TEAD-independent mechanisms of YAP function in cardiomyocytes
Adult mammalian hearts exhibit limited regenerative capacity due to the restricted renewal of cardiomyocytes. Recent studies reveal that mammalian hearts exhibit transient regenerative potential within a short time frame after birth, suggesting a regulatory mechanism that prevents adult hearts from initiating a regenerative response to cardiac injury. Here, we discovered that an active form of YAP, named YAP6SA, which is not inhibited by the Hippo signaling pathway and does not interact with TEADs, induces cardiomyocyte cell cycle re-entry. In addition, YAP6SA interacts with scaffold protein MPDZ to regulate Rho GTPases and promote cell cycle progression in cardiomyocytes (CMs). Importantly, YAP6SA overexpression is well tolerated in mammalian hearts. These findings provide new insights into YAP function in cardiomyocytes. Overall design: Wildtype ICR mice were subcutaneously injected with 1*10^11 viral genomes of AAV9 virus containing cTnT-GFP, cTnT-YAP5SA, or cTnT-YAP6SA expression constructs at P6. Two hearts from each virus were collected at P9 and cardiomyocyte nuclei were enriched using anti-PCM1 pulldown. RNA was isolated using the RNeasy Plus Micro kit and poly-A enriched, non-directional libraries were generated by Novogene America and sequenced on the Illumina NovaSeq6000. Reads were mapped to the mouse genome (mm10, Ensembl GRCm38.94) using STAR. Lowly expressed genes were removed within each condition using median log2-transformed counts per gene per million mapped reads of 1, and a union set of genes was generated from each condition. Differential expression analysis was performed using edgeR using a general linear model framework with an additional covariate to mitigrate an apparent batch effect.