Jiang Xuanzhao, Wen Jiayu, Nelson Mary L, Dijkwel Yasmin, Cairns Bradley, Bauer Uta-Maria, Hart-Smith Gene, Soboleva Tatiana A, Tremethick David J
The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems, Canberra, Australia.
Sci Adv. 2025 Jul 25;11(30):eadx1568. doi: 10.1126/sciadv.adx1568.
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.
用组蛋白变体取代其经典形式能够实现对哺乳动物基因组的动态且依赖于上下文的调控。组蛋白变体在包括恶性肿瘤在内的各种病理过程中也发挥着关键作用。其中，睾丸特异性组蛋白变体H2A.B的异常表达促成了霍奇金淋巴瘤的发病机制。组蛋白变体的多功能性受其翻译后修饰（PTM）调控。然而，H2A.B的PTM及其功能意义尚不清楚。在此，我们证明H2A.B的氨基末端作为一个中心枢纽，用于多种基因调控蛋白 - 蛋白相互作用，这些相互作用由磷酸化和精氨酸甲基化精心编排。这包括一种机制，即非染色质结合的H2A.B与SWI/SNF结合，这限制了它对基因组的接近。最后，我们将磷酸化的H2A.B鉴定为活性RNA聚合酶II转录起始位点的一个先前未被表征的标记。这些发现阐明了H2A.B在基因组调控中的核心作用，并突出了其PTM在调节其多功能作用中的重要性。
