Substantial Adaptability of Mononuclear Polyploid Cardiomyocytes Revealed by Perinatal Loss of Chaf1a

Here, we show that chromatin assembly factor 1 subunit A (Chaf1a), a key regulator of nucleosome deposition during DNA replication, is essential for postnatal cardiomyocyte proliferation and binucleation. Using cardiomyocyte-specific Chaf1a knockout mice (Myh6-Cre; Chaf1af/f), we demonstrate that Chaf1a deficiency disrupts karyokinesis, leading to a marked increase in the proportion of mononuclear polyploid cardiomyocytes and a reduction in binucleated cells. This results in nearly 50% fewer cardiomyocytes, yet strikingly, the hearts preserve baseline function through substantial compensatory hypertrophy without significant fibrosis. Notably, following cardiac apex resection, neonatal Myh6-Cre; Chaf1af/f mice fail to regenerate myocardium, highlighting the essential role of Chaf1a in cardiac regeneration.