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

Title of publication: 

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


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 Bernardes, Robert Häsler, Anne Luzius, Simon Imm, Finn Hinrichsen, Andre Franke, Samuel Huber, Susanna Nikolaus, Konrad Aden, Stefan Schreiber, Felix Sommer, Gioacchino Natoli, Neha Mishra, Philip Rosenstiel

Year of Publication: 


medium resp. publishing house / place: 

Nat Commun

edition / issue: 




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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.

© 2022. The Author(s).