Atopic eczema (AE or atopic dermatitis) is a common inflammatory skin disease with strong heritability. Genome-wide association studies (GWAS) have identified multiple loci affecting AE risk but many loci are intergenic and the functional mechanisms remain undefined. A locus on chromosome 11q13.5 has been widely replicated in GWAS; it lies in an intergenic region between two candidate genes: EMSY and LRRC32. Analysis of genome-wide chromosome conformation capture data generated from differentiating human keratinocytes indicates that EMSY, LRRC32 and 11q13.5 variants may all reside within a single topologically associating domain. siRNA-knockdown of EMSY in skin organotypic culture using primary human keratinocytes reduces EMSY mRNA (n=7, mean 36% reduction p<0.0001) and protein expression (n=7, mean 45% reduction p<0.001) and enhances barrier function defined by water content, water loss and dye penetration. Global mass-spec proteomic analysis detected >8000 proteins per sample with increased expression (fold-change ≥2.5 p<0.05) of 154 proteins, notably filaggrin and filaggrin-2. Mass spec lipidomics showed an increase in longer chain ceramides known to be downregulated in AE. Ultrastructural changes including increased desmosome size and corneodesmosome abundance were also observed by electron microscopy. In contrast, over-expression of EMSY in primary keratinocytes leads to a reduction in markers of differentiation and barrier formation. In keeping with these in vitro observations, skin biopsy samples from patients show greater staining of EMSY in the nucleus (14 AE cases and 18 controls), consistent with an increased functional effect of this transcriptional control protein. Taken together our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach.

Functional assessment of the atopic eczema candidate gene EMSY identifies a role in skin barrier formation