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

doi:10.1016/j.jaci.2019.05.024

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

Division of Biomedical Sciences

Publikation: Article › Begutachtung

20 Zitate (Scopus)

154 Downloads (Pure)

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.

Originalsprache	English
Fachzeitschrift	Journal of Allergy and Clinical Immunology
Frühes Online-Datum	31 Mai 2019
DOIs	https://doi.org/10.1016/j.jaci.2019.05.024
Publikationsstatus	E-pub ahead of print - 31 Mai 2019

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10.1016/j.jaci.2019.05.024Lizenz: CC BY

1-s2.0-S0091674919307419-main
© 2019 The Authors. Published by Elsevier Inc.
Accepted author manuscript, 33 MBLizenz: CC BY

https://linkinghub.elsevier.com/retrieve/pii/S0091674919307419Lizenz: CC BY

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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. Vorzeitige Online-Publikation. https://doi.org/10.1016/j.jaci.2019.05.024

@article{3a9ee34efcf541fe887b300c1fbed02a,

title = "EMSY expression affects multiple components of 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 (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.",

keywords = "Atopic dermatitis, atopic eczema, EMSY, filaggrin, genetics, genomics, organotypic, lipidomics, 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 = "{\textcopyright} 2019 The Authors. Published by Elsevier Inc.",

year = "2019",

month = may,

day = "31",

doi = "10.1016/j.jaci.2019.05.024",

language = "English",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

}

Elias, MS, Wright, SC, Remenyi, J, Abbott, JC, Bray, SE, Cole, C, Edwards, S, Gierlinski, M, Glok, M, Mcgrath, JA, Nicholson, WV, Paternoster, L, Prescott, AR, Have, ST, Whitfield, PD, Lamond, AI & Brown, SJ 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

TY - JOUR

T1 - EMSY expression affects multiple components of 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.

PY - 2019/5/31

Y1 - 2019/5/31

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - atopic eczema

KW - EMSY

KW - filaggrin

KW - genetics

KW - genomics

KW - organotypic

KW - lipidomics

KW - proteomics

KW - siRNA knockdown

U2 - 10.1016/j.jaci.2019.05.024

DO - 10.1016/j.jaci.2019.05.024

M3 - Article

SN - 0091-6749

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

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

Abstract

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