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High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD phenotypes in human lung fibroblasts

Uwe Schwartz, Maria Llamazares Prada, Stephanie T. Pohl, Mandy Richter, Raluca Tamas, Michael Schuler, Corinna Keller, Vedrana Mijosek, Thomas Muley, Marc A. Schneider, Karsten Quast, Joschka Hey, Claus P. Heußel, Arne Warth, Hauke Winter, Özdemirhan Serçin, View ORCID ProfileHarry Karmouty-Quintana, Felix Herth, Ina Koch, Giuseppe Petrosino, Balca R. Mardin, Dieter Weichenhan, Tomasz P. Jurkowski, Charles D. Imbusch, Benedikt Brors, View ORCID ProfileVladimir Benes, Brigit Jung, David Wyatt, Heiko Stahl, View ORCID ProfileChristoph Plass, View ORCID ProfileRenata Z. Jurkowska
doi: https://doi.org/10.1101/2022.03.28.486023
Uwe Schwartz
1BioMed X Institute, Heidelberg, Germany
2NGS Analysis Center Biology and Pre-Clinical Medicine, University of Regensburg, Regensburg, Germany
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Maria Llamazares Prada
1BioMed X Institute, Heidelberg, Germany
3Division of Cancer Epigenomics, German Cancer Research Center (DKFZ) and Translational Lung Research Center, Member of the German Center for Lung Research (DZL), Heidelberg, Germany, Heidelberg, Germany
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Stephanie T. Pohl
1BioMed X Institute, Heidelberg, Germany
4Division of Biomedicine, School of Biosciences, Cardiff University, Cardiff, UK
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Mandy Richter
1BioMed X Institute, Heidelberg, Germany
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Raluca Tamas
1BioMed X Institute, Heidelberg, Germany
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Michael Schuler
5Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
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Corinna Keller
6Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG – Biberach, Germany
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Vedrana Mijosek
1BioMed X Institute, Heidelberg, Germany
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Thomas Muley
7Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, University of Regensburg Germany
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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Marc A. Schneider
7Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, University of Regensburg Germany
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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Karsten Quast
9Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
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Joschka Hey
3Division of Cancer Epigenomics, German Cancer Research Center (DKFZ) and Translational Lung Research Center, Member of the German Center for Lung Research (DZL), Heidelberg, Germany, Heidelberg, Germany
10Ruprecht Karl University of Heidelberg, Heidelberg, Germany
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Claus P. Heußel
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
11Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
12Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
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Arne Warth
7Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, University of Regensburg Germany
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
13Pathological Institute, University Hospital Heidelberg, Heidelberg, Germany
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Hauke Winter
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
14Dept. of Surgery, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
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Özdemirhan Serçin
1BioMed X Institute, Heidelberg, Germany
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Harry Karmouty-Quintana
15Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA
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  • ORCID record for Harry Karmouty-Quintana
Felix Herth
7Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, University of Regensburg Germany
8Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
16Department of Pneumology and Critical Care Medicine and Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany
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Ina Koch
17Asklepios Biobank for Lung Diseases, Department of Thoracic Surgery, Asklepios Fachkliniken München-Gauting, German Center for Lung Research (DZL), Munich, Germany
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Giuseppe Petrosino
1BioMed X Institute, Heidelberg, Germany
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Balca R. Mardin
1BioMed X Institute, Heidelberg, Germany
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Dieter Weichenhan
3Division of Cancer Epigenomics, German Cancer Research Center (DKFZ) and Translational Lung Research Center, Member of the German Center for Lung Research (DZL), Heidelberg, Germany, Heidelberg, Germany
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Tomasz P. Jurkowski
18Division of Molecular Biology, School of Biosciences, Cardiff, UK
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Charles D. Imbusch
19Division of Applied Bioinformatics, German Cancer Research Center, Germany
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Benedikt Brors
19Division of Applied Bioinformatics, German Cancer Research Center, Germany
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Vladimir Benes
20Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
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  • ORCID record for Vladimir Benes
Brigit Jung
6Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG – Biberach, Germany
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David Wyatt
21Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
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Heiko Stahl
6Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG – Biberach, Germany
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Christoph Plass
3Division of Cancer Epigenomics, German Cancer Research Center (DKFZ) and Translational Lung Research Center, Member of the German Center for Lung Research (DZL), Heidelberg, Germany, Heidelberg, Germany
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Renata Z. Jurkowska
1BioMed X Institute, Heidelberg, Germany
4Division of Biomedicine, School of Biosciences, Cardiff University, Cardiff, UK
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  • ORCID record for Renata Z. Jurkowska
  • For correspondence: jurkowskar@cardiff.ac.uk
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Abstract

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering the environmental cause of COPD (e.g., cigarette smoke) and disease phenotypes, including stem-cell senescence and impaired differentiation, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) isolated from distal parenchyma of ex-smoker controls and COPD patients, with both mild and severe disease. The epigenetic landscape is markedly changed in lung fibroblasts across COPD stages, with DNA methylation changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Notably, we identified epigenetic and transcriptional dysregulation already in mild COPD patients, providing unique insights into early disease. Integration of profiling data identified 110 candidate regulators of disease phenotypes, including epigenetic factors. Using phenotypic screens, we verified the regulator capacity of multiple candidates and linked them to repair processes in the human lung.

Our study provides first integrative high-resolution epigenetic and transcriptomic maps of human lung fibroblasts across stages of COPD. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic respiratory diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

Footnotes

  • US and MLP contributed equally to this work

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 29, 2022.
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High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD phenotypes in human lung fibroblasts
Uwe Schwartz, Maria Llamazares Prada, Stephanie T. Pohl, Mandy Richter, Raluca Tamas, Michael Schuler, Corinna Keller, Vedrana Mijosek, Thomas Muley, Marc A. Schneider, Karsten Quast, Joschka Hey, Claus P. Heußel, Arne Warth, Hauke Winter, Özdemirhan Serçin, Harry Karmouty-Quintana, Felix Herth, Ina Koch, Giuseppe Petrosino, Balca R. Mardin, Dieter Weichenhan, Tomasz P. Jurkowski, Charles D. Imbusch, Benedikt Brors, Vladimir Benes, Brigit Jung, David Wyatt, Heiko Stahl, Christoph Plass, Renata Z. Jurkowska
bioRxiv 2022.03.28.486023; doi: https://doi.org/10.1101/2022.03.28.486023
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High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD phenotypes in human lung fibroblasts
Uwe Schwartz, Maria Llamazares Prada, Stephanie T. Pohl, Mandy Richter, Raluca Tamas, Michael Schuler, Corinna Keller, Vedrana Mijosek, Thomas Muley, Marc A. Schneider, Karsten Quast, Joschka Hey, Claus P. Heußel, Arne Warth, Hauke Winter, Özdemirhan Serçin, Harry Karmouty-Quintana, Felix Herth, Ina Koch, Giuseppe Petrosino, Balca R. Mardin, Dieter Weichenhan, Tomasz P. Jurkowski, Charles D. Imbusch, Benedikt Brors, Vladimir Benes, Brigit Jung, David Wyatt, Heiko Stahl, Christoph Plass, Renata Z. Jurkowska
bioRxiv 2022.03.28.486023; doi: https://doi.org/10.1101/2022.03.28.486023

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