title: An atlas of active enhancers across human cell types and tissues.
abstract: Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Robin
authors.initials: R
authors.lastname: Andersson
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gebhard
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Miguel-Escalada
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Ilka
authors.initials: I
authors.lastname: Hoof
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Bornholdt
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Boyd
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidl
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, C.F. Møllers Alle 3, Bldg. 1130, DK-8000 Aarhus, Denmark.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Ntini
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.|Department of Molecular and Cellular Biology, Harvard University, USA.
authors.forename: Eivind
authors.initials: E
authors.lastname: Valen
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Schwarzfischer
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Glatz
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Raithel
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Lilje
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.|The Finsen Laboratory, Rigshospitalet and Danish Stem Cell Centre (DanStem), University of Copenhagen, Ole Maaloes Vej 5, DK-2200, Denmark.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rapin
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.|The Finsen Laboratory, Rigshospitalet and Danish Stem Cell Centre (DanStem), University of Copenhagen, Ole Maaloes Vej 5, DK-2200, Denmark.
authors.forename: Frederik Otzen
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Jørgensen
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, C.F. Møllers Alle 3, Bldg. 1130, DK-8000 Aarhus, Denmark.
authors.forename: Peter Refsing
authors.initials: PR
authors.lastname: Andersen
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bertin
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Owen
authors.initials: O
authors.lastname: Rackham
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: A Maxwell
authors.initials: AM
authors.lastname: Burroughs
authors.affiliation: Roslin Institute, Edinburgh University, Easter Bush, Midlothian, EH25 9RG Scotland, UK.
authors.forename: J Kenneth
authors.initials: JK
authors.lastname: Baillie
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ishizu
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Furuhata
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Maeda
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road MS 64-121, Berkeley, CA 94720, USA.
authors.forename: Christopher J
authors.initials: CJ
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authors.affiliation: EMBL Outstation - Hinxton, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD.
authors.forename: Terrence F
authors.initials: TF
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authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Masayoshi
authors.initials: M
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authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kondo
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Jun
authors.initials: J
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authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Stockholm, Sweden.
authors.forename: Carsten O
authors.initials: CO
authors.lastname: Daub
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Roslin Institute, Edinburgh University, Easter Bush, Midlothian, EH25 9RG Scotland, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, C.F. Møllers Alle 3, Bldg. 1130, DK-8000 Aarhus, Denmark.
authors.forename: Torben Heick
authors.initials: TH
authors.lastname: Jensen
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Müller
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Alistair R R
authors.initials: ARR
authors.lastname: Forrest
authors.affiliation: RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.|RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
authors.affiliation: The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
mesh_terms: D001271:Atlases as Topic; D002460:Cell Line; D002478:Cells, Cultured; D016000:Cluster Analysis; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D058977:Molecular Sequence Annotation; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D024363:Transcription Initiation Site; D061785:Transcription Initiation, Genetic
chemical_list: D012333:RNA, Messenger