Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers

Abstract

Summary The role of cytosine methylation in the structure and function of enhancers is not well understood. In this study, we investigate the role of DNA methylation at enhancers by comparing the epigenomes of the HCT116 cell line and its highly demethylated derivative, DKO1. Unlike promoters, a portion of regular and “super-” or “stretch” enhancers show active H3K27ac marks co-existing with extensive DNA methylation, demonstrating the unexpected presence of “bivalent chromatin” in both cultured and uncultured cells. Furthermore, our findings also show that bivalent regions have fewer nucleosome-depleted regions and transcription factor binding sites than monovalent regions. Reduction of DNA methylation genetically or pharmacologically leads to a decrease of the H3K27ac mark. Thus DNA methylation plays an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity.

A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine

“…A previous study (39) found that loss of KDM5B in mouse embryonic stem cells (mESC’s) resulted in a misregulation of H3K4me3 and a subsequent decrease in H3K27ac at enhancers, implying a loss of activity. Furthermore, DAC has recently been suggested to have an antagonistic effect on super-enhancer activity in a number of cancer cell lines, though the effect at regular enhancers remains unclear (40). We analyzed H3K4me3 and H3K27ac localization at candidate enhancers (as identified by ChromHMM) in MCF-7 via ChIP-seq (32,41).…”

“…2E), although epistatic pathway interactions likely contribute to this observation as well. To our knowledge, only one study regarding the role of DAC at distal regulatory elements has been published (40). The authors found that DNMT inhibition led to decreased activity of super-enhancers in MCF-7.…”

Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks

“…Enhancers are known as tissue-specific regulators of gene expression during cell differentiation and cancer development (33, 38, 40, 41). Enhancers are commonly identified as genomic elements enriched by histone modification (H3K27ac and different H3K4me isoforms), predominantly hypomethylated (42, 43), and occupied by various transcription factors, BRD4 (BET bromodomain protein, an activator of RNA polymerase II - PolII), MED1 (PolII transcription subunit) proteins, and PolII itself (33). H3K27ac enrichment at enhancer regions is recognized by BRD4, whose inhibition leads to a dysregulation in gene expression of oncogenes such as MYC, MYB, MMP9, BCL2, and CCND1 (40, 41, 44, 45).…”

The contributions of cancer cell metabolism to metastasis

“…DNA methylation also occurs at actively transcribed gene bodies and at active enhancers (Baubec et al, 2015; Charlet et al, 2016; Dhayalan et al, 2010; Rinaldi et al, 2016). DNMTs are responsible for catalysing the transfer of a methyl group to DNA.…”