ATAD2 drives HIRA/histone H3.3-dependent chromatin dynamics

ATAD2, expressed predominantly in embryonic stem cells as well as in spermatogenic cells emerges as a pivotal regulator of chromatin dynamics by mediating chromatin-bound histone chaperone turnover. Here, investigating the role of ATAD2 in spermatogenesis, we show that through its preponderant expression in haploid male germ cells, ATAD2 modulates the HIRA-dependent H3.3 genome localization and H3.3-dependent gene transcriptional regulation. Furthermore, by influencing histone eviction and the assembly of protamines, it ensures proper chromatin condensation and genome packaging in mature spermatozoa. The disruption of Atad2 results in aberrant mature spermatozoa genome organization, impacting male fertility. Collectively, these findings confirm the occurrence of an overlooked chromatin dynamic regulatory level controlling histone deposition-removal balance, depending on an ATAD2-controlled histone chaperone-chromatin interaction. Overall design: Transcriptomic analysis was performed in mouse testes samples obtained from WT and Atad2 KO homozygote male pups (wt and ko), sacrificed at 20, 22, 24 and 26 days post-birth (d20, d22, d24 and d26).