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An atlas of active enhancers across human cell types and tissues

Nature volume 507, pages 455–461 (2014)Cite this article

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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.

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Figure 1: Bidirectional capped RNAs is a signature feature of active enhancers.
Figure 2: Features distinguishing enhancer TSSs from mRNA TSSs.
Figure 3: CAGE expression identifies cell-type-specific enhancer usage.
Figure 4: In vivo validation in zebrafish of tissue-specific enhancers.
Figure 5: Enhancer usage and specificity in groups of cells.
Figure 6: Linking enhancers to TSSs and disease-associated SNPs.

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Accession codes

Primary accessions

DDBJ/GenBank/EMBL

Gene Expression Omnibus

Data deposits

The FANTOM5 atlas is accessible from http://fantom.gsc.riken.jp/5. FANTOM5 CAGE, RNA-seq and sRNA data have been deposited in DDBJ/EMBL/GenBank (accession codes DRA000991, DRA001101). Genome browser tracks for enhancers with user-definable expression specificity-constraints can be generated at http://enhancer.binf.ku.dk. Here, processed enhancer expression data, predefined enhancer tracks and motif finding results are also deposited. Blood-cell ChIP-seq data and CAGE data on exosome-depleted HeLa cells have been deposited in the NCBI GEO database (accession codes GSE40668, GSE49834).

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Acknowledgements

FANTOM5 was made possible by a Research Grant for RIKEN Omics Science Center from MEXT to Y.H. and a Grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT, Japan, to Y.H. The A.S. group was supported by funds from the European Research Council FP7/2007-2013/ERC no. 204135, the Novo Nordisk and Lundbeck foundations. Work in the M.R. group was funded by grants from the Deutsche Forschungsgemeinschaft (RE 1310/7, 11, 13) and Rudolf Bartling Stiftung. F.M. and I.M.E. were supported by “BOLD” Marie Curie ITN and “ZF- Health” Integrated project of the European Commission. We thank S. Noma, M. Sakai and H. Tarui for RNA-seq and sRNA-seq preparation, RIKEN GeNAS for generation and sequencing of the Heliscope CAGE libraries, Illumina RNA-seq and sRNA-seq, the Copenhagen National High-throughput DNA Sequencing Center for Illumina CAGE-seq, M. Edinger, P. Hoffmann and R. Eder for cell sorting, A. Albrechtsen, I. Moltke, W. Wasserman for advice, and the Netherlands Brain Bank for post-mortem human brain material.

Author information

Author notes

  1. Robin Andersson and Claudia Gebhard: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology & Biotech Research and Innovation Centre, The Bioinformatics Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark,

    Robin Andersson, Ilka Hoof, Jette Bornholdt, Mette Boyd, Yun Chen, Xiaobei Zhao, Eivind Valen, Kang Li, Berit Lilje, Nicolas Rapin, Frederik Otzen Bagger, Mette Jørgensen & Albin Sandelin

  2. Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany,

    Claudia Gebhard, Christian Schmidl, Lucia Schwarzfischer, Dagmar Glatz, Johanna Raithel & Michael Rehli

  3. Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany,

    Claudia Gebhard & Michael Rehli

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

    Irene Miguel-Escalada & Ferenc Müller

  5. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA,

    Xiaobei Zhao

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

    Takahiro Suzuki, Erik Arner, Nicolas Bertin, Owen Rackham, A. Maxwell Burroughs, Yuri Ishizu, Yuri Shimizu, Erina Furuhata, Shiori Maeda, Yutaka Negishi, Timo Lassmann, Masayoshi Itoh, Hideya Kawaji, Naoto Kondo, Jun Kawai, Carsten O. Daub, Harukazu Suzuki, Yoshihide Hayashizaki, Alistair R. R. Forrest & Piero Carninci

  7. 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,

    Takahiro Suzuki, Erik Arner, Nicolas Bertin, Owen Rackham, A. Maxwell Burroughs, Yuri Ishizu, Yuri Shimizu, Erina Furuhata, Shiori Maeda, Yutaka Negishi, Timo Lassmann, Masayoshi Itoh, Carsten O. Daub, Harukazu Suzuki, Alistair R. R. Forrest & Piero Carninci

  8. Department of Molecular Biology and Genetics, Centre for mRNP Biogenesis and Metabolism, C.F. Møllers Alle 3, Building 1130, DK-8000 Aarhus, Denmark,

    Evgenia Ntini, Peter Refsing Andersen & Torben Heick Jensen

  9. Department of Molecular and Cellular Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Eivind Valen

  10. The Finsen Laboratory, Rigshospitalet and Danish Stem Cell Centre (DanStem), University of Copenhagen, Ole Maaloes Vej 5, DK-2200, Denmark,

    Nicolas Rapin & Frederik Otzen Bagger

  11. Roslin Institute, Edinburgh University, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK,

    J. Kenneth Baillie & David A. Hume

  12. Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road MS 64-121, Berkeley, California 94720, USA,

    Christopher J. Mungall

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

    Terrence F. Meehan

  14. RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan,

    Masayoshi Itoh, Hideya Kawaji, Naoto Kondo, Jun Kawai & Yoshihide Hayashizaki

  15. Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7, SE-4183 Huddinge, Stockholm, Sweden,

    Andreas Lennartsson & Carsten O. Daub

  16. Department of Clinical Genetics, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands,

    Peter Heutink

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  1. Robin Andersson
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The FANTOM Consortium

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R.A., I.H., E.A., E.V., K.L., Y.C., B.L., X.Z., M.J., H.K., T.F.M., T.L., N.B., O.R., A.M.B. , J.K.B, C.J.M, N.R., F.O.B., M.R., A.S. made the computational analysis. J.B., M.B., T.L., H.K., N.K., J.K., H.S., M.I., C.O.D, A.R.R.F., P.C., Y.H. prepared and pre-processed CAGE and/or RNA-seq libraries. E.N., P.R.A., T.H.J., J.B., M.B. made the knockdown experiments followed by CAGE. C.G., C.S., L.S., J.R., D.G., M.R. made the blood cell ChIP experiments, methylation assays and in vitro blood cell validations. T.S., C.G., Y.I., Y.S., E.F., S.M., Y.N., A.R.R.F., P.C. and H.S. made the HeLa/HepG2 in vitro validations. I.M.E., R.A., A.S., F.M. designed and carried out zebrafish in vivo tests. R.A., C.G., I.H., C.S., E.A., E.V., F.M., I.M.E., P.C., A.R.R.F, M.B., J.B., A.L., C.D., D.A.H., P.H., M.R., A.S. interpreted results. R.A., C.G., I.H., E.V., I.M.E., J.B., F.M., D.A.H., M.R., A.S. wrote the paper with input from all authors. M.R. and A.S. coordinated and supervised the project.

Corresponding authors

Correspondence to Alistair R. R. Forrest, Piero Carninci, Michael Rehli or Albin Sandelin.

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The authors declare no competing financial interests.

Additional information

A list of authors and affiliations appears in the Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Table Legends, Supplementary References, a full list of members of the FANTOM consortium and Supplementary Figures 1-33. (PDF 19934 kb)

This file contains Supplementary Text, Supplementary Table Legends, Supplementary References, a full list of members of the FANTOM consortium and Supplementary Figures 1-33.

This file contains Supplementary Tables 1-16 - see Supplementary Information document for legends. (ZIP 436 kb)

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Andersson, R., Gebhard, C., Miguel-Escalada, I. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014). https://doi.org/10.1038/nature12787

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