Nonchromatin regulatory functions of the histone variant H2A.B in SWI/SNF genomic deposition

The replacement of canonical histones with their variant forms enables the dynamic and context-dependent regulation of the mammalian genome. Histone variants also play key roles in various pathological processes including malignancies. Among these, the aberrant expression of the testis-specific histone variant H2A.B contributes to the pathogenesis of Hodgkin lymphoma. The multifunctionality of histone variants is regulated by their post-translational modifications (PTMs). However, the PTMs of H2A.B and their functional implications are unknown. Here, we demonstrate that the Amino terminus of H2A.B serves as a central hub for a diverse range of gene regulatory protein-protein interactions, orchestrated by phosphorylation and arginine methylation. This includes a mechanism whereby non–chromatin-bound H2A.B associates with SWI/SNF, which limits its access to the genome. Last, we identify phosphorylated H2A.B as a previously uncharacterized marker of active RNA polymerase II transcription start sites. These findings elucidate a central role for H2A.B in genome regulation and highlight the importance of its PTMs in modulating its multifunctional roles.