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

Research output: Contribution to journalArticle

  • Martina S Elias
  • Sheila C Wright
  • Judit Remenyi
  • James C Abbott
  • Susan E Bray
  • Christian Cole
  • Sharon Edwards
  • Marek Gierlinski
  • Mateusz Glok
  • John A McGrath
  • William V Nicholson
  • Lavinia Paternosterhttp://orcid.org/0000-0003-2514-0889
  • Alan R Prescott
  • Sara Ten Have
  • Phillip D Whitfield
  • Angus I Lamond
  • Sara J Brown
Original languageEnglish
Pages (from-to)470-481
Number of pages12
JournalJournal of Allergy and Clinical Immunology
Volume144
Issue number2
Early online date31 May 2019
DOIs
DateAccepted/In press - 14 May 2019
DateE-pub ahead of print - 31 May 2019
DatePublished (current) - 1 Aug 2019

Abstract

BACKGROUND: Atopic dermatitis (AD) is a common, complex, and highly heritable inflammatory skin disease. Genome-wide association studies offer opportunities to identify molecular targets for drug development. A risk locus on chromosome 11q13.5 lies between 2 candidate genes, EMSY and LRRC32 (leucine-rich repeat-containing 32) but the functional mechanisms affecting risk of AD remain unclear.

OBJECTIVES: We sought to apply a combination of genomic and molecular analytic techniques to investigate which genes are responsible for genetic risk at this locus and to define mechanisms contributing to atopic skin disease.

METHODS: We used interrogation of available genomic and chromosome conformation data in keratinocytes, small interfering RNA (siRNA)-mediated knockdown in skin organotypic culture and functional assessment of barrier parameters, mass spectrometric global proteomic analysis and quantitative lipid analysis, electron microscopy of organotypic skin, and immunohistochemistry of human skin samples.

RESULTS: Genomic data indicate active promoters in the genome-wide association study locus and upstream of EMSY; EMSY, LRRC32, and intergenic variants all appear to be within a single topologically associating domain. siRNA-knockdown of EMSY in organotypic culture leads to enhanced development of barrier function, reflecting increased expression of structural and functional proteins, including filaggrin and filaggrin-2, as well as long-chain ceramides. Conversely, overexpression of EMSY in keratinocytes leads to a reduction in markers of barrier formation. Skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, which is consistent with an increased functional effect of this transcriptional control protein.

CONCLUSION: Our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach.

    Research areas

  • Atopic dermatitis, atopic eczema, EMSY, filaggrin, genetics, genomics, organotypic, lipidomics, proteomics, siRNA knockdown

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/j.jaci.2019.05.024 . Please refer to any applicable terms of use of the publisher.

    Final published version, 3 MB, PDF document

    Licence: CC BY

DOI

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