EMSY expression affects multiple components of skin barrier with relevance to atopic dermatitis

ABSTRACT: Atopic dermatitis (AD) is a heritable inflammatory disease, characterised by skin barrier dysfunction. Genome-wide association studies (GWAS) have identified molecular targets with relevance for drug development, but the strongest genetic association, FLG, has not yet been successfully targeted in atopic disease. An AD-associated locus on chromosome 11q13.5 lies between two genes - EMSY and LRRC32 - but the functional mechanisms leading to AD are unclear. We applied a combination of genomic and molecular analytical techniques followed up in patient biopsies, to investigate pathomechanisms at this GWAS locus. Chromosome conformation capture data in keratinocytes shows interaction of the intergenic region in threedimensional space with EMSY. siRNA-mediated knockdown of EMSY in skin organoid culture leads to enhanced development of barrier function, measured by water evaporation and dye penetration. Global proteomic analysis of skin organoids with EMSY knockdown shows increased expression of structural and functional proteins, confirmed by histological and ultrastructural features. Lipid analysis shows an increase in ceramides known to be reduced in AD. Conversely, over-expression of EMSY in primary human keratinocytes leads to a reduction in biomarkers of barrier formation. Finally, skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, consistent with increased functional effect of this DNAbinding protein. Together our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach for AD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte, Skin

DISEASE(S): Atopic Dermatitis

SUBMITTER: Sara ten Have  

LAB HEAD: Sara Brown

PROVIDER: PXD014088 | Pride | 2019-06-24

REPOSITORIES: Pride