Lymphocyte signaling and immune cell response

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Abstract

The study of chromatin landscape has shown us how genomic architecture can control immune response. We established that genomic accessibility plays a factor in the differential rate of response of innate versus adaptive immune cells. Super-enhancers (SEs) are another distinct feature of the chromatin landscape where multiple enhancers, transcription factors (TFs), RNA polymerase II and transcriptional co-activators conjugate to regulate the expression of specific genes. Genes regulated by SE are highly linked to the cell identity, but also denote functional hubs. We have shown that SEs in adaptive immune cells are linked to genes that encode cytokines, cytokine receptors and transcription factors, which are vital for their normal development and function. In addition, SE architecture is also enriched for loci encoding long noncoding RNAs, which often flank key protein coding genes. The goal of my research is to understand how the chromatin landscape regulates immune cell development and function. To do so, we identified SEs in natural killer (NK) cells to determine if there are genes within these regions with unknown relevance to NK cell biology. We hypothesize that genes transcribed from SEs in NK cells are likely to play critical roles in NK cell development and effector function and may provide clues to mechanism in removal of virally infected and cancer cells. We anticipated that this SE-based approach has the potential to identify key NK genes that were previously overlooked but likely to have critical functions. Within the top-ranking SE of NK cells was Ugcg, a gene that encodes UDP-glucose ceramide glucotransferase (UGCG), which is an enzyme that catalyzes the first glycosylation step in the synthesis of glycosphingolipids. Along with Ugcg, a putative long noncoding RNA (lncRNA), Gm12596, which also lies within this SE. Our approach in understanding if Ugcg is required for NK cell biology is two-fold. We first developed a conditional mouse model to determine if any aspect of NK cell development will be influenced. This Vav1cre-Ugcgloxp mouse model will help us to determine if NK cells and other hematopoietic cells require Ugcg. For the second arm of the study, we investigated whether NK cells with loss of UGCG activity have the ability to respond to infection and tumor cells. We utilized the drug ibiglustat, which is an inhibitor of UGCG activity. Using flow cytometry, high-throughput sequencing, and in vitro and vivo models, we will study the role of Ugcg in NK cells and other lymphocytes at steady state and in perturbed states (tumor and infection models).