image: The illustration of UHRF1-DNMT1 mediated DNA methylation at a genomic region with (left) or without (right) H3K27me3 modification. The presence of H3K27me3 inhibits UHRF1 mediated H3 ubiquitination, which is required for recruitment and activation of DNMT1. view more
Credit: ©Science China Press
In our cells, genes associated with alternative cell fate have to be silenced. DNA methylation and H3K27me3 on the histone are two of the most prevalent chromatin modifications that control the epigenetic gene silencing. These two modifications are mutually exclusive in the genome. However, whether and how H3K27me3 affects DNA methylation?
A new study published in SCIENCE CHINA Life Sciences reveals that H3K27me3 inhibits DNA methylation through repressing a third chromatin modification, UHRF1-mediated ubiquitination of H3, which is essential for recruiting DNA methyltransferase 1 (DNMT1).
DNA methylation mostly takes place on CpG dinucleotide in mammals and is heritable following cell division, providing a key mechanism for the cell to maintain its cell state. In the mammalian genome, most of the CpG sites are methylated by default, while selected regions are lowly methylated. These lowly methylated regions are associated with dynamic transcriptional regulation by DNA methylation, including CpG islands, H3K27me3 modified regions, and enhancers. Therefore, understanding why these regions are lowly methylated represents a key question in the dynamic regulation of DNA methylation.
In the current study, researchers from Institute of genetics and developmental biology Chinese Academy of Sciences report the mechanism underlying low DNA methylation in regions with H3K27me3 in the genome. They find that ubiquitination on H3, namely H3K18ub and H3K23ub, is depleted from nucleosomes containing H3K27me3 in the chromatin. The H3 ubiquitination is catalyzed by UHRF1 and is essential for recruitment and activation of DNMT1. Removal of H3K27me3 through knockout of key component of the H3K27me3 modifying complex leads to increase of both DNA methylation and H3K18ub in the regions previously marked with H3K27me3 modification, suggesting the potential role of H3K18ub in mediating low DNA methylation at H3K27me3 modified regions. Indeed, the role is further confirmed by the fact that H3K27me3 on the nucleosomes can directly inhibit the ubiquitination activity of UHRF1 toward nucleosomes. Together, these findings indicate that H3K27me3 antagonizes DNA methylation by inhibiting UHRF1-mediated H3 ubiquitination.
CpG sites are lowly methylated mainly in three groups of regions: CpG islands, H3K27me3 modified regions, and enhancers. This study reveals a key mechanism in regulating the low DNA methylation status in H3K27me3 modified regions. Previous study by Dr. Falong Lu, the senior author of the current study, has revealed that active DNA demethylation by Tet family proteins is the key mechanism in regulating the low DNA methylation status in enhancer regions. Therefore, the mechanism that protects CpG islands from DNA methylation is one of the most important questions which remains to be answered for the global DNA methylation regulation in the future.
###
See the article:
H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination
https://doi.org/10.1007/s11427-022-2155-0
Journal
Science China Life Sciences