EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis - 05/08/19
, Sheila C. Wright, HNC a, Judit Remenyi, PhD a, James C. Abbott, PhD b, Susan E. Bray, PhD c, Christian Cole, PhD b, Sharon Edwards, MBChB d, Marek Gierlinski, PhD b, Mateusz Glok a, John A. McGrath, FRCP e, William V. Nicholson, PhD a, Lavinia Paternoster, PhD f, Alan R. Prescott, PhD g, Sara Ten Have, PhD h, Phillip D. Whitfield, PhD i, Angus I. Lamond, PhD h, Sara J. Brown, FRCPE a, j, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Atopic dermatitis, atopic eczema, EMSY, filaggrin, genetics, genomics, organotypic, lipidomics, proteomics, siRNA knockdown
Abbreviations used : AD, DMEM, EGF, FLG, GO, GWAS, Hi-C, LRRC32, NHK, NDF, qPCR, siRNA, SNP, TEWL
Plan
| Supported by a Wellcome Trust Senior Research Fellowship in Clinical Science, awarded to S.J.B. (reference 106865/Z/15/Z). The Brown laboratory has also received financial support from the Manknell Charitable Trust and the Tayside Dermatology Research Charity. L.P. is supported by an Academy of Medical Sciences Springboard award, which is supported by the Wellcome Trust; the Government Department for Business,Energy and Industrial Strategy; the Global Challenges Research Fund; and the British Heart Foundation (SBF003/1094). L.P. works in the MRC Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council (MC_UU_00011/1). The mass spectrometry proteomic analysis was supported by grants to AIL from the Wellcome Trust (105024/Z/14/Z, 108058/Z/15/Z). The Dundee Imaging Facility is supported by a Wellcome Trust Technology Platform award (097945/B/11/Z). The UHI Lipidomics Research Facility acknowledges the support of the European Regional Development Fund, Scottish Funding Council, and Highlands and Islands Enterprise. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 144 - N° 2
P. 470-481 - août 2019 Retour au numéro
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