title: Identification of TNF-α-responsive promoters and enhancers in the intestinal epithelial cell model Caco-2.
abstract: The Caco-2 cell line is one of the most important in vitro models for enterocytes, and is used to study drug absorption and disease, including inflammatory bowel disease and cancer. In order to use the model optimally, it is necessary to map its functional entities. In this study, we have generated genome-wide maps of active transcription start sites (TSSs), and active enhancers in Caco-2 cells with or without tumour necrosis factor (TNF)-α stimulation to mimic an inflammatory state. We found 520 promoters that significantly changed their usage level upon TNF-α stimulation; of these, 52% are not annotated. A subset of these has the potential to confer change in protein function due to protein domain exclusion. Moreover, we locate 890 transcribed enhancer candidates, where ∼50% are changing in usage after TNF-α stimulation. These enhancers share motif enrichments with similarly responding gene promoters. As a case example, we characterize an enhancer regulating the laminin-5 γ2-chain (LAMC2) gene by nuclear factor (NF)-κB binding. This report is the first to present comprehensive TSS and enhancer maps over Caco-2 cells, and highlights many novel inflammation-specific promoters and enhancers.
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Boyd
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark Department of Gastroenterology, Medical Section, University of Copenhagen, Herlev Hospital, Herlev DK-2730, Denmark.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Coskun
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Lilje
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Robin
authors.initials: R
authors.lastname: Andersson
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Ilka
authors.initials: I
authors.lastname: Hoof
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Bornholdt
authors.affiliation: Department of Science, Systems and Models, Roskilde University, Roskilde DK-4000, Denmark.
authors.forename: Katja
authors.initials: K
authors.lastname: Dahlgaard
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen N DK-2200, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Olsen
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
authors.forename: Morana
authors.initials: M
authors.lastname: Vitezic
authors.affiliation: Department of Gastroenterology, Medical Section, University of Copenhagen, Herlev Hospital, Herlev DK-2730, Denmark.
authors.forename: Jacob Tveiten
authors.initials: JT
authors.lastname: Bjerrum
authors.affiliation: Department of Gastroenterology, Medical Section, University of Copenhagen, Herlev Hospital, Herlev DK-2730, Denmark.
authors.forename: Jakob Benedict
authors.initials: JB
authors.lastname: Seidelin
authors.affiliation: Department of Gastroenterology, Medical Section, University of Copenhagen, Herlev Hospital, Herlev DK-2730, Denmark.
authors.forename: Ole Haagen
authors.initials: OH
authors.lastname: Nielsen
authors.affiliation: Department of Science, Systems and Models, Roskilde University, Roskilde DK-4000, Denmark.
authors.forename: Jesper Thorvald
authors.initials: JT
authors.lastname: Troelsen
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark albin@binf.ku.dk.
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
mesh_terms: D018938:Caco-2 Cells; D002874:Chromosome Mapping; D055106:Genome-Wide Association Study; D006801:Humans; D007797:Laminin / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D061785:Transcription Initiation, Genetic / Q000187:drug effects* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C400567:LAMC2 protein, human; D007797:Laminin; D016328:NF-kappa B; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: alternative promoters; inflammation; non-coding RNAs; transcribed enhancers; transcriptional regulation