)¹, N. Hartmann (Heidelberg)², F. Leuschner (Heidelberg)², M. Börries (Freiburg im Breisgau)³, W. Rottbauer (Ulm)¹, S. Just (Ulm)^4
1Universitätsklinikum Ulm Klinik für Innere Medizin II Ulm, Deutschland; ²Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ³Medizinische Fakultät der Universität Freiburg Freiburg im Breisgau, Deutschland; ⁴Universitätsklinikum Ulm Molekulare Kardiologie, Klinik für Innere Medizin II Ulm, Deutschland

Molecular pathways that regulate organ growth during embryonic development are often reactivated in adulthood to orchestrate organ repair and regeneration after injury. The molecular mechanisms that regulate heart growth during development and regeneration after injury are only poorly defined yet, but of major clinical importance for therapeutic heart repair. In search of novel regulators of cardiac growth, we identified the zebrafish mutant heart of stone (hos), which displays massively increased numbers of cardiomyocytes during development. We found that loss of the SWI/SNF chromatin remodeling complex member Smarce1 leads to elevated cardiomyocyte proliferation in hos, whereas cardiomyocyte-specific Smarce1 overexpression represses cardiomyocyte proliferation in the developing zebrafish heart. By analyzing RNA-seq data, we found that Smarce1 is downregulated during heart regeneration in cryo-injured adult zebrafish heart. Furthermore, modulating myocardial-specific Smarce1 in the hearts of Smarce1 Cre-loxP or Smarce1 TetON zebrafish fosters or impedes proliferative potential of cardiomyocyte as well as cardiac tissue regeneration. To assess whether the role of SMARCE1 is conserved in the mammalian heart, we transduced neonatal mouse cardiomyocytes (P1) with adeno-associated viruses (AAVs) harboring human SMARCE1-shRNA or -TetON to modulate SMARCE1 expression. Likewise, knockdown or overexpression of SMARCE1 induces or represses proliferation of neonatal murine cardiomyocyte, respectively. Interestingly, we verified increased SMARCE1 expression in the infarct myocardium of adult mouse heart (LAD-ligation) whereby proliferating cardiomyocytes are insufficient to regenerate the cardiac tissue, implying regulation of SMARCE1 may be key to enhance the regenerative capacity in the mammalian heart. Thus, tight regulation of the SWI/SNF chromatin remodeling complex subunit Smarce1/SMARCE1 is essential to orchestrate cardiomyocyte proliferation during development and regeneration in the vertebrate heart.