title: HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation.
abstract: The terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion. We show that a histone deacetylase 3 (Hdac3)-mediated epigenetic pathway is critical for the proper remodeling and expansion of the distal lung saccules into primitive alveoli. Loss of Hdac3 in the developing lung epithelium leads to a reduction of alveolar type 1 cell spreading and a disruption of lung sacculation. Hdac3 represses miR-17-92 expression, a microRNA cluster that regulates transforming growth factor β (TGF-β) signaling. De-repression of miR-17-92 in Hdac3-deficient lung epithelium results in decreased TGF-β signaling activity. Importantly, inhibition of TGF-β signaling and overexpression of miR-17-92 can phenocopy the defects observed in Hdac3 null lungs. Conversely, loss of miR-17-92 expression rescues many of the defects caused by loss of Hdac3 in the lung. These studies reveal an intricate epigenetic pathway where Hdac3 is required to repress miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Frank
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong 250021, China.
authors.forename: Xiaoru
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Research Center, University of Pennsylvania, Room 11-124, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104-5129, USA. Electronic address: emorrise@mail.med.upenn.edu.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000378:metabolism*; D008168:Lung / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D000099186:Histone Deacetylase 3; C575895:MIRN17-92 microRNA, mouse
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