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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Elias, Martina S.¹  Wright, Sheila C.¹  Remenyi, Judit¹  Abbott, James C.²  Bray, Susan E.⁵  Cole, Christian²  Edwards, Sharon⁶  Gierlinski, Marek²  Glok, Mateusz¹  McGrath, John A.⁷  Nicholson, William V.¹  Paternoster, Lavinia⁸  Prescott, Alan R.³  Ten Have, Sara⁴  Whitfield, Phillip D.⁹  Lamond, Angus I.⁴  Brown, Sara J.^1,10 

[1] Univ Dundee, Sch Med, Div Mol & Clin Med, Skin Res Grp, Dundee DD1 9SY, Scotland

[2] Univ Dundee, Data Anal Bioinformat Grp, Dundee, Scotland

[3] Univ Dundee, Dundee Imaging Facil, Dundee, Scotland

[4] Univ Dundee, Sch Life Sci, Ctr Gene Regulat & Express, Dundee, Scotland

[5] Univ Dundee, Ninewells Hosp & Med Sch, NHS Res Scotland Biorepository Tayside, Dundee, Scotland

[6] Ninewells Hosp & Med Sch, Dept Pathol, Dundee, Scotland

[7] Kings Coll London, St Johns Inst Dermatol, Guys Campus, London, England

[8] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[9] Univ Highlands & Islands, Div Biomed Sci, Lipid Res Facil, Inverness, Scotland

[10] Ninewells Hosp, Dept Dermatol, Dundee, Scotland

关键词: Atopic dermatitis;    atopic eczema;    EMSY;    filaggrin;    genetics;    genomics;    organotypic;    lipidomics;    proteomics;    siRNA knockdown;   

DOI  :  10.1016/j.jaci.2019.05.024

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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