Palmitoyltransferase ZDHHC19 regulates histone-to-protamine exchange during spermiogenesis in mice

Spermiogenesis, the final phrase of spermatogenesis, involves replacing histones by protamines, a process known as histone-to-protamine exchange, which is crucial for chromatin condensation. While this exchange is essential, the precise mechanisms remain incompletely understood. In this study, we discovered that the palmitoyltransferase ZDHHC19 functions as a key regulator of mouse spermiogenesis. Loss of Zdhhc19 leads to male infertility and abnormal sperm morphology. Zdhhc19 -deficient sperm exhibit impaired histone-to-protamine exchange, leading to retention of histones and misdistribution of protamines. Similarly, the palmitoyltransferase catalytic site mutant Zdhhc19 C142S knock-in mice show reduced fertility, sperm abnormalities, and histone retention. Mechanistically, ZDHHC19 mediates histone H3 palmitoylation at cysteine-110, weakening H3-H4 interactions and increasing chromatin accessibility. Palmitoylation of H3 facilitates histone-to-protamine exchange. This study highlights the essential role of ZDHHC19’s palmitoyl-transferase activity in histone-to-protamine exchange during spermiogenesis and underscores the broader role of histone palmitoylation in chromatin remodeling.