DAXX Directs H3.4-to-H3.3 Histone Replacement During Spermatogenesis [Cut & Run]

During spermatogenesis, extensive chromatin remodeling and histone replacement reshape the male germline epigenome. While HIRA is known to mediate transcription-coupled incorporation of histone variant H3.3, we identify DAXX as a key histone chaperone directing genome-wide, transcription-dependent replacement of H3.4 (H3T) with H3.3 on autosomes during male meiosis. Simultaneously, DAXX also directs transcription-independent H3.4-to-H3.3 replacement on the sex chromosomes during meiotic sex chromosome inactivation (MSCI). These distinct, chromosome-specific modes of DAXX-mediated H3.3 deposition are essential for epigenomic integrity in the male germline. Loss of DAXX disrupts this process, leading to widespread transcriptional dysregulation in haploid round spermatids and male infertility.