title: Glucocorticoid Receptor ChIP-Seq Identifies PLCD1 as a KLF15 Target that Represses Airway Smooth Muscle Hypertrophy.
abstract: Glucocorticoids exert important therapeutic effects on airway smooth muscle (ASM), yet few direct targets of glucocorticoid signaling in ASM have been definitively identified. Here, we show that the transcription factor, Krüppel-like factor 15 (KLF15), is directly induced by glucocorticoids in primary human ASM, and that KLF15 represses ASM hypertrophy. We integrated transcriptome data from KLF15 overexpression with genome-wide analysis of RNA polymerase (RNAP) II and glucocorticoid receptor (GR) occupancy to identify phospholipase C delta 1 as both a KLF15-regulated gene and a novel repressor of ASM hypertrophy. Our chromatin immunoprecipitation sequencing data also allowed us to establish numerous direct transcriptional targets of GR in ASM. Genes with inducible GR occupancy and putative antiinflammatory properties included IRS2, APPL2, RAMP1, and MFGE8. Surprisingly, we also observed GR occupancy in the absence of supplemental ligand, including robust GR binding peaks within the IL11 and LIF loci. Detection of antibody-GR complexes at these areas was abrogated by dexamethasone treatment in association with reduced RNA polymerase II occupancy, suggesting that noncanonical pathways contribute to cytokine repression by glucocorticoids in ASM. Through defining GR interactions with chromatin on a genome-wide basis in ASM, our data also provide an important resource for future studies of GR in this therapeutically relevant cell type.
authors.affiliation: 1 Department of Medicine and.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Sasse
authors.affiliation: 1 Department of Medicine and.
authors.forename: Vineela
authors.initials: V
authors.lastname: Kadiyala
authors.affiliation: 2 Center for Genes, Health, and the Environment, National Jewish Health, Denver, Colorado.
authors.forename: Thomas
authors.initials: T
authors.lastname: Danhorn
authors.affiliation: 3 Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, New Jersey; and.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: 4 Department of Medicine, University of Colorado, Denver, Colorado.
authors.forename: Tzu L
authors.initials: TL
authors.lastname: Phang
authors.affiliation: 1 Department of Medicine and.|4 Department of Medicine, University of Colorado, Denver, Colorado.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D056151:Airway Remodeling / Q000235:genetics*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D006984:Hypertrophy; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000502:physiology*; D054803:Phospholipase C delta / Q000235:genetics / Q000502:physiology*; D061251:Primary Cell Culture; D012319:RNA Polymerase II / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology*; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C414172:KLF15 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D012319:RNA Polymerase II; C518024:PLCD1 protein, human; D054803:Phospholipase C delta
keywords: Krüppel-like factor 15; airway smooth muscle; asthma; chromatin; glucocorticoid receptor