清华大学颉伟团队近日取得一项新成果。经过不懈努力，他们的论文发现了EZHIP限制非规范PRC2结合，调控H3K27me3代际遗传和重编程。相关论文于2025年10月20日发表在《细胞—干细胞》杂志上。

课题组研究人员发现，在生长中的卵母细胞中，催化H3K27me3的PRC2结合了经典的Polycomb靶点和非规范的H3K27me3结构域，但在完全发育的卵母细胞中与染色质分离。受精后，PRC2在囊胚中重新结合非规范的H3K27me3结构域，然后重新定位到Polycomb靶点。有趣的是，PRC2的结合和活性受到母体抑制因子EZH抑制蛋白（EZHIP）的限制，该因子与PRC2共结合。在敲除Ezhip后，过度活跃的PRC2会在全基因组范围内混杂地沉积H3K27me3。这覆盖了H3K27me3在非规范印迹基因上的记忆，矛盾的是，H3K27me3靶点的抑制、缺陷的X染色体失活和稀释的染色质PRC2。植入Polycomb靶后H3K27me3的恢复也减弱，并伴有亚致死。这些数据揭示了表观遗传的原理，即异色不足和过多都标志着表观遗传记忆和抑制的丧失。

据了解，在小鼠中，抑制性组蛋白标记H3K27me3在亲代到胚胎的转变过程中经历了区域特异性遗传和擦除，其潜在机制尚不清楚。

附：英文原文

Title: EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming

Author: Yitian Zeng, Feng Kong, Zihan Xu, Xukun Lu, Qian Li, Bofeng Liu, Shu Liu, Lijun Dong, Ling Liu, Wenying Wang, Bing Zhu, Wei Xie

Issue&Volume: 2025-10-20

Abstract: In mice, the repressive histone mark H3K27me3 undergoes both region-specific inheritance and erasure during the parental-to-embryonic transition, with the underlying mechanisms poorly understood. Here, we show that PRC2, which catalyzes H3K27me3, binds both classic Polycomb targets and noncanonical H3K27me3 domains in growing oocytes but dissociates from chromatin in fully grown oocytes. After fertilization, PRC2 rebinds noncanonical H3K27me3 domains before relocating to Polycomb targets in blastocysts. Interestingly, the binding and activity of PRC2 are restricted by a maternal inhibitory factor, EZH inhibitory protein (EZHIP), which co-binds with PRC2. Upon knockout of Ezhip, hyperactive PRC2 promiscuously deposits H3K27me3 genome-wide. This overwrites H3K27me3 memories at noncanonical imprinted genes and paradoxically causes derepression of H3K27me3 targets, defective X chromosome inactivation, and diluted chromatin PRC2. H3K27me3 restoration at Polycomb targets after implantation is also attenuated, accompanied by sub-lethality. These data unveil principles of epigenetic inheritance that both insufficient and excessive heterochromatic marks cause loss of epigenetic memories and repression.

DOI: 10.1016/j.stem.2025.09.009

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00340-6