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

Feldmann, Angelika
Ivanek, Robert
Gaidatzis, Dimos
Burger, Lukas
Schübeler, Dirk
Published in PLOS genetics. 2013, vol. 9, no. 12, e1003994
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.
Keywords AnimalsBinding SitesCell DifferentiationCpG Islands/geneticsCytosine/analogs & derivatives/pharmacologyDNA Methylation/geneticsDNA-Binding Proteins/geneticsEmbryonic Stem CellsGene Expression Regulation/drug effectsGenomeMicePromoter Regions, GeneticRegulatory Sequences, Nucleic Acid/geneticsRepressor Proteins/geneticsTranscription Factors/geneticsTranscription, Genetic
PMID: 24367273
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Research group Epigénétique et développement (950)
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FELDMANN, Angelika et al. Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. In: PLOS genetics, 2013, vol. 9, n° 12, p. e1003994. doi: 10.1371/journal.pgen.1003994 https://archive-ouverte.unige.ch/unige:42923

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Deposited on : 2014-12-09

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