Determining how sequence variation associated with type 1 diabetes affects the chromatin organization of T cells

Although the main function of T cells is to protect us from infectious agents, many medically important diseases are associated with abnormal T cell responses directed against proteins produced by our own body’s tissues. This broad category of immune-mediated diseases is referred to as autoimmune disorders and includes diseases such as type 1 diabetes (T1D), inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. In the case of T1D, interactions between T lymphocytes and insulin-producing beta cells lead to loss of beta-cell mass and a dependence on exogenous insulin administration for survival. The role of genetics in T1D development is evident from its clustering in families. Genetic susceptibility to T1D and other common diseases has been assessed over the last two decades by large-scale genome-wide association studies, which look for a correlation between disease frequency and genetic variation mostly in the form of single-nucleotide polymorphisms. However, the status quo in the broader field of complex traits has thus far been that an individual disease-associated single-nucleotide polymorphism can alter interactions between a gene and its regulatory elements.

As a drastic departure from the status quo, our laboratory discovered misfolding of DNA at megabase-pair diabetes-susceptibility regions, leading to reorganization of large transcriptionally coordinated regions in a mouse model of T1D as a result of sequence variation associated with diabetes development (Fasolino and Goldman et al, Immunity, 2020). Remarkably, we demonstrated the relevance of these findings to human T1D, thanks to our team efforts in the Human Pancreas Analysis Program (HPAP) at the University of Pennsylvania. Our ongoing work, assessing if and how the genome is misfolded in primary immune cells from pancreatic tissues of individuals with T1D, will not only enable us to devise molecular and optical strategies to detect T1D at critical time points where interventions can delay progression to clinical diagnosis, but is also key for understanding the molecular etiology of this disease. Due to the unprecedented opportunity to work with primary immune cells in pancreatic tissues of more than 60 human organ donors and our ability to work with the mouse model of T1D, my laboratory is at an exemplary position to describe the cause and effect relationships between genetics, nuclear architecture, and gene regulation in T1D.