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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868540/ https://www.ncbi.nlm.nih.gov/pubmed/24367273 http://dx.doi.org/10.1371/journal.pgen.1003994 |
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author | Feldmann, Angelika Ivanek, Robert Murr, Rabih Gaidatzis, Dimos Burger, Lukas Schübeler, Dirk |
author_facet | Feldmann, Angelika Ivanek, Robert Murr, Rabih Gaidatzis, Dimos Burger, Lukas Schübeler, Dirk |
author_sort | Feldmann, Angelika |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-3868540 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38685402013-12-23 Transcription Factor Occupancy Can Mediate Active Turnover of DNA Methylation at Regulatory Regions Feldmann, Angelika Ivanek, Robert Murr, Rabih Gaidatzis, Dimos Burger, Lukas Schübeler, Dirk PLoS Genet Research Article 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. Public Library of Science 2013-12-19 /pmc/articles/PMC3868540/ /pubmed/24367273 http://dx.doi.org/10.1371/journal.pgen.1003994 Text en © 2013 Feldmann et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Feldmann, Angelika Ivanek, Robert Murr, Rabih Gaidatzis, Dimos Burger, Lukas Schübeler, Dirk Transcription Factor Occupancy Can Mediate Active Turnover of DNA Methylation at Regulatory Regions |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868540/ https://www.ncbi.nlm.nih.gov/pubmed/24367273 http://dx.doi.org/10.1371/journal.pgen.1003994 |
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