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Microbiota-sensitive epigenetic signature predicts inflammation in Crohn’s disease
Daniel Kelly, … , Lee A. Denson, Theresa Alenghat
Daniel Kelly, … , Lee A. Denson, Theresa Alenghat
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e122104. https://doi.org/10.1172/jci.insight.122104.
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Research Article Gastroenterology

Microbiota-sensitive epigenetic signature predicts inflammation in Crohn’s disease

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Abstract

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.

Authors

Daniel Kelly, Michael Kotliar, Vivienne Woo, Sajjeev Jagannathan, Jordan Whitt, Jessica Moncivaiz, Bruce J. Aronow, Marla C. Dubinsky, Jeffrey S. Hyams, James F. Markowitz, Robert N. Baldassano, Michael C. Stephens, Thomas D. Walters, Subra Kugathasan, Yael Haberman, Nambirajan Sundaram, Michael J. Rosen, Michael Helmrath, Rebekah Karns, Artem Barski, Lee A. Denson, Theresa Alenghat

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Figure 1

Histone methylation signature of ileal epithelium defines treatment-naive pediatric Crohn’s disease patients.

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Histone methylation signature of ileal epithelium defines treatment-naiv...
(A and B) Representative tracks from individual samples of differentially enriched peaks for genes with (A) increased H3K4me3 sites in Crohn’s disease (CD) versus controls and (B) decreased H3K4me3 sites in CD. (C) Volcano plot representation of genes with differential H3K4me3 peaks (P < 0.05, n = 8 per group). (D) Heatmap of H3K4me3 enrichment across all samples for genes in C. (E) Genomic locations of sites with significantly increased or decreased H3K4me3 peaks in CD.

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