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

Spermiogenesis, the final phase 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 reducing its affinity for DNA. 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 significance of histone palmitoylation in chromatin remodeling.