Cis-regulatory elements in the Epidermal Differentiation Complex (EDC): Towards understanding atopic dermatitis and psoriasis. C. de Guzman Strong1, K. Sears2, J. Segre1 1) National Human Genome Research Institute, Bethesda, MD; 2) University of Illinois at Urbana-Champaign, Urbana, IL.
The Epidermal Differentiation Complex (EDC) locus (1q21) harbors a set of genes that are specifically expressed upon epidermal differentiation and barrier formation. Atopic dermatitis (AD) and psoriasis are common skin inflammatory disorders that both share independent linkage to the EDC suggesting a role for these genes in disease etiology. Recently, mutations in filaggrin (FLG) in the EDC are strongly linked to familial ichthyosis vulgaris and are highly associated with cases of AD that often advance to asthma (atopic march). AD familial studies excluding FLG continue to demonstrate EDC linkage suggesting additional genetic variants within the EDC in AD pathogenesis. The proximity and density of genes in the EDC suggest coordinate regulation via cis-regulatory elements for temporal and spatial epidermal expression. We hypothesize that evolutionarily conserved noncoding sequences (CNS) function as cis-regulatory elements to coordinate transcriptional regulation of the EDC genes. A genomics approach using comparative multi-species sequence analysis (MultiPip) of the EDC loci from human, chimpanzee, rhesus, mouse, rat, dog, and opossum genomes has identified 43 CNS as potential regulatory elements. The use of the opossum genome as a stringent criterion in annotating CNS in the EDC has been confirmed based on the evolutionary conservation of dorsal to ventral patterning of epidermal barrier acquisition in the opossum. Our functional analysis of the CNS using dual luciferase reporter assays in differentiating keratinocytes has identified either enhancer or repressor activity in roughly 50% of the CNS. We are currently correlating our findings with Genetic Association Information Network (GAIN) psoriasis studies. Taken together, our results suggest a high proportion of regulatory activity in the CNS that may coordinate expression of the genes in the EDC and could pose as genetic variants contributing to either AD or psoriasis.