Agradecimentos: We are grateful to all staff from Babraham Institute BSU for support with the mouse work; Dr. Rebecca Roberts, Babraham Institute flow cytometry, for assistance with cell sorting; Kristina Tabbada and Clare Murnane, Babraham Institute Next Generation Sequencing Facility, for sequencing support; Drs. Anne Segonds-Pichon, Felix Krueger, and Simon Andrews, Babraham Institute Bioinformatics, for help with statistics and bioinformatics; Drs. Wendy Dean and Wolf Reik, Babraham Institute Epigenetics, for mice with ZP3-cre allele; Dr. Keith M. Porter for optimizing the genotyping protocol; Dr. Marika Kullberg, University of York, for mice; Dr. Dianne Proudfoot for discussion about osteocalcins; Michelle Miniter and Dr. Jonathan Powell, Department of Veterinary Medicine, Cambridge, for discussions and advice regarding Ca2+ in the gut; and Simon Clare, Sanger Institute, for help with some pilot experiments. This work was supported by BBSRC Institute Strategic Programme Grants (BBS/E/B/000C0404, BBS/E/B/000C0405), a MRC project grant to PVW and MV (MR/N009398/1), a BBSRC-Fundação de Amparo à Pesquisa do Estado de São Paulo/FAPESP-Brazil Pump-priming award (BB/N013565/1,FAPESP#2015/50379-1), and a Newton Advanced Fellowship from the Royal Society to MARV and PVW (NAF\R1\180116) Ver menos

Abstract: 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. 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. 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. Ver menos