Juri Kazakevych1, Jérémy Denizot1,2, Anke Liebert1,3, Mariana Portovedo4, Mia Mosavie5, Payal Jain1, Claudia Stellato1, Claire Fraser1, Renan Oliveira Corrêa4, Marina Célestine1, Raphaël Mattiuz1, Hanneke Okkenhaug6, J Ross Miller1, Marco Aurélio Ramirez Vinolo4, Marc Veldhoen7,8, Patrick Varga-Weisz9,10. 1. Nuclear Dynamics, Babraham Institute, Cambridge, CB22 3AT, UK. 2. Present Address: Université Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, F-63000, Clermont-Ferrand, France. 3. Present Address: The Francis Crick Institute, London, NW1 1AT, UK. 4. Laboratory of Immunoinflammation, Institute of Biology, UNICAMP, Campinas, 13083-862, Brazil. 5. School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK. 6. Imaging Facility, Babraham Institute, Cambridge, CB22 3AT, UK. 7. Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB22 3AT, UK. 8. Present Address: Instituto de Medicina Molecular | Joâo Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisbon, Portugal. 9. Nuclear Dynamics, Babraham Institute, Cambridge, CB22 3AT, UK. patrick.varga-weisz@essex.ac.uk. 10. School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK. patrick.varga-weisz@essex.ac.uk.
Abstract
BACKGROUND: How 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. RESULTS: Specific 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. CONCLUSIONS: Our 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.
BACKGROUND: How 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. RESULTS: Specific 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. CONCLUSIONS: Our 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.
Authors: Ben P Willing; Johan Dicksved; Jonas Halfvarson; Anders F Andersson; Marianna Lucio; Zongli Zheng; Gunnar Järnerot; Curt Tysk; Janet K Jansson; Lars Engstrand Journal: Gastroenterology Date: 2010-10-08 Impact factor: 22.682
Authors: Mirjana Rajilić-Stojanović; Elena Biagi; Hans G H J Heilig; Kajsa Kajander; Riina A Kekkonen; Sebastian Tims; Willem M de Vos Journal: Gastroenterology Date: 2011-08-05 Impact factor: 22.682
Authors: Subra Kugathasan; Lee A Denson; Dirk Gevers; Yoshiki Vázquez-Baeza; Will Van Treuren; Boyu Ren; Emma Schwager; Dan Knights; Se Jin Song; Moran Yassour; Xochitl C Morgan; Aleksandar D Kostic; Chengwei Luo; Antonio González; Daniel McDonald; Yael Haberman; Thomas Walters; Susan Baker; Joel Rosh; Michael Stephens; Melvin Heyman; James Markowitz; Robert Baldassano; Anne Griffiths; Francisco Sylvester; David Mack; Sandra Kim; Wallace Crandall; Jeffrey Hyams; Curtis Huttenhower; Rob Knight; Ramnik J Xavier Journal: Cell Host Microbe Date: 2014-03-12 Impact factor: 21.023
Authors: Eran Elinav; Till Strowig; Andrew L Kau; Jorge Henao-Mejia; Christoph A Thaiss; Carmen J Booth; David R Peaper; John Bertin; Stephanie C Eisenbarth; Jeffrey I Gordon; Richard A Flavell Journal: Cell Date: 2011-05-12 Impact factor: 41.582
Authors: Han Han; Guangzhen Jiang; Rashmi Kumari; Martin R Silic; Jake L Owens; Chang-Deng Hu; Suresh K Mittal; GuangJun Zhang Journal: Genes Chromosomes Cancer Date: 2021-08-07 Impact factor: 4.263