The control of gene expression and cell identity by H3K9 trimethylation

Abstract

Histone 3 lysine 9 trimethylation (H3K9me3) is a conserved histone modification that is best known for its role in constitutive heterochromatin formation and the repression of repetitive DNA elements. More recently, it has become evident that H3K9me3 is also deposited at certain loci in a tissue-specific manner and plays important roles in regulating cell identity. Notably, H3K9me3 can repress genes encoding silencing factors, pointing to a fundamental principle of repressive chromatin auto-regulation. Interestingly, recent studies have shown that H3K9me3 deposition requires protein SUMOylation in different contexts, suggesting that the SUMO pathway functions as an important module in gene silencing and heterochromatin formation. In this Review, we discuss the role of H3K9me3 in gene regulation in various systems and the molecular mechanisms that guide the silencing machinery to target loci.

Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

“…We also looked for genomic sites where gene expression levels might be affected by promoter DNA hypomethylation (at least 15% methylation change, 7CpGs), but found only one such locus ( Figure S3). Indeed, a number of Zbtb24-hypoDMRs are targets for H3K9me3 (Figure 3), which is associated with gene repression and a major silencing pathway in mESCs (Ninova et al 2019). Therefore, at these Zbtb24-hypoDMRs, persistent H3K9me3 could explain the absence of gene expression changes.…”

Epigenetic Reprogramming During Somatic Cell Nuclear Transfer: Recent Progress and Future Directions

“…During SCNT-mediated nuclear reprogramming, H3K4me3 level decreases and H3K27me3 level increases (Cao et al, 2015;Xie et al, 2016;Zhai et al, 2018;Zhou et al, 2019). Another modification, H3K9me3, is catalyzed by suppressor of variegation 39H1/2 (Suv39H1/2) and removed by lysine demethylase (Kdm)4 (Kdm4a, Kdm4b, Kdm4d, and Kdm4e), and can alter chromatin conformation to inhibit gene expression (Ninova et al, 2019). H3K9me3 can be removed in donor somatic cells, but incomplete H3K9me3 demethylation in cloned embryos inhibits their development.…”

Alternative Lengthening of Telomeres and Chromatin Status

“…First of all, H3K9me3 is not always associated with silencing. Studies in flies have shown that active genes that reside in constitutive heterochromatin are usually enriched in H3K9me3 across their bodies but not around the transcription start site, and loss of H3K9me3 results in transcriptional downregulation [29]. Moreover, Vakoc et al [30] showed that H3K9me3 and H3K9me2 occur, altogether with HP1γ, in the transcribed region of active genes in mammalian chromatin and are rapidly removed upon gene repression.…”

“…Differences are probably due to the type and status of the cell, but also to the different techniques used. A hypothesis that could be put forward is that the epigenetic feature of telomeres is not spatially homogenous: the proximal part is heterochromatic, due to the vicinity of the subtelomere (in fact, H3K9me3 can spread in cis over several kilobases [29], whereas the distal part is marked by active histones and compacted by shelterins (and not repressive histones).…”