美国纽约大学Karim-Jean Armache小组揭示了Polycomb抑制复合物1对H2A泛素化的读写机制。2024年11月13日，《自然》杂志在线发表了这项成果。

研究人员表示，沉默染色质区域的表观遗传遗传性对胚胎发生期间的细胞记忆至关重要，但它必须克服在DNA复制过程中抑制性组蛋白修饰的稀释。组蛋白H2A赖氨酸119单泛素化（H2AK119Ub）就是其中一种修饰，它需要通过Polycomb抑制复合物1（PRC1）E3连接酶重新建立，以恢复沉默的Polycomb区域。然而，恢复的具体机制仍不清楚。

研究人员结合了冷冻电子显微镜（cryo-EM）和功能性方法，表征了非经典PRC1含RYBP（ncPRC1^RYBP）的读写机制。这一机制作为表观遗传调控中的正反馈环路，强调了ncPRC1^RYBP在恢复H2AK119Ub中的关键作用。

研究人员观察到ncPRC1^RYBP不对称地结合到H2AK119Ub核小体上，部分是通过RYBP的N末端锌指结构域与新生染色质上的残留H2AK119Ub结合。这一识别将RING1B和BMI1的RING结构域定位在未修饰的核小体一侧，从而使E2酶的招募能够在同一核小体内对H2AK119进行泛素化（核小体内读写）或跨核小体泛素化（跨核小体读写）。

总的来说，这些研究结果为表观遗传调控的动态相互作用提供了关键的结构和机制见解，突显了ncPRC1^RYBP在恢复H2AK119Ub并维持抑制性染色质区域中的重要性。

附：英文原文

Title: Read–write mechanisms of H2A ubiquitination by Polycomb repressive complex 1

Author: Lpez, Victoria Godnez, Valencia-Snchez, Marco Igor, Abini-Agbomson, Stephen, Thomas, Jonathan F., Lee, Rachel, De Ioannes, Pablo, Sosa, Brian A., Armache, Jean-Paul, Armache, Karim-Jean

Issue&Volume: 2024-11-13

Abstract: Epigenetic inheritance of silent chromatin domains is fundamental to cellular memory during embryogenesis, but it must overcome the dilution of repressive histone modifications during DNA replication1. One such modification, histone H2A lysine 119 monoubiquitination (H2AK119Ub), needs to be re-established by the Polycomb repressive complex 1 (PRC1) E3 ligase to restore the silent Polycomb domain2,3. However, the exact mechanism behind this restoration remains unknown. Here, combining cryo-electron microscopy (cryo-EM) and functional approaches, we characterize the read–write mechanism of the non-canonical PRC1-containing RYBP (ncPRC1RYBP). This mechanism, which functions as a positive-feedback loop in epigenetic regulation4,5, emphasizes the pivotal role of ncPRC1RYBP in restoring H2AK119Ub. We observe an asymmetrical binding of ncPRC1RYBP to H2AK119Ub nucleosomes, guided in part by the N-terminal zinc-finger domain of RYBP binding to residual H2AK119Ub on nascent chromatin. This recognition positions the RING domains of RING1B and BMI1 on the unmodified nucleosome side, enabling recruitment of the E2 enzyme to ubiquitinate H2AK119 within the same nucleosome (intra-nucleosome read–write) or across nucleosomes (inter-nucleosome read–write). Collectively, our findings provide key structural and mechanistic insights into the dynamic interplay of epigenetic regulation, highlighting the significance of ncPRC1RYBP in H2AK119Ub restoration to sustain repressive chromatin domains.

DOI: 10.1038/s41586-024-08183-5

Source: https://www.nature.com/articles/s41586-024-08183-5