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

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.

SUBMITTER: Schwartz U

PROVIDER: S-EPMC10267701 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Schwartz Uwe U Llamazares Prada Maria M Pohl Stephanie T ST Richter Mandy M Tamas Raluca R Schuler Michael M Keller Corinna C Mijosek Vedrana V Muley Thomas T Schneider Marc A MA Quast Karsten K Hey Joschka J Heußel Claus P CP Warth Arne A Winter Hauke H Serçin Özdemirhan Ö Karmouty-Quintana Harry H Jyothula Soma Sk SS Patel Manish K MK Herth Felix F Koch Ina I Petrosino Giuseppe G Titimeaua Alexandru A Mardin Balca R BR Weichenhan Dieter D Jurkowski Tomasz P TP Imbusch Charles D CD Brors Benedikt B Benes Vladimir V Jung Birgit B Wyatt David D Stahl Heiko F HF Plass Christoph C Jurkowska Renata Z RZ

The EMBO journal 20230505 12

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 regi ...[more]

PMID: 37143403

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Project description:Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.

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

Publications

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

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