Crohn's disease (CD), one of the two major inflammatory bowel diseases, results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. Genome wide association studies (GWAS) have linked 163 specific single nucleotide polymorphisms (SNPs) to CD disease pathogenesis. Within these regions, there are over 5600 additional SNPs that are in linkage disequilibrium (LD) with the tag SNPs, and it is not known which of these contribute to CD. Most of these SNPs map to non-coding regions of the genome, suggesting that causal variants contribute to CD by modifying gene regulatory element activity. An important first step is to identify genomic regions that have differential regulatory activity in CD-relevant intestinal tissues, including colon, and cells, namely epithelial and immune cells, between affected and unaffected individuals. Towards this end, we have generated genetic, open chromatin, and transcriptome data from the colon tissue and immune cells obtained from 27 CD patients and 14 normal controls, and from macrophages, T cells and epithelial cells isolated from the colons of 5 CD patients and 5 normal controls. Open chromatin assays identify nucleosome-depleted genomic regions that are associated with all types of regulatory elements, including promoters, enhancers, and silencers. While these assays provide the most complete annotation of where all regulatory elements are in a particular tissue or cell sample, a weakness is their inability to identify the precise function (promoter, enhancer, silencer) of each regulatory element. The Epigenomics Roadmap Project and ENCODE Project has generated histone modification data in CD-relevant tissues and immune cells that when integrated with our data will provide critical regulatory annotations and will help explain the functions of these variable elements. Our long-term goal is to elucidate the genomic regions and molecular mechanisms by which genetic variation contributes to CD. This proposal will contribute to this goal through the following specific aims: 1) To identify genomic regions with genetically-driven differential regulatory activity in colon tissue and immune cells of CD patients. Integrating GWAS data with our open chromatin and transcriptome data from genotyped CD patients and controls, we will determine an evidence-based set of genomic regions with differential regulatory activity in CD patients;2) To integrate epigenetic data from the Epigenomics Roadmap Project (ERP) and the ENCODE project to annotate functions of CD-associated regulatory regions. The ERP and ENCODE have generated data from a wide range of tissues, including colon mucosa, and cell types, including monocytes, T cells, epithelial, and non-immune cell populations. We will use these data to better characterize regulatory activity in CD-relevant cells, and the cell-specificity of this activity. Tis project will help fill the gap between our ability to detect genetic, chromatin, and transcriptiona variation linked to CD and our ability to explain how that variation ultimately contributes to CD.

Public Health Relevance

This project will identify and functionally characterize genomic regions that are associated with the susceptibility and presence of Crohn's Disease. By helping uncover the mechanisms by which genetic and epigenetic variation contribute to Crohn's Disease, this work will lead to the development of new diagnostic and therapeutic strategies to manage patients with this disease and improve overall human health.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMST-R (51))
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Chadwick, Lisa
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42
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