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

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  • Michael B. Stadler

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Swiss Institute of Bioinformatics, 4058 Basel, Switzerland)

  • Rabih Murr

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland)

  • Lukas Burger

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Swiss Institute of Bioinformatics, 4058 Basel, Switzerland)

  • Robert Ivanek

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland)

  • Florian Lienert

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Faculty of Science, University of Basel, 4056 Basel, Switzerland)

  • Anne Schöler

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Swiss Institute of Bioinformatics, 4058 Basel, Switzerland
    Faculty of Science, University of Basel, 4056 Basel, Switzerland)

  • Erik van Nimwegen

    (Biozentrum of the University of Basel and Swiss Institute of Bioinformatics, Klingelbergstrasse 50–70, CH 4056, Basel, Switzerland)

  • Christiane Wirbelauer

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland)

  • Edward J. Oakeley

    (Novartis Institutes for BioMedical Research, Biomarker Development, 4056 Basel, Switzerland)

  • Dimos Gaidatzis

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Swiss Institute of Bioinformatics, 4058 Basel, Switzerland)

  • Vijay K. Tiwari

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland)

  • Dirk Schübeler

    (Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Faculty of Science, University of Basel, 4056 Basel, Switzerland)

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.

Suggested Citation

  • Michael B. Stadler & Rabih Murr & Lukas Burger & Robert Ivanek & Florian Lienert & Anne Schöler & Erik van Nimwegen & Christiane Wirbelauer & Edward J. Oakeley & Dimos Gaidatzis & Vijay K. Tiwari & Di, 2011. "DNA-binding factors shape the mouse methylome at distal regulatory regions," Nature, Nature, vol. 480(7378), pages 490-495, December.
    • Handle: RePEc:nat:nature:v:480:y:2011:i:7378:d:10.1038_nature10716
    DOI: 10.1038/nature10716
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    Cited by:

    1. Graeme J. Thorn & Christopher T. Clarkson & Anne Rademacher & Hulkar Mamayusupova & Gunnar Schotta & Karsten Rippe & Vladimir B. Teif, 2022. "DNA sequence-dependent formation of heterochromatin nanodomains," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Nina Schmolka & Ino D. Karemaker & Richard Cardoso da Silva & Davide C. Recchia & Vincent Spegg & Jahnavi Bhaskaran & Michael Teske & Nathalie P. Wagenaar & Matthias Altmeyer & Tuncay Baubec, 2023. "Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Marko Dunjić & Felix Jonas & Gilad Yaakov & Roye More & Yoav Mayshar & Yoach Rais & Ayelet-Hashahar Orenbuch & Saifeng Cheng & Naama Barkai & Yonatan Stelzer, 2023. "Histone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Fasil Tekola-Ayele & Cuilin Zhang & Jing Wu & Katherine L Grantz & Mohammad L Rahman & Deepika Shrestha & Marion Ouidir & Tsegaselassie Workalemahu & Michael Y Tsai, 2020. "Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy," PLOS Genetics, Public Library of Science, vol. 16(5), pages 1-20, May.
    5. Abrar Aljahani & Peng Hua & Magdalena A. Karpinska & Kimberly Quililan & James O. J. Davies & A. Marieke Oudelaar, 2022. "Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Yanting Luo & Jianlin He & Xiguang Xu & Ming-an Sun & Xiaowei Wu & Xuemei Lu & Hehuang Xie, 2018. "Integrative single-cell omics analyses reveal epigenetic heterogeneity in mouse embryonic stem cells," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-21, March.
    7. Changhu Lee & Min Kim & Chanho Park & Woobeen Jo & Jeong Kon Seo & Sahee Kim & Jiyoung Oh & Chu-Sook Kim & Han Suk Ryu & Kyung-Hun Lee & Jiyoung Park, 2023. "Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Jingting Xu & Hong Hu & Yang Dai, 2016. "LMethyR-SVM: Predict Human Enhancers Using Low Methylated Regions based on Weighted Support Vector Machines," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-18, September.

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