H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination  

作　　者：Honglian Zhang Ying Liu Yali Xie Yunji Zhu Jingwen Liu Falong Lu 

机构地区：[1]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Innovative Academy of Seed Design,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Science China(Life Sciences)》2022年第9期1685-1700,共16页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China (2018YFA0107001, 2018YFC1004000);the CAS Project for Young Scientists in Basic Research (YSBR-012);the National Natural Science Foundation of China (32070607)。

摘　　要：DNA methylation and histone lysine tri-methylation at H3K27(H3K27me3)are two chromatin modifications for transcriptional gene silencing,which play important roles in diverse biological processes,including cell fate determination and cell lineage commitment.These two marks are largely mutually exclusive and target distinct sets of genes in the mammalian genome.However,how H3K27me3 shapes the DNA methylome remains elusive.Here,we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites,indicating that H3K27me3 negatively regulates DNA methylation.Genome-wide analysis of H3 ubiquitination,essential for recruitment and activation of DNA methyltransferase DNMT1,reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes.Moreover,loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hyper-methylated loci.Importantly,we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay.Taken together,our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination.

关 键 词：DNA methylation H3K27me3 UHRF1 POLYCOMB H3 ubiquitination 

分 类 号：Q523[生物学—生物化学]