Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions.
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...
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doaj-a8e985109e104cbfb7c573e1c3f4a2052020-11-25T00:53:44ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-01912e100399410.1371/journal.pgen.1003994Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions.Angelika FeldmannRobert IvanekRabih MurrDimos GaidatzisLukas BurgerDirk SchübelerDistal 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.http://europepmc.org/articles/PMC3868540?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Angelika Feldmann Robert Ivanek Rabih Murr Dimos Gaidatzis Lukas Burger Dirk Schübeler |
spellingShingle |
Angelika Feldmann Robert Ivanek Rabih Murr Dimos Gaidatzis Lukas Burger Dirk Schübeler Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. PLoS Genetics |
author_facet |
Angelika Feldmann Robert Ivanek Rabih Murr Dimos Gaidatzis Lukas Burger Dirk Schübeler |
author_sort |
Angelika Feldmann |
title |
Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. |
title_short |
Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. |
title_full |
Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. |
title_fullStr |
Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. |
title_full_unstemmed |
Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. |
title_sort |
transcription factor occupancy can mediate active turnover of dna methylation at regulatory regions. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2013-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3868540?pdf=render |
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