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Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of
Polycomb target genes
#MMPMID23531360
Reddington JP
; Perricone SM
; Nestor CE
; Reichmann J
; Youngson NA
; Suzuki M
; Reinhardt D
; Dunican DS
; Prendergast JG
; Mjoseng H
; Ramsahoye BH
; Whitelaw E
; Greally JM
; Adams IR
; Bickmore WA
; Meehan RR
Genome Biol
2013[Mar]; 14
(3
): R25
PMID23531360
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BACKGROUND: DNA methylation and the Polycomb repression system are epigenetic
mechanisms that play important roles in maintaining transcriptional repression.
Recent evidence suggests that DNA methylation can attenuate the binding of
Polycomb protein components to chromatin and thus plays a role in determining
their genomic targeting. However, whether this role of DNA methylation is
important in the context of transcriptional regulation is unclear. RESULTS: By
genome-wide mapping of the Polycomb Repressive Complex 2-signature histone mark,
H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that
hypomethylation leads to widespread H3K27me3 redistribution, in a manner that
reflects the local DNA methylation status in wild-type cells. Unexpectedly, we
observe striking loss of H3K27me3 and Polycomb Repressive Complex 2 from Polycomb
target gene promoters in DNA hypomethylated cells, including Hox gene clusters.
Importantly, we show that many of these genes become ectopically expressed in DNA
hypomethylated cells, consistent with loss of Polycomb-mediated repression.
CONCLUSIONS: An intact DNA methylome is required for appropriate
Polycomb-mediated gene repression by constraining Polycomb Repressive Complex 2
targeting. These observations identify a previously unappreciated role for DNA
methylation in gene regulation and therefore influence our understanding of how
this epigenetic mechanism contributes to normal development and disease.
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