title: Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD.
abstract: Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that Epas1 gene expression is reduced in mice chronically exposed to cigarette smoke. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human endothelial cells. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a 'causal' role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology.
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Seungyeul
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takikawa
authors.affiliation: Department of Medicine, St. Luke's Roosevelt Medical Center, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Luan
authors.initials: L
authors.lastname: Lin
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Tu
authors.forename: Robert F
authors.initials: RF
authors.lastname: Foronjy
authors.affiliation: Department of Medicine, St. Luke's Roosevelt Medical Center, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Feronjy
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1