title: Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis.
abstract: The gain-of-function mucin 5B (MUC5B) promoter variant, rs35705950, confers the largest risk, genetic or otherwise, for the development of idiopathic pulmonary fibrosis; however, the mechanisms underlying the regulation of MUC5B expression have yet to be elucidated. Here, we identify a critical regulatory domain that contains the MUC5B promoter variant and has a highly conserved forkhead box protein A2 (FOXA2) binding motif. This region is differentially methylated in association with idiopathic pulmonary fibrosis, MUC5B expression, and rs35705950. In addition, we show that this locus binds FOXA2 dynamically, and that binding of FOXA2 is necessary for enhanced expression of MUC5B. In aggregate, our findings identify novel targets to regulate the expression of MUC5B.
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Britney A
authors.initials: BA
authors.lastname: Helling
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.|2 Department of Medicine, National Jewish Health, Denver, Colorado; and.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
authors.affiliation: 2 Department of Medicine, National Jewish Health, Denver, Colorado; and.
authors.forename: Vineela
authors.initials: V
authors.lastname: Kadiyala
authors.affiliation: 2 Department of Medicine, National Jewish Health, Denver, Colorado; and.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Sasse
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Pedersen
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Lenore
authors.initials: L
authors.lastname: Sparks
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.|3 University of Colorado-Denver, School of Public Health, Denver, Colorado.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.affiliation: 1 Department of Medicine, School of Medicine, University of Colorado-Denver, Denver, Colorado.|2 Department of Medicine, National Jewish Health, Denver, Colorado; and.
authors.forename: David A
authors.identifier: 0000-0001-6743-8443
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D055785:Gene Knockdown Techniques; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055257:Mucin-5B / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C496502:FOXA2 protein, human; D055257:Mucin-5B; D034741:RNA, Small Interfering; D051542:Hepatocyte Nuclear Factor 3-beta; D012319:RNA Polymerase II
keywords: DNA methylation; gene regulation; idiopathic pulmonary fibrosis; mucin 5B; mucins