Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks

Abstract

To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or (ii) genes with high CpG density and DNA methylation in the gene body. We observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 occupancy is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For genes with high intragenic CpG density, transcription and H3K36me3 occupancy were not changed in conditions of partial or intensive loss of DNA methylation in gene bodies. siRNA knockdown of SETD2, the major histone methyltransferase responsible for production of H3K36me3, did not reduce DNA methylation in gene bodies. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established largely independently of each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively.

Linkage disequilibrium analysis of allelic heterogeneity in DNA methylation

“…16 Furthermore, gene body methylation is associated with intragenic chromatin modifications such as H3K9me3. 17 Thus, the present finding that the transitional boundary differs among alleles may indicate that the boundary of gene body methylation differs among cells, possibly depending on the degree of histone modifications and/or activity of gene expression.…”

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

“…There could be several possible mechanisms for why there is increased variation in this genic region and how this may influence variability in gene expression that should be tested in future research. These include modified transcription efficiency, different levels of sense and antisense mRNA, or altering (or being altered by) the variability in local histone marks that are focused on this promoter proximal intragenic region, such as H3K36me3 (42,43). There is considerable evidence from monozygotic twin studies (44,45) and cross-sectional studies (5,46,47) that the epigenome changes with age.…”

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

“…Although other groups have previously analyzed DNA methylation and gene expression in DKO1 cells [24][25][26], this had not been done on a genome-wide scale. Because methylated promoters are in condensed chromatin which cannot be accessed by transcription factors and because DNA methylation of recognition motifs has been shown to inhibit transcription factor binding [27,28], we had anticipated that the de-methylation of promoters in DKO1 cells would expose thousands of previously inaccessible binding motifs, many of which would be recognized by transcription factors that are ubiquitously expressed.…”