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.
Highlights
Methylation of cytosines at promoters is an epigenetic mark, which is linked to gene silencing
It is well known that DNA methylation prevents binding of a number of transcription factors and attracts methylated-CpG binding domain proteins (MBDs) together with chromatin modifiers, which are responsible for the repressive chromatin structure [1]
The H3K9 methyltransferase, SUV39H1 interacts with DNA-methyltransferase 1 (DNMT1) and due to a common interaction partner, HP1, SUV39H1 can be found in the same complex with the de novo DNA methyltransferase, DNMT3B [12,14,15,16]
Summary
Methylation of cytosines at promoters is an epigenetic mark, which is linked to gene silencing. The main regulatory function of DNA methylation has been associated with CpG-rich regions, CpG islands, which are frequently co-localized with gene promoters. Aberrant CpG island DNA methylation in cancer has been linked to the Polycomb-associated repressive histone mark, H3K27me3 [4,5,6]. This histone mark or its associated Polycomb components predispose target sequences to DNA methylation, for example during aging, inflammation and carcinogenesis [6,7,8,9]. SETDB1, a methyltransferase that produces H3K9me, has been detected in complex with the de novo DNA methyltransferase, DNMT3A [17]
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