Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis

Marcus M. Soliai; Atsushi Kato; Katherine A. Naughton; James E. Norton; Aiko I. Klinger; Robert C Kern; Bruce Kuang-Huay Tan; Dan L. Nicolae; Robert P. Schleimer; Carole Ober; Jayant M. Pinto

doi:10.1111/all.15837

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis

Marcus M. Soliai^*, Atsushi Kato, Katherine A. Naughton, James E. Norton, Aiko I. Klinger, Robert C Kern, Bruce Kuang-Huay Tan, Dan L. Nicolae, Robert P. Schleimer, Carole Ober^*, Jayant M. Pinto^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. Objectives: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. Methods: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. Results: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p <.01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. Conclusion: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

Original language	English (US)
Pages (from-to)	2698-2711
Number of pages	14
Journal	Allergy: European Journal of Allergy and Clinical Immunology
Volume	78
Issue number	10
DOIs	https://doi.org/10.1111/all.15837
State	Published - Oct 2023

Funding

This work was supported by NIH grants U19 AI106683, R01 HL129735, and by the Ernest S. Bazley Charitable Fund. A.K.'s research was supported in part by NIH R01 AI104733, R01 AI137174, R37 HL068546, U19 AI106683, and P01 AI145818. M.M.S. was supported by NIH T32 GM07197. This work was supported by NIH grants U19 AI106683 and R01 HL129735. M.M.S. was supported in part by T32 GM007197.

Keywords

DNA methylation
airway epithelium
chronic rhinosinusitis
gene expression
nasal polyposis

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/all.15837

Cite this

Soliai, M. M., Kato, A., Naughton, K. A., Norton, J. E., Klinger, A. I., Kern, R. C., Tan, B. K.-H., Nicolae, D. L., Schleimer, R. P., Ober, C., & Pinto, J. M. (2023). Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis. Allergy: European Journal of Allergy and Clinical Immunology, 78(10), 2698-2711. https://doi.org/10.1111/all.15837

@article{e9d0ca3e819c4502aa8e802e3e995578,

title = "Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis",

abstract = "Background: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. Objectives: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. Methods: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. Results: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p <.01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. Conclusion: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.",

keywords = "DNA methylation, airway epithelium, chronic rhinosinusitis, gene expression, nasal polyposis",

author = "Soliai, {Marcus M.} and Atsushi Kato and Naughton, {Katherine A.} and Norton, {James E.} and Klinger, {Aiko I.} and Kern, {Robert C} and Tan, {Bruce Kuang-Huay} and Nicolae, {Dan L.} and Schleimer, {Robert P.} and Carole Ober and Pinto, {Jayant M.}",

note = "Funding Information: This work was supported by NIH grants U19 AI106683, R01 HL129735, and by the Ernest S. Bazley Charitable Fund. A.K.'s research was supported in part by NIH R01 AI104733, R01 AI137174, R37 HL068546, U19 AI106683, and P01 AI145818. M.M.S. was supported by NIH T32 GM07197. Funding Information: This work was supported by NIH grants U19 AI106683 and R01 HL129735. M.M.S. was supported in part by T32 GM007197. Publisher Copyright: {\textcopyright} 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.",

year = "2023",

month = oct,

doi = "10.1111/all.15837",

language = "English (US)",

volume = "78",

pages = "2698--2711",

journal = "Allergy: European Journal of Allergy and Clinical Immunology",

issn = "0105-4538",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "10",

}

Soliai, MM, Kato, A, Naughton, KA, Norton, JE, Klinger, AI, Kern, RC , Tan, BK-H, Nicolae, DL, Schleimer, RP, Ober, C & Pinto, JM 2023, 'Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis', Allergy: European Journal of Allergy and Clinical Immunology, vol. 78, no. 10, pp. 2698-2711. https://doi.org/10.1111/all.15837

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis. / Soliai, Marcus M.; Kato, Atsushi; Naughton, Katherine A. et al.
In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 78, No. 10, 10.2023, p. 2698-2711.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis

AU - Soliai, Marcus M.

AU - Kato, Atsushi

AU - Naughton, Katherine A.

AU - Norton, James E.

AU - Klinger, Aiko I.

AU - Kern, Robert C

AU - Tan, Bruce Kuang-Huay

AU - Nicolae, Dan L.

AU - Schleimer, Robert P.

AU - Ober, Carole

AU - Pinto, Jayant M.

N1 - Funding Information: This work was supported by NIH grants U19 AI106683, R01 HL129735, and by the Ernest S. Bazley Charitable Fund. A.K.'s research was supported in part by NIH R01 AI104733, R01 AI137174, R37 HL068546, U19 AI106683, and P01 AI145818. M.M.S. was supported by NIH T32 GM07197. Funding Information: This work was supported by NIH grants U19 AI106683 and R01 HL129735. M.M.S. was supported in part by T32 GM007197. Publisher Copyright: © 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

PY - 2023/10

Y1 - 2023/10

N2 - Background: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. Objectives: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. Methods: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. Results: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p <.01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. Conclusion: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

AB - Background: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. Objectives: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. Methods: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. Results: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p <.01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. Conclusion: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

KW - DNA methylation

KW - airway epithelium

KW - chronic rhinosinusitis

KW - gene expression

KW - nasal polyposis

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UR - http://www.scopus.com/inward/citedby.url?scp=85167657929&partnerID=8YFLogxK

U2 - 10.1111/all.15837

DO - 10.1111/all.15837

M3 - Article

C2 - 37571876

AN - SCOPUS:85167657929

SN - 0105-4538

VL - 78

SP - 2698

EP - 2711

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

IS - 10

ER -

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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