The goal of this proposal is to decipher the genetic basis of inflammatory bowel disease (IBD) by integrating genome-wide association studies (GWAS) with the chromatin modification information in human immune system. Accumulating evidence suggests that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Among complex diseases, GWAS methods have been successful in IBD, identifying hundreds of non-overlapping genetic risk loci. However, the majority of these disease-associated DNA variants fall into the gene-desert part of the genome, complicating their functional evaluation. There is now overwhelming evidence that the noncoding disease-associated DNA variants disrupt the action of key regulatory elements in relevant cell types. Since genomic coordinates of active regulatory elements can be charted using unique chromatin features, genome-wide profiling of chromatin modifications in relevant cell types can be used to pinpoint to DNA variants disrupting active regulatory elements. Two recent studies discovered a novel kind of enhancers that occurs within exceptionally large genomic domains. These regions were initially dubbed as 'super-enhancers'. Super-enhancer domains occur at key identity genes in a variety of cell types. Strikingly, these enhancer domains are more sensitive to perturbation such as loss of transcription factors than typical shorter enhancers. Because of the fragility of super-enhancers to perturbation, I postulate that super-enhancer domains of relevant immune cells harbor IBD-associated DNA variants. To test this hypothesis, in Aim 1 of this proposal, I will characterize super-enhancer structures of the human immune system. I will first develop an unsupervised machine learning technique to chart super-enhancer structures from histone acetylation (H3K27Ac) data in diverse immune cells. Using this technique, I will next delineate cell type- specific enhancer domains in the immune cells and investigate the relationship among cells types with respect to their super-enhancer structures.
In Aim 2 of this proposal, I will investigate the enrichment of IBD-associated DNA variants within the super-enhancers of the most relevant immune cells. I then link these variants to genes and pathways that they regulate and are affected in disease utilizing gene expression and long-range chromatin interaction datasets. Completion of these aims, along with training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.
Crohn's disease and ulcerative colitis, the two common forms of (IBD), affect over 2.5 million people in North America and Europe. GWAS methods have identified hundreds of non-overlapping genetic risk loci in IBD. Yet, the functional effects of mos IBD-implicated variants remain largely unexplained. The finding that nearly 90% of these sites occur outside of protein-coding sequences suggests that many associated variants may instead have a role in gene regulation. Cell context is a key determinant of gene regulation but where IBD genetic variants are functional is largely unknown. This proposal seeks to utilize the chromatin structure of human immune cells to discover the cell context for IBD-associated variants. The identification of the pathogenic cell types as well as the molecular pathways that contribute to the disease will contribute greatly to our ability to treat patients.
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