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      Perspectives on ENCODE

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          Abstract

          The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression 1 . The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

          Abstract

          The authors summarize the history of the ENCODE Project, the achievements of ENCODE 1 and ENCODE 2, and how the new data generated and analysed in ENCODE 3 complement the previous phases.

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          Expanded encyclopaedias of DNA elements in the human and mouse genomes

          The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE 1 and Roadmap Epigenomics 2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
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            Identification of functional elements and regulatory circuits by Drosophila modENCODE.

            To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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              Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project.

              We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
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                Author and article information

                Contributors
                mpsnyder@stanford.edu
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                29 July 2020
                29 July 2020
                2020
                : 583
                : 7818
                : 693-698
                Affiliations
                [1 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Genetics, School of Medicine, , Stanford University, ; Palo Alto, CA USA
                [2 ]ISNI 0000000419368956, GRID grid.168010.e, Cardiovascular Institute, , Stanford School of Medicine, ; Stanford, CA USA
                [3 ]ISNI 0000 0004 0387 3667, GRID grid.225279.9, Functional Genomics, , Cold Spring Harbor Laboratory, ; Cold Spring Harbor, NY USA
                [4 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, University of Massachusetts Medical School, Program in Bioinformatics and Integrative Biology, ; Worcester, MA USA
                [5 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Thoracic Surgery, Clinical Translational Research Center, Shanghai Pulmonary Hospital, The School of Life Sciences and Technology, , Tongji University, ; Shanghai, China
                [6 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Bioinformatics Program, Boston University, ; Boston, MA USA
                [7 ]ISNI 0000000419368710, GRID grid.47100.32, Yale University, ; New Haven, CT USA
                [8 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Ludwig Institute for Cancer Research, , University of California, San Diego, ; La Jolla, CA USA
                [9 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Center for Epigenomics, , University of California, San Diego, ; La Jolla, CA USA
                [10 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Department of Biochemistry and Molecular Biology, , The Pennsylvania State University, ; University Park, PA USA
                [11 ]GRID grid.488617.4, Altius Institute for Biomedical Sciences, ; Seattle, WA USA
                [12 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Genome Sciences, , University of Washington, ; Seattle, WA USA
                [13 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Medicine, , University of Washington, ; Seattle, WA USA
                [14 ]ISNI 0000000419370394, GRID grid.208078.5, Department of Genetics and Genome Sciences, , Institute for Systems Genomics, UConn Health, ; Farmington, CT USA
                [15 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, MD USA
                [16 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Broad Institute and Department of Pathology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [17 ]ISNI 0000 0000 8796 4945, GRID grid.265893.3, Biological Sciences, , University of Alabama in Huntsville, ; Huntsville, AL USA
                [18 ]ISNI 0000 0004 0408 3720, GRID grid.417691.c, HudsonAlpha Institute for Biotechnology, ; Huntsville, AL USA
                [19 ]ISNI 0000 0000 9709 7726, GRID grid.225360.0, European Molecular Biology Laboratory, , European Bioinformatics Institute, Wellcome Genome Campus, ; Cambridge, UK
                [20 ]GRID grid.66859.34, The Broad Institute of Harvard and MIT, ; Cambridge, MA USA
                [21 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, MGH, ; Boston, MA USA
                [22 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Dana-Farber Cancer Institute, ; Boston, MA USA
                [23 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, MA USA
                [24 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Boston Children’s Hospital, ; Boston, MA USA
                [25 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard University, ; Cambridge, MA USA
                [26 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Computer Science and Artificial Intelligence Laboratory, , Massachusetts Institute of Technology, ; Cambridge, MA USA
                [27 ]Max Planck Institute for Molecular Genetics, Department of Genome Regulation, Berlin, Germany
                [28 ]ISNI 0000000096214564, GRID grid.266190.a, University of Colorado Boulder, ; Boulder, CO USA
                [29 ]GRID grid.473715.3, Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), , The Barcelona Institute of Science and Technology and Universitat Pompeu Fabra, ; Barcelona, Spain
                [30 ]IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, U1220, CHU Purpan, CS60039 Toulouse, France
                [31 ]ISNI 0000 0004 0555 3608, GRID grid.454320.4, Skolkovo Institute for Science and Technology, ; Moscow, Russia
                [32 ]ISNI 0000 0004 0387 3667, GRID grid.225279.9, Functional Genomics, Cold Spring Harbor Laboratory, ; Woodbury, NY USA
                [33 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Department of Clinical Research, , University of Bern, ; Bern, Switzerland
                [34 ]GRID grid.419362.b, International Institute of Molecular and Cell Biology, ; Warsaw, Poland
                [35 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Department of Biology, , Massachusetts Institute of Technology, ; Cambridge, MA USA
                [36 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Cellular and Molecular Medicine, Institute for Genomic Medicine, Stem Cell Program, Sanford Consortium for Regenerative Medicine, , University of California, San Diego, ; La Jolla, CA USA
                [37 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Département de Biochimie et Médecine Moléculaire, , Université de Montréal, Montréal, ; Quebec, Canada
                [38 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Division of Experimental Medicine, , McGill University, ; Quebec, Canada
                [39 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Institut de Recherches Cliniques de Montréal (IRCM), ; Montréal, Quebec Canada
                [40 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Program in Computational and Systems Biology, , Massachusetts Institute of Technology, ; Cambridge, MA USA
                [41 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, , University of California, San Diego, ; San Diego, CA USA
                [42 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Department of Pharmaceutical Sciences, , St. Jude Children’s Research Hospital, ; Memphis, TN USA
                [43 ]ISNI 0000000107068890, GRID grid.20861.3d, Division of Biology, California Institute of Technology, ; Pasadena, CA USA
                [44 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, MD USA
                [45 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Department of Biostatistics and Bioinformatics, , Duke University, ; Durham, NC USA
                [46 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Center for Genomic and Computational Biology, , Duke University, ; Durham, NC USA
                [47 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Biological Sciences, , University of California, Irvine, ; Irvine, CA USA
                [48 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [49 ]ISNI 0000 0001 2231 4551, GRID grid.184769.5, Environmental Genomics and Systems Biology Division, , Lawrence Berkeley National Laboratory, ; Berkeley, CA USA
                [50 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Chemistry and Biochemistry, , Department of Cellular and Molecular Medicine, UC San Diego, ; La Jolla, CA USA
                [51 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Institute for Human Genetics, Department of Neurology, , University of California, San Francisco, ; San Francisco, CA USA
                [52 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Department of Biochemistry and Molecular Genetics, , Northwestern University Feinberg School of Medicine, ; Chicago, IL USA
                [53 ]ISNI 0000 0004 0543 9901, GRID grid.240473.6, Penn State Health Milton S. Hershey Medical Center, ; Hershey, PA USA
                [54 ]ISNI 0000 0001 2231 4551, GRID grid.184769.5, US Department of Energy Joint Genome Institute, , Lawrence Berkeley National Laboratory, ; Berkeley, CA USA
                [55 ]ISNI 0000 0001 0049 1282, GRID grid.266096.d, School of Natural Sciences, , University of California, Merced, ; Merced, CA USA
                [56 ]ISNI 0000 0001 2181 7878, GRID grid.47840.3f, Comparative Biochemistry Program, , University of California, ; Berkeley, CA USA
                [57 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Howard Hughes Medical Institute, , The Salk Institute for Biological Studies, ; La Jolla, CA USA
                [58 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Computational Medicine and Bioinformatics, , University of Michigan, ; Ann Arbor, MI USA
                [59 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Human Genetics, , University of Michigan, ; Ann Arbor, MI USA
                [60 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Molecular and Cellular Physiology, School of Medicine, , Stanford University, ; Palo Alto, CA USA
                [61 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Terrence Donnelly Centre for Cellular and Biomolecular Research, , University of Toronto, ; Toronto, Ontario Canada
                [62 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Genetics, School of Medicine, , Yale University, ; New Haven, CT USA
                [63 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                [64 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Radiation Oncology, School of Medicine, , Stanford University, ; Palo Alto, CA USA
                [65 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Department of Human Genetics, Institute for Genomics and Systems Biology, , The University of Chicago, ; Chicago, IL USA
                [66 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of General Surgery, Section of Transplant Surgery, School of Medicine, , Washington University, ; St. Louis, MO USA
                [67 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, , Southern Medical University, ; Guangzhou, China
                [68 ]GRID grid.484195.5, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, ; Guangzhou, China
                [69 ]ISNI 0000000122483208, GRID grid.10698.36, Department of Cell Biology & Physiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                [70 ]ISNI 0000000122483208, GRID grid.10698.36, Thurston Arthritis Research Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                [71 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Molecular Genetics, , University of Toronto, ; Toronto, Ontario Canada
                [72 ]ISNI 0000 0001 0743 511X, GRID grid.440785.a, School of Medicine, , Jiangsu University, ; Zhenjiang, China
                [73 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Molecular Genetics, Donnelly Centre, , University of Toronto, ; Toronto, Ontario Canada
                [74 ]Tempus Labs, Chicago, IL USA
                [75 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Medicine, , University of Washington, ; Seattle, WA USA
                [76 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Fred Hutchinson Cancer Research Center, ; Seattle, WA USA
                [77 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, HHMI and Program in Systems Biology, , University of Massachusetts Medical School, Albert Sherman Center, ; Worcester, MA USA
                [78 ]ISNI 0000 0001 2184 9220, GRID grid.266683.f, University of Massachusetts Amherst, ; Amherst, MA USA
                [79 ]ISNI 0000 0004 0620 7694, GRID grid.418705.f, Institute for Infocomm Research, ; Singapore, Singapore
                [80 ]ISNI 0000 0004 1936 7494, GRID grid.61971.38, Simon Fraser University, ; Burnaby, British Columbia Canada
                [81 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, ; Boston, MA USA
                [82 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Data Sciences, , Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [83 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Center for Public Health Genomics, , University of Virginia, ; Charlottesville, VA USA
                [84 ]Molecular Pathology Unit & Cancer Center, Boston, MA USA
                [85 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, Department of Biostatistics and Bioinformatics, , Moffitt Cancer Center, ; Tampa, FL USA
                [86 ]ISNI 0000000419368956, GRID grid.168010.e, Institute for Stem Cell Biology and Regenerative Medicine, , Stanford University, ; Stanford, CA USA
                [87 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Department of Medicine, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [88 ]Department of Statistics, Medical Sciences Center, Madison, WI USA
                [89 ]Department of Biostatistics and Medical Informatics, Madison, WI USA
                [90 ]ISNI 0000 0001 2151 7939, GRID grid.267323.1, Department of Mathematical Sciences, , University of Texas at Dallas, ; Richardson, TX USA
                [91 ]ISNI 0000 0004 1937 0060, GRID grid.24434.35, Department of Statistics, , University of Nebraska-Lincoln, ; Lincoln, NE USA
                [92 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Biomedical Informatics, , The Ohio State University, ; Columbus, OH USA
                [93 ]ISNI 0000 0001 2167 3675, GRID grid.14003.36, Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, , University of Wisconsin School of Medicine and Public Health, University of Wisconsin, ; Madison, WI USA
                [94 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Genetics and Genomic Sciences, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [95 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Wellcome Sanger Institute, ; Cambridge, UK
                [96 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Program in Computational Biology, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [97 ]610 Charles E. Young Drive S, Terasaki Life Sciences Building, Room 2000E, Los Angeles, CA USA
                [98 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, McKusick-Nathans Institute of Genetic Medicine, , Johns Hopkins University, ; Baltimore, MD USA
                [99 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Biomedical Engineering, , Johns Hopkins University, ; Baltimore, MD USA
                [100 ]ISNI 0000 0001 0740 6917, GRID grid.205975.c, University of California, Santa Cruz, ; Santa Cruz, CA USA
                [101 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Center for Integrative Genomics, , University of Lausanne, ; Lausanne, Switzerland
                [102 ]ISNI 0000 0001 0125 7682, GRID grid.467824.b, Centro Nacional de Investigaciones Cardiovasculares (CNIC) and CIBER de Enfermedades Cardiovasculares (CIBERCV), ; Madrid, Spain
                [103 ]ISNI 0000 0000 8700 1153, GRID grid.7719.8, Spanish National Cancer Research Centre (CNIO), ; Madrid, Spain
                [104 ]ISNI 0000 0001 0724 6933, GRID grid.7728.a, Brunel University London, ; London, UK
                [105 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, King’s College London, Guy’s Hospital, ; London, UK
                [106 ]ELIXIR Hub, Wellcome Genome Campus, Cambridge, UK
                [107 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Institute of Cancer Research, ; London, UK
                [108 ]ISNI 0000 0004 0472 0419, GRID grid.255986.5, Department of Biological Science, , Florida State University, ; Tallahassee, FL USA
                [109 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Biochemistry, Molecular Biology and Biophysics, , University of Minnesota Medical School, ; Minneapolis, MN USA
                [110 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Center for Vaccines and Immunology University of Georgia, ; Athens, GA USA
                [111 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Center for Molecular Medicine and Department of Biochemistry and Molecular Biology, , University of Georgia, ; Athens, GA USA
                [112 ]Gift of Life Donor Program, Philadelphia, PA USA
                [113 ]ISNI 0000 0001 0484 4997, GRID grid.478397.6, American Society for Radiation Oncology, ; Arlington, VA USA
                [114 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Cancer Institute, , National Institutes of Health, ; Bethesda, MD USA
                [115 ]Leidos Biomedical, Inc, Frederick, MD USA
                [116 ]ISNI 0000 0000 8828 962X, GRID grid.422233.6, National Disease Research Interchange (NDRI), ; Philadelphia, PA USA
                [117 ]4407 Puller Drive, Kensington, MD USA
                Author information
                http://orcid.org/0000-0003-0784-7987
                http://orcid.org/0000-0002-3023-0806
                http://orcid.org/0000-0002-5435-1127
                http://orcid.org/0000-0003-4084-7516
                http://orcid.org/0000-0001-9163-5180
                http://orcid.org/0000-0002-5726-6278
                http://orcid.org/0000-0002-7395-6295
                http://orcid.org/0000-0002-3897-7955
                Article
                2449
                10.1038/s41586-020-2449-8
                7410827
                32728248
                ce30b211-563f-44b5-ba5a-a64d8c99a86d
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 7 December 2019
                : 5 May 2020
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                © The Author(s), under exclusive licence to Springer Nature Limited 2020

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                epigenomics,genome,epigenetics,transcriptomics
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                epigenomics, genome, epigenetics, transcriptomics

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