title: Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily and are important regulators in IPF. Here we identified BMP endothelial cell precursor-derived regulator (BMPER) as a key regulator of fibroblast activation. BMPER is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-β/BMP signaling, but its role in lung fibrosis is not clear. BMPER is highly expressed in human IPF lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased BMPER expression in fibroblasts, and attenuated the invasion and migration of IPF lung fibroblasts. Furthermore, siRNA-mediated reduction of BMPER in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated BMPER expression and reduced lung fibrosis in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for IPF by modulating fibroblast activation.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, China.|Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Caijuan
authors.initials: C
authors.lastname: Huan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Ningshan
authors.initials: N
authors.lastname: Liu
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Kurkciyan
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Monterrosa Mena
authors.affiliation: China-Japan Friendship Hospital, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Dai
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C476724:BMPER protein, human; D002352:Carrier Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C517553:crossveinless 2 protein, mouse