Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

Martin Pech; Markus Weckmann; ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)

doi:10.1371/journal.pone.0205275

Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

Martin Pech, Markus Weckmann, ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)

Abstract

Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the Human-Methylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.

Original language	English
Article number	e0205275
Journal	PLoS ONE
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0205275
Publication status	Published - 11.2018

Funding

This research was supported by the German Center of Lung Research (DZL) grant number:82DZL00106; https://www.dzl.de/index. php/en/research/disease-areas/asthma-and-allergy). Funders had no role in any of the experimental work or publication. The present work was enabled by the participants of the ALLIANCE cohort and members of the ALLIANCE study group including the following scientists: Oliver Fuchs, Barbara Roesler, Nils Welchering, Naschla Kohistani-Greif, Katja Landgraf-Rauf, Kristina Laubhahn, Nicole Maison, Claudia Liebl, Bianca Schaub, Markus Ege, Erika von Mutius, Isabell Ricklef, Gesa Diekmann, Laila Sultansei, Markus Weckmann, Matthias V Kopp, Gyde Nissen, Inke R. König, Dominik Thiele, Thomas Bahmer, Anne-Marie Kirsten, Frauke Pedersen, Henrik Watz, Benjamin Waschki, Klaus F. Rabe, Christian Herzmann, Annika Opitz, Karoline I. Gaede, Peter Zabel, Folke Brinkmann, Anna-Maria Dittrich, Christine Happle, Ruth Grychtol, Aydin Malik, Nicolaus Schwerk, Christian Dopfer, Mareike Price, Gesine Hansen, Michael Zemlin, Matthias Müller, Ernst Rietschel, and Silke van Koningsbruggen-Rietschel. A special thanks goes to the laboratory team at the University Medical Center Schleswig-Holstein which organized and conducted the recruitment of the participants of the ALLIANCE cohort. Members of the German Center of Lung Research (DZL) within the Airway Research Center North (ARCN) are Martin Pech, Markus Weckmann, Isabell Ricklefs, Klaus Rabe and Matthias V. Kopp. Members of the German Center of Lung Research (DZL) within the Comprehensive Pneumology Center Munich (CPC-M) are Oliver Fuchs and Erika v. Mutius. Gesine Hansen is a member of the German Center of Lung Research (DZL) within the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH). Funding:Thisresearchwassupportedbythe GermanCenterofLungResearch(DZL)grant number:82DZL00106;https://www.dzl.de/index.

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Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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10.1371/journal.pone.0205275

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@article{2da884d754da40ed824f03a62df9adc2,

title = "Rhinovirus infections change DNA methylation and mRNA expression in children with asthma",

abstract = "Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the Human-Methylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3\% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.",

author = "Martin Pech and Markus Weckmann and \{ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)\} and K{\"o}nig, \{Inke R.\} and Andre Franke and Heinsen, \{Femke Anouska\} and Brian Oliver and Isabell Ricklefs and Oliver Fuchs and Rabe, \{Klaus F.\} and Gesine Hansen and Mutius, \{Erika V.\} and Kopp, \{Matthias V.\}",

note = "Funding Information: This research was supported by the German Center of Lung Research (DZL) grant number:82DZL00106; https://www.dzl.de/index. php/en/research/disease-areas/asthma-and-allergy). Funders had no role in any of the experimental work or publication. The present work was enabled by the participants of the ALLIANCE cohort and members of the ALLIANCE study group including the following scientists: Oliver Fuchs, Barbara Roesler, Nils Welchering, Naschla Kohistani-Greif, Katja Landgraf-Rauf, Kristina Laubhahn, Nicole Maison, Claudia Liebl, Bianca Schaub, Markus Ege, Erika von Mutius, Isabell Ricklef, Gesa Diekmann, Laila Sultansei, Markus Weckmann, Matthias V Kopp, Gyde Nissen, Inke R. K{\"o}nig, Dominik Thiele, Thomas Bahmer, Anne-Marie Kirsten, Frauke Pedersen, Henrik Watz, Benjamin Waschki, Klaus F. Rabe, Christian Herzmann, Annika Opitz, Karoline I. Gaede, Peter Zabel, Folke Brinkmann, Anna-Maria Dittrich, Christine Happle, Ruth Grychtol, Aydin Malik, Nicolaus Schwerk, Christian Dopfer, Mareike Price, Gesine Hansen, Michael Zemlin, Matthias M{\"u}ller, Ernst Rietschel, and Silke van Koningsbruggen-Rietschel. A special thanks goes to the laboratory team at the University Medical Center Schleswig-Holstein which organized and conducted the recruitment of the participants of the ALLIANCE cohort. Members of the German Center of Lung Research (DZL) within the Airway Research Center North (ARCN) are Martin Pech, Markus Weckmann, Isabell Ricklefs, Klaus Rabe and Matthias V. Kopp. Members of the German Center of Lung Research (DZL) within the Comprehensive Pneumology Center Munich (CPC-M) are Oliver Fuchs and Erika v. Mutius. Gesine Hansen is a member of the German Center of Lung Research (DZL) within the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH). Funding Information: Funding:Thisresearchwassupportedbythe GermanCenterofLungResearch(DZL)grant number:82DZL00106;https://www.dzl.de/index. Publisher Copyright: {\textcopyright} 2018 Pech et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

month = nov,

doi = "10.1371/journal.pone.0205275",

language = "English",

volume = "13",

journal = "PLoS ONE",

number = "11",

}

TY - JOUR

T1 - Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

AU - Pech, Martin

AU - Weckmann, Markus

AU - ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)

AU - König, Inke R.

AU - Franke, Andre

AU - Heinsen, Femke Anouska

AU - Oliver, Brian

AU - Ricklefs, Isabell

AU - Fuchs, Oliver

AU - Rabe, Klaus F.

AU - Hansen, Gesine

AU - Mutius, Erika V.

AU - Kopp, Matthias V.

N1 - Funding Information: This research was supported by the German Center of Lung Research (DZL) grant number:82DZL00106; https://www.dzl.de/index. php/en/research/disease-areas/asthma-and-allergy). Funders had no role in any of the experimental work or publication. The present work was enabled by the participants of the ALLIANCE cohort and members of the ALLIANCE study group including the following scientists: Oliver Fuchs, Barbara Roesler, Nils Welchering, Naschla Kohistani-Greif, Katja Landgraf-Rauf, Kristina Laubhahn, Nicole Maison, Claudia Liebl, Bianca Schaub, Markus Ege, Erika von Mutius, Isabell Ricklef, Gesa Diekmann, Laila Sultansei, Markus Weckmann, Matthias V Kopp, Gyde Nissen, Inke R. König, Dominik Thiele, Thomas Bahmer, Anne-Marie Kirsten, Frauke Pedersen, Henrik Watz, Benjamin Waschki, Klaus F. Rabe, Christian Herzmann, Annika Opitz, Karoline I. Gaede, Peter Zabel, Folke Brinkmann, Anna-Maria Dittrich, Christine Happle, Ruth Grychtol, Aydin Malik, Nicolaus Schwerk, Christian Dopfer, Mareike Price, Gesine Hansen, Michael Zemlin, Matthias Müller, Ernst Rietschel, and Silke van Koningsbruggen-Rietschel. A special thanks goes to the laboratory team at the University Medical Center Schleswig-Holstein which organized and conducted the recruitment of the participants of the ALLIANCE cohort. Members of the German Center of Lung Research (DZL) within the Airway Research Center North (ARCN) are Martin Pech, Markus Weckmann, Isabell Ricklefs, Klaus Rabe and Matthias V. Kopp. Members of the German Center of Lung Research (DZL) within the Comprehensive Pneumology Center Munich (CPC-M) are Oliver Fuchs and Erika v. Mutius. Gesine Hansen is a member of the German Center of Lung Research (DZL) within the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH). Funding Information: Funding:Thisresearchwassupportedbythe GermanCenterofLungResearch(DZL)grant number:82DZL00106;https://www.dzl.de/index. Publisher Copyright: © 2018 Pech et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/11

Y1 - 2018/11

N2 - Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the Human-Methylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.

AB - Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the Human-Methylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.

UR - https://www.scopus.com/pages/publications/85057503938

U2 - 10.1371/journal.pone.0205275

DO - 10.1371/journal.pone.0205275

M3 - Journal articles

C2 - 30485264

AN - SCOPUS:85057503938

VL - 13

JO - PLoS ONE

JF - PLoS ONE

IS - 11

M1 - e0205275

ER -

Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

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