Chromatin and Gene Regulation
Chromosomes are compacted into increasingly complex chromatin structures within eukaryotic nuclei. High-throughput sequence-based assays have been developed to identify regions of nucleosome-depleted open chromatin that mark all types of regulatory elements genome-wide in tissues and cell-types. The computational integration of these data with related gene expression, transcription factor binding, and epigenetic data provide a more complete picture of the complex process of gene transcription and regulation. With these data, we are also investigating the effects of genetic variation on regulation, as can been seen through allelic imbalance in signal from chromatin and transcription factor data, as well as in quantitative trait loci (QTL)-based analyses of these data across individuals.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD), primarily consisting of Crohn’s disease and ulcerative colitis, is the result of an inappropriate immune response to the intestinal microbiota in a genetically susceptible individual. We have partnered with Dr. Shehzad Sheikh (Dept of Medicine, CGIBD) to uncover molecular and microbial characteristics of IBD disease phenotypes. We hypothesize that changes in the chromatin landscape in key intestinal cell types such as macrophages, influenced by the host genetic background, are significantly contributing to aberrant intestinal inflammation. Using both human tissue and mouse models, we seek to identify where chromatin is altered, the impacts on gene expression, and the relationship to the microbial community in tissues and cells from affected individuals.
Exposure to naturally occurring toxicants or by-products of manufacturing process can result in serious health challenges. We hypothesize that toxicant exposure can alter normal cellular function through changes to the chromatin architecture and transcriptional profiles in tissues contributing to the onset of medical complications. In a collaboration with Dr. Greg Crawford (Duke), Dr. Ivan Rusyn (Texas A&M), and Dr. Jason Lieb (Univ of Chicago), we are investigating the effects of exposure to 1,3-butadiene gas, a carcinogenic by-product of rubber and plastic manufacturing, in mouse models. In particular, we are assaying chromatin structure, transcription rates, and key histone modifications in two target tissues (lung, liver) and one non-target tissue (kidney).