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

Martina S. Elias (Lead / Corresponding author), 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

Research output: Contribution to journalArticle

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.

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
Publication statusPublished - Aug 2019

Fingerprint

Atopic Dermatitis
Skin
Genome-Wide Association Study
Keratinocytes
Skin Diseases
Leucine
Small Interfering RNA
Chromosomes
Ceramides
Proteomics
Genes
Electron Microscopy
Proteins
Immunohistochemistry
Staining and Labeling
Lipids
Biopsy
Pharmaceutical Preparations
filaggrin

Keywords

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

Cite this

@article{3c45f34765be4e9180302f0712dc188b,
title = "EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis",
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.",
keywords = "Atopic dermatitis, EMSY, atopic eczema, filaggrin, genetics, genomics, lipidomics, organotypic, proteomics, siRNA knockdown",
author = "Elias, {Martina S.} and Wright, {Sheila C.} and Judit Remenyi and Abbott, {James C.} and Bray, {Susan E.} and Christian Cole and Sharon Edwards and Marek Gierlinski and Mateusz Glok and McGrath, {John A.} and Nicholson, {William V.} and Lavinia Paternoster and Prescott, {Alan R.} and Have, {Sara Ten} and Whitfield, {Phillip D.} and Lamond, {Angus I.} and Brown, {Sara J.}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "8",
doi = "10.1016/j.jaci.2019.05.024",
language = "English",
volume = "144",
pages = "470--481",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Elsevier",
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TY - JOUR

T1 - EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis

AU - Elias, Martina S.

AU - Wright, Sheila C.

AU - Remenyi, Judit

AU - Abbott, James C.

AU - Bray, Susan E.

AU - Cole, Christian

AU - Edwards, Sharon

AU - Gierlinski, Marek

AU - Glok, Mateusz

AU - McGrath, John A.

AU - Nicholson, William V.

AU - Paternoster, Lavinia

AU - Prescott, Alan R.

AU - Have, Sara Ten

AU - Whitfield, Phillip D.

AU - Lamond, Angus I.

AU - Brown, Sara J.

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - EMSY

KW - atopic eczema

KW - filaggrin

KW - genetics

KW - genomics

KW - lipidomics

KW - organotypic

KW - proteomics

KW - siRNA knockdown

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U2 - 10.1016/j.jaci.2019.05.024

DO - 10.1016/j.jaci.2019.05.024

M3 - Article

C2 - 31158401

VL - 144

SP - 470

EP - 481

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

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ER -