Leveraging the Epigenome of Inflammatory Bowel Disease to Gain Mechanistic Insights Into Disease Pathophysiology

Ulcerative colitis (UC) is a chronic relapsing and remitting intestinal inflammatory disorder with a very heterogeneous clinical course. While on life-long maintenance therapy, although most patients achieve complete mucosal healing with no disease activity during the course of treatment of UC, a subgroup (~40%) experience chronically active severe disease with persistent inflammation as reflected by need for escalation of medical therapy or surgery. The reasons underlying such differential clinical course/disease severity are not well understood. Cross-sectional studies of DNA methylation, a key regulator of gene expression and molecular phenotype, have begun to reveal epigenetic associations with UC. However, owing to the dynamic plasticity of DNA methylation and UC disease behavior, it is critical to understand the temporal relationship between the methylome and the disease in order to establish the direction of causality and leverage the epigenome for therapeutic benefits. Here we hypothesize that, longitudinal framework – having DNA methylation data and well documented disease measures collected concurrently during the disease onset and at later time – supplemented by genetic association and the concept of Mendelian randomization, can help identify methylation changes that causally underlie disease pathology. Herein, using methylation data generated from DNA derived from the disease-relevant tissue, rectal mucosa, obtained at two time points – at diagnosis and 1 year follow-up – from participants in the PROTECT cohort, a pediatric prospective inception UC cohort, we plan to (i) identify DNA methylation changes that causally influence the development of UC, and modify its phenotypic expression and severity; and (ii) integrate these methylation data with prior genotype and gene expression data in order to elucidate the functional consequence of disrupted methylation patterns and to gain insights into molecular underpinnings of UC. In completion, the results of this project will provide new insights into the epigenetic basis of UC. Understanding the temporal relationship between how methylome changes during the course of the disease, as a result of varying clinical characteristics, and how disease subgroups evolve may aid in the identification of potentially causal epigenetic targets which could subsequently be leveraged for therapeutic benefits.