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 posttranslational 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.