Autoimmune rheumatologic diseases
Super-enhancers (SEs) are large stretches of the genome characterized by permissive chromatin marks indicating active transcription. SEs recruit clusters of transcriptional regulators and regulate expression of genes important determining cell fate and immune cell functional state. We analyzed SEs from naïve, memory and regulatory CD4+ T cells purified from peripheral blood of systemic lupus erythematosus (SLE) patients to identify key drivers of SLE pathogenesis. We used chromatin immunoprecipitation sequencing to assess genome-wide regions enriched in histone H3K27 acetylation, a marker of active enhancer regions. SE regions were computationally linked to specific genes and Ingenuity Pathway Analysis was then used to map these into specific signaling pathways and identify upstream drivers of gene expression. Additionally, differential SEs between SLE patients and matched healthy donor T cells were determined. This analysis identified both known and unexpected novel differences in epigenetic landscape between SLE and healthy cells and delineated how critical pathways in T cell biology are differentially regulated in SLE. Specifically, we found that all T cell subpopulations in SLE display altered epigenetic programming at genes encoding key T cell effector molecules. Our data also suggests that T cells in SLE may not rely on survival pathways typically utilized by T cells in the absence of autoimmune disease (e.g. IL-7) and identifies key upstream transcription regulators in disease. Epigenetic profiling also confirms a deficiency in regulatory T cell function in SLE (e.g. loss of SE at CTLA4 in SLE). We are in the process of validating putative targets derived from this analysis.