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PLoS Genet. 2013;9(12):e1003994. doi: 10.1371/journal.pgen.1003994. Epub 2013 Dec 19.

Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions.

Author information

1
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
2
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland ; Swiss Institute of Bioinformatics, Basel, Switzerland.
3
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland ; Faculty of Science, University of Basel, Basel, Switzerland.

Abstract

Distal regulatory elements, including enhancers, play a critical role in regulating gene activity. Transcription factor binding to these elements correlates with Low Methylated Regions (LMRs) in a process that is poorly understood. Here we ask whether and how actual occupancy of DNA-binding factors is linked to DNA methylation at the level of individual molecules. Using CTCF as an example, we observe that frequency of binding correlates with the likelihood of a demethylated state and sites of low occupancy display heterogeneous DNA methylation within the CTCF motif. In line with a dynamic model of binding and DNA methylation turnover, we find that 5-hydroxymethylcytosine (5hmC), formed as an intermediate state of active demethylation, is enriched at LMRs in stem and somatic cells. Moreover, a significant fraction of changes in 5hmC during differentiation occurs at these regions, suggesting that transcription factor activity could be a key driver for active demethylation. Since deletion of CTCF is lethal for embryonic stem cells, we used genetic deletion of REST as another DNA-binding factor implicated in LMR formation to test this hypothesis. The absence of REST leads to a decrease of hydroxymethylation and a concomitant increase of DNA methylation at its binding sites. These data support a model where DNA-binding factors can mediate turnover of DNA methylation as an integral part of maintenance and reprogramming of regulatory regions.

PMID:
24367273
PMCID:
PMC3868540
DOI:
10.1371/journal.pgen.1003994
[Indexed for MEDLINE]
Free PMC Article

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