Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension
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Aurélie Hautefort1,2,*, Julie Chesné3,*, Jens Preussner4, Soni S Pullamsetti4, Jorg Tost5, Mario Looso4, Fabrice Antigny1,2, Barbara Girerd1,2,6, Marianne Riou1,2, Saadia Eddahibi7, Jean-François Deleuze5, Werner Seeger4, Elie Fadel8, Gerald Simonneau1,2,6, David Montani1,2,6, Marc Humbert1,2,6 and Frédéric Perros1,2
1INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
2Univ Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France
3UMR_S 1087 CNRS UMR_6291, Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France
4Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
5Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
6AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
7INSERM U1046, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France
8Hôpital Marie Lannelongue, Service de Chirurgie Thoracique et Vasculaire, Le Plessis Robinson, France
*These authors contributed equally to this work
Frédéric Perros, email: firstname.lastname@example.org
Keywords: pulmonary arterial hypertension, epigenetic, DNA methylation, endothelial cells, ABC transporters
Received: December 02, 2016 Accepted: May 09, 2017 Published: May 19, 2017
Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation.
DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analyzed using bioinformatics tools.
Unsupervised hierarchical clustering allowed the identification of two clusters of probes that discriminates controls and PAH patients. Among 147 differential methylated promoters, 46 promoters coding for proteins or miRNAs were related to lipid metabolism. Top 10 up and down-regulated genes were involved in lipid transport including ABCA1, ABCB4, ADIPOQ, miR-26A, BCL2L11. NextBio meta-analysis suggested a contribution of ABCA1 in PAH. We confirmed ABCA1 mRNA and protein downregulation specifically in PAH PEC by qPCR and immunohistochemistry and made the proof-of-concept in an experimental model of the disease that its targeting may offer novel therapeutic options.
In conclusion, DNA methylation analysis identifies a set of genes mainly involved in lipid transport pathway which could be relevant to PAH pathophysiology.
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