清华大学颉伟与合作者研究开发出了H3K36me2的重编程引导谱系特异性植入后新生DNA甲基化。这一研究成果于2025年11月11日发表在国际顶尖学术期刊《自然—细胞生物学》上。

本研究探讨了H3K36me2重编程在小鼠早期发育中的作用及其在着床后DNA甲基化重建中的作用。在卵母细胞中，H3K36me2通过转录沉默在基因体中积累，并部分持续到8细胞期。除了在失活的X染色体上，H3K36me2在受精卵基因组激活后，在植入后全基因组扩散之前，在增强子上发生新生。H3K36me2甲基转移酶NSD1的突变在胚胎外谱系和甲基化易发启动子（包括种系特异性基因）中优先破坏着床后的整体DNA甲基化。

然而，DNA甲基化的建立通过上调的DNMT3B部分绕过H3K36me2， DNMT3B是一个“泄漏”的H3K36me2/3读取器。这与DNMT3A形成对比，DNMT3A通过其PWWP结构域严格要求H3K36me2/3进行DNA甲基化。最后，DNA甲基化谷通过PRC1/ h2ak119ub1介导的H3K36me2排除来逃避DNA甲基化。因此，H3K36me2重编程调节谱系和位点特异性植入后DNA甲基化的建立。

研究人员表示，在哺乳动物中，DNA甲基化在受精后整体消除后植入后重新建立。然而，潜在的机制仍然是未知的。

附：英文原文

Title: Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation

Author: Lu, Xukun, Wang, Lijuan, Liu, Bofeng, Hu, Xiaoyu, Wang, Zhengmao, Liu, Ling, Yu, Guang, Dong, Lijun, Kong, Feng, Fan, Qiang, Zhang, Yu, Xie, Wei

Issue&Volume: 2025-11-11

Abstract: In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment.

DOI: 10.1038/s41556-025-01805-8

Source: https://www.nature.com/articles/s41556-025-01805-8