Immune cells have diverse functions, from regulatory roles in tissue homeostasis to inflammatory responses against foreign challenges. In autoimmune disease, affected immune cells acquire a pathogenic state characterized by chronic activation of proinflammatory genes. CD4+ Th17 cells exemplify this functional plasticity, acting as protective agents in gut function or harmful instigators of inflammation in autoimmune disease. Th17 cells have been shown to be disease-causing agents in several autoimmune disorders affecting >10 million Americans, including multiple sclerosis, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Previous studies have revealed considerable heterogeneity in the ability of Th17 cells to induce disease and become pathogenic in animal models of multiple sclerosis. My objective is to identify the epigenetic regulatory mechanisms that control Th17 plasticity toward a pathogenic fate in autoimmune disease. I hypothesize that Th17 effector function is encoded in the epigenome and this can be leveraged to identify transcription regulators and remodeling events that distinguish the pathogenic state from regulatory function in Th17 cells in autoimmune disease. By applying recent advances in massively parallel single-cell epigenomics, computational methods for predicting transcription factor binding and deciphering single-cell variation, and technologies for targeted genetic perturbation10,12,17, I will test my hypothesis through the following aims: (1) Use the assay for transposase accessible chromatin (ATAC)-seq to identify an epigenetic signature defining the Th17 pathogenic fate in the context of in vitro cytokine-induced Th17 polarization; (2) Characterize epigenetic heterogeneity in Th17 pathogenic cell fate using single-cell ATAC-seq during experimental autoimmune encephalomyelitis, an autoimmune disease model of multiple sclerosis, and use this heterogeneity to identify potential transcription factor regulators of Th17 autoimmunity; and (3) Perform genetic perturbation experiments during Th17 polarization and measure impact on gene expression and chromatin accessibility in order to determine mechanisms of candidate drivers for establishing the Th17 pathogenic fate. With these studies, I will reconstruct the epigenetic regulatory circuits, consisting of transcription factors, target genes, and regulatory elements that control the disease-causing, pro-inflammatory cell fate of Th17 cells. These studies will provide important insights into the epigenetic networks that control nuanced cell function and reveal targeted strategies to reprogram immune cell pathogenic states in autoimmune disease without affecting non-pathogenic Th17 function.
IL-17 expressing T helper cells (Th17) can aberrantly acquire a pro-inflammatory state that contributes to tissue damage and autoimmunity. I seek to map the epigenetic regulatory mechanisms that distinguish disease causing Th17 cells from their non-pathogenic counterparts. These studies will reveal gene targets that can be selectively modified to inhibit pro-inflammatory Th17 cells without affecting normal Th17 function.