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DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon

Author

Listed:
  • Antonella Fazio

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Dora Bordoni

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Jan W. P. Kuiper

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Saskia Weber-Stiehl

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Stephanie T. Stengel

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Philipp Arnold

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU))

  • David Ellinghaus

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Go Ito

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein
    Tokyo Medical and Dental University)

  • Florian Tran

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein
    Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Berith Messner

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Anna Henning

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Joana P. Bernardes

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Robert Häsler

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein
    University Hospital Schleswig-Holstein)

  • Anne Luzius

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Simon Imm

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Finn Hinrichsen

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Andre Franke

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Samuel Huber

    (University Medical Center Hamburg-Eppendorf)

  • Susanna Nikolaus

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Konrad Aden

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein
    Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Stefan Schreiber

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Felix Sommer

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Gioacchino Natoli

    (European Institute of Oncology IRCCS (IEO))

  • Neha Mishra

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

  • Philip Rosenstiel

    (Christian-Albrechts-University and University Hospital Schleswig-Holstein)

Abstract

Genetic variants in the DNA methyltransferase 3 A (DNMT3A) locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells from IBD patients and upon tumor necrosis factor treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in intestinal epithelial cells (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.

Suggested Citation

  • Antonella Fazio & Dora Bordoni & Jan W. P. Kuiper & Saskia Weber-Stiehl & Stephanie T. Stengel & Philipp Arnold & David Ellinghaus & Go Ito & Florian Tran & Berith Messner & Anna Henning & Joana P. Be, 2022. "DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33844-2
    DOI: 10.1038/s41467-022-33844-2
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    References listed on IDEAS

    as
    1. Christopher E. Duymich & Jessica Charlet & Xiaojing Yang & Peter A. Jones & Gangning Liang, 2016. "DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    2. Toshiro Sato & Robert G. Vries & Hugo J. Snippert & Marc van de Wetering & Nick Barker & Daniel E. Stange & Johan H. van Es & Arie Abo & Pekka Kujala & Peter J. Peters & Hans Clevers, 2009. "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche," Nature, Nature, vol. 459(7244), pages 262-265, May.
    3. N. T. Ventham & N. A. Kennedy & A. T. Adams & R. Kalla & S. Heath & K. R. O'Leary & H. Drummond & D. C. Wilson & I. G. Gut & E. R. Nimmo & J. Satsangi, 2016. "Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    4. Tuncay Baubec & Daniele F. Colombo & Christiane Wirbelauer & Juliane Schmidt & Lukas Burger & Arnaud R. Krebs & Altuna Akalin & Dirk Schübeler, 2015. "Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation," Nature, Nature, vol. 520(7546), pages 243-247, April.
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    Cited by:

    1. Han Zhang & Rahul Kalla & Jie Chen & Jianhui Zhao & Xuan Zhou & Alex Adams & Alexandra Noble & Nicholas T. Ventham & Judith Wellens & Gwo-Tzer Ho & Malcolm G. Dunlop & Jan Krzysztof Nowak & Yuan Ding , 2024. "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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