YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo

Dev Cell. 2019 Feb 12 piiS1534-5807(19)30045-0.

Doi: 10.1016/j.devcel.2019.01.017

Research into the regulation of the cardiomyocyte cell cycle has made a significant contribution to our understanding of the fundamental mechanisms underlying adult heart muscle homeostasis. Although the myocardium was considered to be a post-mitotic tissue for quite a long time, overwhelming evidence now suggests that adult cardiac muscle cells retain basal proliferation abilities, so that around 1% of cardiomyocytes are renewed every year (1-2). This crucial finding could be instrumental in the design, development and implementation of cell-based substitutive therapies aiming at healing the damaged heart.  However, the molecular mechanisms that control adult cardiomyocyte mitosis –either blocking or promoting it–, have remained elusive. In this study, Monroe and colleagues report new data on the crucial role played by the Hippo (YAP/TAZ) signalling pathway in the negative regulation of cardiac myocyte proliferation. These authors had already shown that YAP/TAZ can be experimentally manipulated to improve cardiomyocyte renewal (3), but results in this paper reveal a new, specific role for the Hippo pathway in controlling chromatin accessibility and cardiomyocyte proliferation. The authors asked if "more completely bypassing Hippo pathway negative regulation would more efficiently increase adult cardiomyocyte renewal" To test this hypothesis, they generated mice that conditionally overexpressed YAP5SA, a version of YAP that has all LATS1/2 phosphorylation sites mutated, in adult cardiomyocytes (4). YAP5SA mutant hearts display thickened ventricular hyperplastic walls and smaller chambers, a finding that is in accordance with the ability of YAP5SA cardiomyocytes to progress through the cell cycle. YAP5SA-induced promotion of cardiomyocyte proliferation is paralleled by a marked enrichment of mononuclear diploid, less mature cardiomyocytes in YAP5SA hearts (increase of cardiomyocyte ploidy normally arrests adult cardiac muscle proliferation). Nevertheless, the key finding of this study is that chromatin accessibility, including regions containing embryonic developmental enhancers, is sharply increased in YAP5SA mice. In summary, YAP5SA induces adult cardiomyocyte reversion to a proliferative, fetal-like cell state by both decreasing repression on cell cycle regulators and increasing the accessibility to chromatin domains that include essential cardiomyocyte developmental transcription factors like Mef2C and Nkx2.5..