Impact of human MLL/COMPASS and polycomb complexes on the DNA methylome

Emily L. Putiri, Rochelle L. Tiedemann, Chunsheng Liu, Jeong Hyeon Choi, Keith D. Robertson

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The correlation between DNA methylation and a subset of histone posttranslational 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 coregulated 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.

Original languageEnglish (US)
Pages (from-to)6338-6352
Number of pages15
JournalOncotarget
Volume5
Issue number15
DOIs
Publication statusPublished - 2014

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Keywords

  • Cancer
  • DNA methylation
  • Epigenetics
  • Histone methylation
  • Histone modification

ASJC Scopus subject areas

  • Oncology

Cite this

Putiri, E. L., Tiedemann, R. L., Liu, C., Choi, J. H., & Robertson, K. D. (2014). Impact of human MLL/COMPASS and polycomb complexes on the DNA methylome. Oncotarget, 5(15), 6338-6352. https://doi.org/10.18632/oncotarget.2215