Beyond epithelial-to-mesenchymal transition

Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

L. F. Loffredo, Hiam Abdala-Valencia, K. R. Anekalla, L. Cuervo-Pardo, Cara Gottardi, Sergejs Berdnikovs*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. Methods: We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. Results: We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this “core” signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. Conclusions: The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.

Original languageEnglish (US)
Pages (from-to)1988-2004
Number of pages17
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume72
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Epithelial-Mesenchymal Transition
Asthma
Transcriptome
Epithelial Cells
Insulin
Data Mining
Gene Regulatory Networks
Epigenomics
Genes
Inflammation
Gene Expression
Wounds and Injuries
Research

Keywords

  • asthma
  • differentiation and remodeling
  • epithelial-to-mesenchymal transition
  • epithelium
  • “omics” and systems biology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Beyond epithelial-to-mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma",
abstract = "Background: Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. Methods: We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. Results: We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this “core” signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. Conclusions: The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.",
keywords = "asthma, differentiation and remodeling, epithelial-to-mesenchymal transition, epithelium, “omics” and systems biology",
author = "Loffredo, {L. F.} and Hiam Abdala-Valencia and Anekalla, {K. R.} and L. Cuervo-Pardo and Cara Gottardi and Sergejs Berdnikovs",
year = "2017",
month = "12",
day = "1",
doi = "10.1111/all.13222",
language = "English (US)",
volume = "72",
pages = "1988--2004",
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publisher = "Wiley-Blackwell",
number = "12",

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TY - JOUR

T1 - Beyond epithelial-to-mesenchymal transition

T2 - Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

AU - Loffredo, L. F.

AU - Abdala-Valencia, Hiam

AU - Anekalla, K. R.

AU - Cuervo-Pardo, L.

AU - Gottardi, Cara

AU - Berdnikovs, Sergejs

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background: Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. Methods: We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. Results: We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this “core” signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. Conclusions: The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.

AB - Background: Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. Methods: We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. Results: We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this “core” signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. Conclusions: The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.

KW - asthma

KW - differentiation and remodeling

KW - epithelial-to-mesenchymal transition

KW - epithelium

KW - “omics” and systems biology

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U2 - 10.1111/all.13222

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JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

SN - 0105-4538

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ER -