Abstract Body: RNA-binding proteins (RBPs) are increasingly recognized as critical modulators of cardiac development and pathology. Among them, RBM24 plays essential roles in cardiomyocyte development and sarcomere organization, yet the scope of its downstream effectors is not fully understood. Here, we identify TF1, a transcription factor indispensable for ventricular morphogenesis, as a major downstream effector of RBM24.
Loss of RBM24 resulted in a marked reduction of TF1 expression and a pronounced alteration in its subcellular distribution. Ectopic expression of RBM24 in the knockout background restored both TF1 level and localization, indicating that RBM24 is required to maintain proper TF1 regulation. Mechanistically, RNA immunoprecipitation and enhanced crosslinked immunoprecipitation (eCLIP) analyses revealed direct binding of RBM24 to the TF1 transcript. Consistently, mRNA decay assays demonstrated that RBM24 stabilizes TF1 mRNA. In parallel, RBM24 deficiency disrupted the poly(A)-binding protein network, including PABPN1 and PABPC1, suggesting broader perturbation of mRNP organization.
Functionally, TF1 knockout in hPSC-derived cardiomyocytes caused severe sarcomere disorganization, underscoring its essential role in maintaining cardiomyocyte structural integrity. Together, these findings uncover a previously unrecognized RBM24–TF1 regulatory axis that integrates RNA stability and protein localization to control cardiogenesis, providing new mechanistic insight into congenital heart disease and may inform future therapeutic strategies.