We are working toward understanding the genetic circuits that control human immune cell function in health and disease, including exploring the genetic basis of immune-mediated diseases, both monogenic and complex. We participate in collaborative research aimed at broadly understanding chromatin and gene expression regulation of human primary immune cells, allowing downstream annotation of candidate causal non-coding autoimmunity variants that appear to alter key immune cell cis-regulatory sequences. These systems-scale analyses implicate specific cell types, biological processes, and key non-coding sequences in autoimmunity.
Our expertise in CRISPR-based perturbations in immune cells allows us to directly test and manipulate the cellular effects of disease-associated variants, coding and non-coding. We have integrated CRISPRa with genome editing in murine models to decode regulatory elements controlling IL2RA, an immune homeostasis gene, gaining functional insights into an autoimmunity risk variant in that locus. Furthermore, we have been able to correct a rare IL2RA mutation in cells from patients with a monogenic autoimmune disease and are advancing this technology toward clinical trial.