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  Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

Qi, H., Liu, H., Pullamsetti, S. S., Gunther, S., Kuenne, C., Atzberger, A., et al. (2021). Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease. CIRCULATION, 144(13), 1042-1058. doi:10.1161/CIRCULATIONAHA.120.051680.

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 Creators:
Qi, Hui1, Author              
Liu, Hang1, Author              
Pullamsetti, Soni Savai2, Author              
Gunther, Stefan1, Author              
Kuenne, Carsten3, Author              
Atzberger, Ann4, Author              
Sommer, Natascha, Author
Hadzic, Stefan, Author
Gunther, Andreas, Author
Weissmann, Norbert, Author
Zhou, Yonggang1, Author              
Yuan, Xuejun1, Author              
Braun, Thomas1, Author              
Affiliations:
1Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              
2Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              
3Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591704              
4Facs Service, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591706              

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Free keywords: WEB SERVER; HEART; MONOMETHYLATION; IDENTIFICATION; PHENOTYPE; DELETION; PATHWAYS; PROTEIN; CHIPCardiovascular System & Cardiology; alveoli; pulmonary; hypertension; pulmonary; oxidation-reduction; pulmonary disease; chronic obstructive; superoxide dismutase 3; mouse;
 Abstract: Background: The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals. Methods: To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Results: We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5 '-upstream regulatory element of the superoxide dismutase 3 (Sod3) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization. Conclusions: Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.

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Language(s): eng - English
 Dates: 2021-07-122021-09-28
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
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Title: CIRCULATION
Source Genre: Journal
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Publ. Info: TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA : LIPPINCOTT WILLIAMS & WILKINS
Pages: - Volume / Issue: 144 (13) Sequence Number: - Start / End Page: 1042 - 1058 Identifier: ISSN: 0009-7322