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An atlas of active enhancers across human cell types and tissues

Author

Listed:
  • Robin Andersson

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Claudia Gebhard

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany
    Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany)

  • Irene Miguel-Escalada

    (School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK)

  • Ilka Hoof

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Jette Bornholdt

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Mette Boyd

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Yun Chen

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Xiaobei Zhao

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA)

  • Christian Schmidl

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany)

  • Takahiro Suzuki

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Evgenia Ntini

    (Centre for mRNP Biogenesis and Metabolism, C.F. Møllers Alle 3, Building 1130, DK-8000 Aarhus, Denmark)

  • Erik Arner

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Eivind Valen

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark
    Harvard University)

  • Kang Li

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Lucia Schwarzfischer

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany)

  • Dagmar Glatz

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany)

  • Johanna Raithel

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany)

  • Berit Lilje

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Nicolas Rapin

    (The Bioinformatics 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)

  • Frederik Otzen Bagger

    (The Bioinformatics 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)

  • Mette Jørgensen

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

  • Peter Refsing Andersen

    (Centre for mRNP Biogenesis and Metabolism, C.F. Møllers Alle 3, Building 1130, DK-8000 Aarhus, Denmark)

  • Nicolas Bertin

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Owen Rackham

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • A. Maxwell Burroughs

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • J. Kenneth Baillie

    (Roslin Institute, Edinburgh University, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK)

  • Yuri Ishizu

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Yuri Shimizu

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Erina Furuhata

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Shiori Maeda

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Yutaka Negishi

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Christopher J. Mungall

    (Lawrence Berkeley National Laboratory, 1 Cyclotron Road MS 64-121, Berkeley, California 94720, USA)

  • Terrence F. Meehan

    (EMBL Outstation - Hinxton, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK)

  • Timo Lassmann

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Masayoshi Itoh

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    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)

  • Hideya Kawaji

    (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)

  • Naoto Kondo

    (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)

  • Jun Kawai

    (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)

  • Andreas Lennartsson

    (Karolinska Institutet, Hälsovägen 7, SE-4183 Huddinge, Stockholm, Sweden)

  • Carsten O. Daub

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    Karolinska Institutet, Hälsovägen 7, SE-4183 Huddinge, Stockholm, Sweden)

  • Peter Heutink

    (VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands)

  • David A. Hume

    (Roslin Institute, Edinburgh University, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK)

  • Torben Heick Jensen

    (Centre for mRNP Biogenesis and Metabolism, C.F. Møllers Alle 3, Building 1130, DK-8000 Aarhus, Denmark)

  • Harukazu Suzuki

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Yoshihide Hayashizaki

    (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)

  • Ferenc Müller

    (School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK)

  • Alistair R. R. Forrest

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Piero Carninci

    (RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
    RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan)

  • Michael Rehli

    (University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany
    Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany)

  • Albin Sandelin

    (The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark)

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.

Suggested Citation

  • Robin Andersson & Claudia Gebhard & Irene Miguel-Escalada & Ilka Hoof & Jette Bornholdt & Mette Boyd & Yun Chen & Xiaobei Zhao & Christian Schmidl & Takahiro Suzuki & Evgenia Ntini & Erik Arner & Eivi, 2014. "An atlas of active enhancers across human cell types and tissues," Nature, Nature, vol. 507(7493), pages 455-461, March.
  • Handle: RePEc:nat:nature:v:507:y:2014:i:7493:d:10.1038_nature12787
    DOI: 10.1038/nature12787
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    Cited by:

    1. Duc-Hau Le, 2021. "A network-based method for predicting disease-associated enhancers," PLOS ONE, Public Library of Science, vol. 16(12), pages 1-20, December.
    2. Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Feng Bai & Peng Shu & Heng Deng & Yi Wu & Yao Chen & Mengbo Wu & Tao Ma & Yang Zhang & Julien Pirrello & Zhengguo Li & Yiguo Hong & Mondher Bouzayen & Mingchun Liu, 2024. "A distal enhancer guides the negative selection of toxic glycoalkaloids during tomato domestication," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. María Gordillo-Marañón & Magdalena Zwierzyna & Pimphen Charoen & Fotios Drenos & Sandesh Chopade & Tina Shah & Jorgen Engmann & Nishi Chaturvedi & Olia Papacosta & Goya Wannamethee & Andrew Wong & Ree, 2021. "Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    5. Yuanyuan Luan & Yan Fang & Lin Jiang & Yuehui Ma & Shangjie Wu & Junwen Zhou & Yabin Pu & Qianjun Zhao & Xiaohong He, 2022. "Landscape of Global Gene Expression Reveals Distinctive Tissue Characteristics in Bactrian Camels ( Camelus bactrianus )," Agriculture, MDPI, vol. 12(7), pages 1-15, July.
    6. Charley Xia & Sarah J. Pickett & David C. M. Liewald & Alexander Weiss & Gavin Hudson & W. David Hill, 2023. "The contributions of mitochondrial and nuclear mitochondrial genetic variation to neuroticism," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Kota Hamamoto & Yusuke Umemura & Shiho Makino & Takashi Fukaya, 2023. "Dynamic interplay between non-coding enhancer transcription and gene activity in development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Parker C. Wilson & Yoshiharu Muto & Haojia Wu & Anil Karihaloo & Sushrut S. Waikar & Benjamin D. Humphreys, 2022. "Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Takayoshi Matsumura & Haruhito Totani & Yoshitaka Gunji & Masahiro Fukuda & Rui Yokomori & Jianwen Deng & Malini Rethnam & Chong Yang & Tze King Tan & Tadayoshi Karasawa & Kazuomi Kario & Masafumi Tak, 2022. "A Myb enhancer-guided analysis of basophil and mast cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Zhishan Chen & Xingyi Guo & Ran Tao & Jeroen R. Huyghe & Philip J. Law & Ceres Fernandez-Rozadilla & Jie Ping & Guochong Jia & Jirong Long & Chao Li & Quanhu Shen & Yuhan Xie & Maria N. Timofeeva & Mi, 2024. "Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Vladyslava Gorbovytska & Seung-Kyoon Kim & Filiz Kuybu & Michael Götze & Dahun Um & Keunsoo Kang & Andreas Pittroff & Theresia Brennecke & Lisa-Marie Schneider & Alexander Leitner & Tae-Kyung Kim & Cl, 2022. "Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    12. Charles Limouse & Owen K. Smith & David Jukam & Kelsey A. Fryer & William J. Greenleaf & Aaron F. Straight, 2023. "Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    13. Bingnan Li & Patrice Zeis & Yujie Zhang & Alisa Alekseenko & Eliska Fürst & Yerma Pareja Sanchez & Gen Lin & Manu M. Tekkedil & Ilaria Piazza & Lars M. Steinmetz & Vicent Pelechano, 2023. "Differential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    14. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    15. Jiankang Wang & Masashige Bando & Katsuhiko Shirahige & Ryuichiro Nakato, 2022. "Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    16. Roger Mulet-Lazaro & Stanley Herk & Margit Nuetzel & Aniko Sijs-Szabo & Noelia Díaz & Katherine Kelly & Claudia Erpelinck-Verschueren & Lucia Schwarzfischer-Pfeilschifter & Hanna Stanewsky & Ute Acker, 2024. "Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    17. Annkatrin Bressin & Olga Jasnovidova & Mirjam Arnold & Elisabeth Altendorfer & Filip Trajkovski & Thomas A. Kratz & Joanna E. Handzlik & Denes Hnisz & Andreas Mayer, 2023. "High-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    18. Xavier Contreras & David Depierre & Charbel Akkawi & Marina Srbic & Marion Helsmoortel & Maguelone Nogaret & Matthieu LeHars & Kader Salifou & Alexandre Heurteau & Olivier Cuvier & Rosemary Kiernan, 2023. "PAPγ associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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