High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD

Schwartz, Uwe, Llamazares Prada, Maria, Pohl, Stephanie T., Richter, Mandy, Tamas, Raluca, Schuler, Michael, Keller, Corinna, Mijosek, Vedrana, Muley, Thomas, Schneider, Marc A., Quast, Karsten, Hey, Joschka, Heubel, Claus P., Warth, Arne, Winter, Hauke, Sercin, Ozdemirhan, Karmouty-Quintana, Harry, Jyothula, Soma S.K., Patel, Manish K., Herth, Felix, Koch, Ina, Petrosino, Giuseppe, Titimeaua, Alexandru, Mardin, Balca R., Weichenhan, Dieter, Jurkowski, Tomasz P. ORCID: https://orcid.org/0000-0002-2012-0240, Imbusch, Charles D., Brors, Benedikt, Benes, Vladimir, Jung, Birgit, Wyatt, David, Stahl, Heiko F., Plass, Christoph and Jurkowska, Renata Z. ORCID: https://orcid.org/0000-0002-4507-2222 2023. High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD. The EMBO Journal 42 , e111272. 10.15252/embj.2022111272

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Abstract

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, 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) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked to fibroblast repair processes using phenotypic screens. Our study provides high-resolution multi-omic maps of HLFs across COPD stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic lung 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	EMBO Press
ISSN:	0261-4189
Date of First Compliant Deposit:	24 April 2023
Date of Acceptance:	27 March 2023
Last Modified:	17 Aug 2023 03:10
URI:	https://orca.cardiff.ac.uk/id/eprint/159006

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