Role of chromatin dynamics in regulation of intestinal innate immunity gene expression

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In the intestine, a single layer of cells mediates the uptake of nutrients and creates a niche for beneficial microbes while at the same time it provides a barrier against invasion by pathogenic organisms. Important aspects of this defensive function are processes of innate immunity, which summarize various cell intrinsic mechanisms by which cells fend off pathogens. Examples for such processes are the secretion of anti-bacterial peptides and hydrolytic enzymes, detoxification processes and autophagy. If the barrier function of the intestine is impaired, this can lead to deadly infections but also devastating chronic, inflammatory diseases, such as Crohn's disease and ulcerative colitis. How the expression of factors involved in innate immunity processes is regulated and orchestrated is an important question with huge relevance to our understanding of health and disease.In this application we will contribute towards this by building on exciting findings from our labs that link the packaging of the genome to the regulation of innate immunity genes in the intestine. We found that deletion in intestinal epithelial cells of an enzyme that regulates the packaging of the genome (a chromatin remodeling factor) renders mice more resistant to experimentally induced colitis. This unprecedented finding appears to be linked to the fact that the mice without this factor over-express many genes involved in innate immunity even without any challenge. Thus, this factor appears to orchestrate the regulation of many genes involved in innate immunity. Furthermore, in the absence of this factor we find changes in the packaging of many gene regulatory elements closely linked to genes, including many genes involved in innate immunity. We hypothesize that these changes facilitate the expression of these genes and may represent a general mechanism by which cells adapt to stress.We wish to test these ideas and examine if the changes we observe are linked to the colitis response. This work will reveal potential new diagnostic markers and therapeutic targets for intestinal inflammatory conditions, while providing insights into very fundamental gene regulatory processes.