Targeting Transcriptional Dysregulation in Atopic Dermatitis
Principle Investigator: Leah Kottyan, PhD
Atopic dermatitis (AD) is one of the most common skin disorders in children. Genome-wide association studies identified 29 independent genetic risk loci associated with AD. Over 95% of these genetic risk variants are in the noncoding region: they do not change amino acid usage but instead likely affect mRNA expression. We are using massively parallel reporter assays (MPRAs) to nominate causal AD risk variants that result in the genotype-dependent regulation through tag expression. Next, we will employ a novel approach using our AD MPRA library as a tool to identify potential therapies that attenuate genotype-dependent regulatory activity. We are applying our computational tool RELI (Regulatory Element Locus Intersection) to detect enriched binding of TFs at AD risk loci to identify enriched TFs including NFKB1 and FOS in CD4+ T cells. We have set up a research clinic to recruit patients with and without moderate-to-severe AD. In addition, we are using using chromatin immunoprecipitation (ChIP-seq or CUT&RUN) to measuring genotype-dependent binding of NFKB1, FOS, and other TFs we identify throughout this research project.