Restoration of RBM22 overcomes the transcriptional and epigenetic barriers of cardiomyocyte proliferation for heart regeneration.

Stimulating endogenous cardiomyocyte proliferation holds great therapeutic promise for cardiac repair, but how chromatin remodeling governs this process remains poorly understood. RNA-binding motif 22 (RBM22) participates in the regulation of various biological contexts, whereas its role in cardiac regeneration and repair is largely unknown. Here, we identify RBM22 as a pivotal regulator of cardiomyocyte proliferation. Cardiomyocyte-specific deletion of Rbm22 impairs neonatal heart regeneration and exacerbates post-infarction ventricular remodeling in adult mice. Mechanistically, RBM22 selectively binds to the proximal promoters of key cell cycle genes (Cdk4, Ccna2, and Ccne1), where it cooperates with chromatin remodeler SMARCA4 to enhance transcriptional accessibility. Furthermore, RBM22 is essential for the gene-specific recruitment of RNA Polymerase II to these gene loci to drive transcription. AAV9-mediated delivery of Rbm22 promotes cardiomyocyte proliferation in vivo following cardiac damage and increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. Our findings establish RBM22 as a transcriptional and epigenetic regulator that overcomes cell-cycle barriers in cardiomyocytes, highlighting its therapeutic potential for cardiac injury.