Abstract
The correlation between DNA methylation and a subset of histone post-translational modifications (positive and negative) has hinted at an underlying regulatory crosstalk between histone marks and DNA methylation in patterning the human DNA methylome, an idea further supported by corresponding alterations to both histone marks and DNA methylation during malignant transformation. This study investigated the framework by which histone marks influence DNA methylation at a genome-wide level. Using RNAi in a pluripotent human embryonic carcinoma cell line we depleted essential components of the MLL/COMPASS, polycomb repressive complex 2 (PRC2), and PRC1 histone modifying complexes that establish, respectively, the post-translational modifications H3K4me3, H3K27me3, and H2AK119ub, and assayed the impact of the subsequent depletion of these marks on the DNA methylome. Absence of H2AK119ub resulted predominantly in hypomethylation across the genome. Depletion of H3K4me3 and, surprisingly, H3K27me3 caused CpG island hypermethylation at a subset of loci. Intriguingly, many promoters were co-regulated by all three histone marks, becoming hypermethylated with loss of H3K4me3 or H3K27me3 and hypomethylated with depletion of H2AK119ub, and many of these co-regulated loci were among those commonly targeted for aberrant hypermethylation in cancer. Taken together, our results elucidate novel roles for polycomb and MLL/COMPASS in regulating DNA methylation and define targets of this regulation.
Highlights
Cytosine methylation and histone posttranslational modifications create a complex epigenetic system required for the regulation and maintenance of gene expression programs that specify cell state
NCCIT is a nonseminomatous germ cell-derived teratoma that exhibits characteristics of pluripotent cells, in that it can be induced to differentiate into embryonic germ layers, and the NCCIT transcriptome resembles that of human embryonic stem cells (ESC) [28, www.impactjournals.com/oncotarget
We asked whether depletion of H3K4me3 by siRNA against WDR5 would result in DNA hypermethylation, if these two epigenetic marks are functionally interrelated
Summary
Cytosine methylation and histone posttranslational modifications create a complex epigenetic system required for the regulation and maintenance of gene expression programs that specify cell state (i.e., pluripotent and differentiated cell states). Determining how CpG methylation and histone marks cooperate to instruct normal cell expression programs and how this cooperation breaks down in human disease is an important area only just beginning to be understood. Numerous histone modifications involved in transcriptional regulation have been identified [1]. Three such marks are monoubiquitination of histone. PcG proteins regulate gene expression programs for developmental processes such as ESC pluripotency, cell fate decisions, and tissue patterning [2], and PcG binding and aberrant repression of tumor suppressor target genes facilitates cancer stem cell maintenance in many tumor types [3]. H3K27me is established by the histone methyltransferase enhancer of zeste homolog 2 (EZH2), but EZH2’s catalytic activity is dependent on embryonic ectoderm development (EED) and suppressor of zeste www.impactjournals.com/oncotarget
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