title: Cell-type-specific long-range looping interactions identify distant regulatory elements of the CFTR gene.
abstract: Identification of regulatory elements and their target genes is complicated by the fact that regulatory elements can act over large genomic distances. Identification of long-range acting elements is particularly important in the case of disease genes as mutations in these elements can result in human disease. It is becoming increasingly clear that long-range control of gene expression is facilitated by chromatin looping interactions. These interactions can be detected by chromosome conformation capture (3C). Here, we employed 3C as a discovery tool for identification of long-range regulatory elements that control the cystic fibrosis transmembrane conductance regulator gene, CFTR. We identified four elements in a 460-kb region around the locus that loop specifically to the CFTR promoter exclusively in CFTR expressing cells. The elements are located 20 and 80 kb upstream; and 109 and 203 kb downstream of the CFTR promoter. These elements contain DNase I hypersensitive sites and histone modification patterns characteristic of enhancers. The elements also interact with each other and the latter two activate the CFTR promoter synergistically in reporter assays. Our results reveal novel long-range acting elements that control expression of CFTR and suggest that 3C-based approaches can be used for discovery of novel regulatory elements.
authors.affiliation: Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-0103, USA.
authors.forename: Nele
authors.initials: N
authors.lastname: Gheldof
authors.forename: Emily M
authors.initials: EM
authors.lastname: Smith
authors.forename: Tomoko M
authors.initials: TM
authors.lastname: Tabuchi
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Koch
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D006801:Humans; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D002843:Chromatin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator