Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation

Abstract

The precise regulation of gene transcription is required to establish and maintain cell type-specific gene expression programs during multicellular development. In addition to transcription factors, chromatin, and its chemical modification, play a central role in regulating gene expression. In vertebrates, DNA is pervasively methylated at CG dinucleotides, a modification that is repressive to transcription. However, approximately 70% of vertebrate gene promoters are associated with DNA elements called CpG islands (CGIs) that are refractory to DNA methylation. CGIs integrate the activity of a range of chromatin-regulating factors that can post-translationally modify histones and modulate gene expression. This is exemplified by the trimethylation of histone H3 at lysine 4 (H3K4me3), which is enriched at CGI-associated gene promoters and correlates with transcriptional activity. Through studying H3K4me3 at CGIs it has become clear that CGIs shape the distribution of H3K4me3 and, in turn, H3K4me3 influences the chromatin landscape at CGIs. Here we will discuss our understanding of the emerging relationship between CGIs, H3K4me3, and gene expression.

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

“…Demethylation of CpG islands may shape the distribution of H3K4me3, and, in turn, H3K4me3 may influence the chromatin landscape at CpG islands. 227,228 Therefore, the detailed mechanism linking H3K4me3 to upregulation of gene expression remains to be explored.…”

Enhancer-associated H3K4 methylation safeguards in vitro germline competence

“…Our data suggest that a significant fraction of PGCLC enhancers display permissive chromatin features in EpiLC that might contribute to their increased germline competence compared to EpiSC. These permissive features could be attributed, at least partly, to the persistence of H3K4me1 in EpiLC, as this histone mark could (i) protect PGCLC enhancers from mCpG and H3K9me2/3 52, 55–59 and/or (ii) facilitate the recruitment of chromatin remodelling complexes 40 . To directly assess the importance of H3K4me1 for germline competence and PGCLC specification, we used mESC catalytically deficient for MLL3 and MLL4 (dCD and dCT ESC lines; Fig.…”

“…However, it is important to consider that, in comparison to mammalian cells, the D. melanogaster genome is largely devoid (< 0.03 %) of cytosine methylation throughout its entire life cycle 77 . Previous studies have extensively documented the protective role of H3K4me1/2 against CpG methylation and heterochromatinization 36,[61][62][63][64][65] . Congruently, we found that H3K4me1/2 deficient cells displayed increased mCpG levels within PGCLC enhancers.…”

Dynamics of transcription-mediated conversion from euchromatin to facultative heterochromatin at the Xist promoter by Tsix

“…The introduction of DNA methylation can be explained in terms of the following three prerequisites: (1) removing H3K4me3, (2) introducing H3K36me3, and (3) chromatin remodeling accompanied by reoccupation of the À1 nucleosome position of the TSS. A potential link between removal of H3K4me3 and introduction of DNA methylation has been proposed because they are mutually and exclusively enriched on the genome, and perturbation of H3K4me3 is associated with increased DNA methylation at certain genomic loci (Hughes et al, 2020). Furthermore, a potential link between H3K36me3 and DNA methylation has been suggested through the affinity of the PWWP domain of de novo methyltransferase Dnmt3 to H3K36me3 (Dhayalan et al, 2010;Heyn et al, 2019).…”