Zinc finger protein Znf296 is a cardiac-specific splicing regulator required for cardiomyocyte formation

Heart formation and function are tightly regulated at transcriptional and post-transcriptional levels. The dysfunction of cardiac cell-specific regulatory genes leads to various heart diseases. Heart failure is one of the most severe and complex cardiovascular diseases, which could be fatal if not treated promptly. However, the exact causes of heart failure are still unclear, especially at the level of single-gene causation. Here, we uncover an essential role for the zinc finger protein Znf296 in heart development and cardiac contractile function. Specifically, znf296-deficient zebrafish embryos display heart defects characterized by decreased systolic and diastolic capacities of the ventricle and atrium. This is associated with reduced numbers and disrupted structural integrity of cardiomyocytes, including disorganized cytoskeleton and absence of sarcomeres. Mechanistically, the loss of Znf296 alters the alternative splicing of a subset of genes important for heart development and disease, such as mef2ca, sparc, tpm2, camk2g1, tnnt3b and pdlim5b. Furthermore, we demonstrate that Znf296 biochemically and functionally interacts with Myt1la in regulating cardiac-specific splicing and heart development. Importantly, we show that ZNF296 also regulates alternative splicing in human cardiomyocytes to maintain structural integrity. These results suggest that Znf296 plays a conserved role for the differentiation of cardiomyocytes and the proper function of the cardiovascular system.