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Chromatin remodelling is essential for cardiac development. Interestingly, the role of histone chaperones has not been investigated in this regard. HIRA is a member of the HUCA (HIRA/UBN1/CABIN1/ASF1a) complex that deposits the variant histone H3.3 on chromatin independently of replication. Lack of HIRA has general effects on chromatin and gene expression dynamics in embryonic stem cells and mouse oocytes. Here we describe the conditional ablation of  Hira  in the cardiogenic mesoderm of mice. We observed surface oedema, ventricular and atrial septal defects and embryonic lethality. We identified dysregulation of a subset of cardiac genes, notably upregulation of troponins  Tnni2  and  Tnnt3 , involved in cardiac contractility and decreased expression of  Epha3 , a gene necessary for the fusion of the muscular ventricular septum and the atrioventricular cushions. We found that HIRA binds GAGA rich DNA loci in the embryonic heart, and in particular a previously described enhancer of  Tnni2/Tnnt3  ( TTe ) bound by the transcription factor NKX2.5. HIRA-dependent H3.3 enrichment was observed at the  TTe  in embryonic stem cells (ESC) differentiated toward cardiomyocytes  in vitro . Thus, we show here that HIRA has locus-specific effects on gene expression and that histone chaperone activity is vital for normal heart development, impinging on pathways regulated by an established cardiac transcription factor.

HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3