Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines postnatally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.

Department of Anatomy and Histology Bosch Institute University of Sydney Sydney NSW 2006 Australia

Department of Cardiology Boston Children's Hospital 300 Longwood Avenue Boston MA 02115 USA

Department of Cardiology Boston Children's Hospital 300 Longwood Avenue Boston MA 02115 USA; Department of Anatomy School of Basic Medicine Shanghai University of Traditional Chinese Medicine Shanghai 201203 China

Department of Cardiology Boston Children's Hospital 300 Longwood Avenue Boston MA 02115 USA; Harvard Stem Cell Institute Harvard University Cambridge MA 02138 USA

Department of Cardiology Boston Children's Hospital 300 Longwood Avenue Boston MA 02115 USA; Peking University 5th School of Clinical Medicine Beijing 100730 China

Department of Cardiology Leiden University Medical Center 2300 RC Leiden the Netherlands

Institute of Molecular Medicine Peking University PKU Tsinghua U Joint Center for Life Sciences Beijing 100871 China

Rowland Institute at Harvard Harvard University Cambridge MA 02142 USA

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