Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer

Abstract

While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a lowpassage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

“…This de-methylation was most prominent in ''partially methylated domains'' (PMDs, Hon et al, 2012;Lister et al, 2009), a feature shared in memory differentiation of B cells, but absent during the differentiation of monocytes into macrophages (Wallner et al, 2016). PMDs have been associated with heterochromatic histone signatures and correlate to regions, which are replicated late during S phase and progressively lose methylation during strong proliferation (Aran et al, 2011).…”

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

“…A slight tendency for the enrichment of H3K27Ac, a histone mark characteristic of active enhancers (Creyghton et al., 2010), was also detected in our analyses. Intriguingly, the chromatin signature of DNA hypomethylation in cancer was substantially different, being primarily enriched in the posttranslational repressive histone modification H3K9me3, a relationship that has been investigated in colon and breast cancer (Berman et al., 2011; Hon et al., 2012). This observation might be conceptually relevant because DNA methylation has been proposed to be a molecular link between aging and cancer (Fraga, Agrelo & Esteller, 2007; Klutstein, Nejman, Greenfield & Cedar, 2016).…”

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

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