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Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Authors
  • Kazakevych, Juri1
  • Denizot, Jérémy1, 2
  • Liebert, Anke1, 3
  • Portovedo, Mariana4
  • Mosavie, Mia5
  • Jain, Payal1
  • Stellato, Claudia1
  • Fraser, Claire1
  • Corrêa, Renan Oliveira4
  • Célestine, Marina1
  • Mattiuz, Raphaël1
  • Okkenhaug, Hanneke1
  • Miller, J. Ross1
  • Vinolo, Marco Aurélio Ramirez4
  • Veldhoen, Marc1, 6
  • Varga-Weisz, Patrick1, 5
  • 1 Babraham Institute, Cambridge, CB22 3AT, UK , Cambridge (United Kingdom)
  • 2 Present Address: Université Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, Clermont–Ferrand, F-63000, France , Clermont–Ferrand (France)
  • 3 Present Address: The Francis Crick Institute, London, NW1 1AT, UK , London (United Kingdom)
  • 4 UNICAMP, Campinas, 13083-862, Brazil , Campinas (Brazil)
  • 5 University of Essex, Colchester, CO4 3SQ, UK , Colchester (United Kingdom)
  • 6 Faculdade de Medicina da Universidade de Lisboa, Lisbon, 1649-028, Portugal , Lisbon (Portugal)
Type
Published Article
Publication Date
Mar 11, 2020
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s13059-020-01976-7
Source
Springer Nature
License
Green

Abstract

BackgroundHow intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue.ResultsSpecific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum.ConclusionsOur study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases.

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