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

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 Paternoster, Alan R. Prescott, Sara Ten Have, Phillip D. Whitfield, Angus I. Lamond, Sara J. Brown

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Abstract

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

Objectives
To apply a combination of genomic and molecular analytical techniques to investigate which genes are responsible for genetic risk at this locus and to define mechanisms contributing to atopic skin disease.

Methods
Interrogation of available genomic and chromosome conformation (Hi-C) data in keratinocytes; siRNA-mediated knockdown in skin organotypic culture and functional assessment of barrier parameters; mass-spectrometry 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 GWAS locus and upstream of EMSY; EMSY, LRRC32 and the intergenic variants may all 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, over-expression 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, consistent with 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.
Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Early online date31 May 2019
DOIs
Publication statusE-pub ahead of print - 31 May 2019

Keywords

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

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    Elias, M. S., Wright, S. C., Remenyi, J., Abbott, J. C., Bray, S. E., Cole, C., Edwards, S., Gierlinski, M., Glok, M., Mcgrath, J. A., Nicholson, W. V., Paternoster, L., Prescott, A. R., Have, S. T., Whitfield, P. D., Lamond, A. I., & Brown, S. J. (2019). EMSY expression affects multiple components of skin barrier with relevance to atopic dermatitis. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2019.05.024