Cited by 1,383Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

DNA-binding factors shape the mouse methylome at distal regulatory regions

Open access
Stadler, Michael B., Murr, Rabih, Burger, Lukas, Ivanek, Robert, Lienert, Florian, Schöler, Anne, Nimwegen, Erik van, Wirbelauer, Christiane +4 more·2011·Nature

Abstract

Methylation of cytosines is an essential epigenetic modification in mammalian genomes, yet the rules that govern methylation patterns remain largely elusive. To gain insights into this process, we generated base-pair-resolution mouse methylomes in stem cells and neuronal progenitors. Advanced quantitative analysis identified low-methylated regions (LMRs) with an average methylation of 30%. These represent CpG-poor distal regulatory regions as evidenced by location, DNase I hypersensitivity, presence of enhancer chromatin marks and enhancer activity in reporter assays. LMRs are occupied by DNA-binding factors and their binding is necessary and sufficient to create LMRs. A comparison of neuronal and stem-cell methylomes confirms this dependency, as cell-type-specific LMRs are occupied by cell-type-specific transcription factors. This study provides methylome references for the mouse and shows that DNA-binding factors locally influence DNA methylation, enabling the identification of active regulatory regions.

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Crossref · 10.1038/nature10716

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  • Some evidence points to inhibition of SETD2 methyltransferase by H3G34R.

    “while some evidence points to inhibition of SET domain containing 2 (SETD2) methyltransferase by H3G34R 225 .”
  • The model that differentially methylated regions reflect collective local demethylation induced by specific transcription factor binding is supported by mouse embryonic stem cell experiments with CTCF and REST.

    “This model has been supported by experiments in mouse embryonic stem cell (mESC) using insulator protein CCCTC-binding factor (CTCF) and a transcriptional repressor of neural genes - RE1-Silencing Transcription factor (REST) (6).”
  • Deletion of REST increases 5mC at lowly methylated regions normally bound by REST.

    “The deletion of REST led to increased 5mC at lowly methylated regions normally bound by REST.”
  • This gain of 5mC can be reversed by re-introducing REST.

    “Notably, such gain of 5mC can be reversed by re-introducing REST.”
  • Regions with low methylation levels (10-50%) often occur at distal regulatory regions enriched for enhancer marks.

    “regions with a low level of methylation, ranging from 10% to 50%, often occur at distal regulatory regions78; that is, regions that are enriched for enhancer marks, including high levels of histone H3 lysine 4 monomethylation (H3K4me1) as well as binding sites for p300 histone acetyltransferase and other regulatory factors.”

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Authors
Stadler, M. B., Murr, R., Burger, L., Ivanek, R., Lienert, F., Schöler, A., Nimwegen, E. V., Wirbelauer, C., Oakeley, E. J., Gaidatzis, D., Tiwari, V. K., & Schübeler, D.
Affiliations
  • Friedrich Miescher Institute (CH)
  • SIB Swiss Institute of Bioinformatics (CH)
  • University of Basel (CH)
  • Novartis (Switzerland) (CH)
Corresponding author
Schübeler, Dirk
Venue
Nature
Published
2011-12-14
Volume
480
Issue
7378
Pages
490-495
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2039053594
Cited by
1,383
References
51
Citations by year
2026: 41 · 2025: 44 · 2024: 92 · 2023: 71 · 2022: 78 · 2021: 97 · 2020: 98 · 2019: 89 · 2018: 100 · 2017: 104 · 2016: 106 · 2015: 139 · 2014: 131 · 2013: 131 · 2012: 58
FWCI
41.42
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
DNA methylation, distal regulatory regions, DNA-binding factors, transcription factors, enhancers, DNase I hypersensitivity, stem cells, neuronal precursors, cell type-specific methylation, epigenetic regulation
MeSH terms
Animals, Cell Differentiation, Cytosine, DNA-Binding Proteins, Neurons, Promoter Regions, Genetic, Protein Binding, Stem Cells, Transcription Factors, CpG Islands, DNA Methylation, Mice, Embryonic Stem Cells, Epigenomics

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