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      A Comparative Encyclopedia of DNA Elements in the Mouse Genome

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 4 , 2 , 7 , 6 , 1 , 3 , 3 , 4 , 4 , 4 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 7 , 7 , 7 , 7 , 7 , 3 , 3 , 3 , 3 , 9 , 9 , 10 , 11 , 12 , 12 , 12 , 13 , 1 , 1 , 1 , 1 , 1 , 14 , 14 , 14 , 5 , 5 , 5 , 5 , 5 , 5 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 16 , 2 , 17 , 2 , 17 , 17 , 2 , 17 , 18 , 19 , 19 , 19 , 20 , 21 , 22 , 17 , 18 , 19 , 23 , 3 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 24 , 24 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 25 , 26 , 27 , 27 , 27 , 4 , 28 , 29 , 30 , 30 , 31 , 31 , 32 , 33 , 34 , 35 , 36 , 35 , 36 , 37 , 37 , 37 , 37 , 37 , 37 , 8 , 9 , 14 , 15 , 16 , 20 , 4 , 2 , 3 , 7 , 6 , 5 , 22 , 1
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          As the premier model organism in biomedical research, the laboratory mouse shares the majority of protein-coding genes with humans, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of other sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

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          Most cited references67

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          Is Open Access

          An Integrated Encyclopedia of DNA Elements in the Human Genome

          Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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            Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions

            The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories (CT), and numerous models have been proposed for how chromosomes fold within CTs 1 . These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid revolutions in the study of 3D genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide 2 . In the present study, we investigated the 3D organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term “topological domains”, as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, suggesting that topological domains are an inherent property of mammalian genomes. Lastly, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, tRNAs, and SINE retrotransposons, suggesting that these factors may play a role in establishing the topological domain structure of the genome.
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              Is Open Access

              The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression

              The human genome contains many thousands of long noncoding RNAs (lncRNAs). While several studies have demonstrated compelling biological and disease roles for individual examples, analytical and experimental approaches to investigate these genes have been hampered by the lack of comprehensive lncRNA annotation. Here, we present and analyze the most complete human lncRNA annotation to date, produced by the GENCODE consortium within the framework of the ENCODE project and comprising 9277 manually annotated genes producing 14,880 transcripts. Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts, they are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences—particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Importantly, about one-third seem to have arisen within the primate lineage. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. This GENCODE annotation represents a valuable resource for future studies of lncRNAs.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                28 October 2014
                20 November 2014
                20 May 2015
                : 515
                : 7527
                : 355-364
                Affiliations
                [1 ]Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
                [2 ]Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, CA 94305, USA
                [3 ]Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, Barcelona 08003, Catalonia, Spain
                [4 ]Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
                [5 ]Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
                [6 ]Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, FL 32306-4295, USA
                [7 ]Functional Genomics, Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, New York 11724, USA
                [8 ]Division of Biology, California Institute of Technology, Pasadena, CA 91125
                [9 ]Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA
                [10 ]Departments of Pediatrics, University of Washington, Seattle, Washington 98195, USA
                [11 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                [12 ]Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA
                [13 ]Departments of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA
                [14 ]Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA, 02139, USA
                [15 ]Broad Institute of MIT and Harvard, Cambridge
                [16 ]Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
                [17 ]Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz (UCSC), Santa Cruz, CA 95064, USA
                [18 ]Departments of Ob/Gyn and Pathology, and Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA
                [19 ]European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton Cambridge CB10 1SD, UK
                [20 ]Yale University, Department of Genetics, PO Box 208005, 333 Cedar Street, New Haven, CT 06520-8005
                [21 ]Computer & Information Sciences & Engineering, University of Florida, Gainesville, FL 32611, USA
                [22 ]McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, BRB 573 Baltimore, Maryland 21205, USA
                [23 ]Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK
                [24 ]Department of Biological Structure, University of Washington, HSB I-516, 1959 NE Pacific Street, Seattle, Washington 98195, USA
                [25 ]MRC Molecular Haemotology Unit, University of Oxford, Oxford, UK
                [26 ]Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
                [27 ]HHMI and Ludwig Center at Memorial Sloan Kettering Cancer Center, Immunology Program, Memorial Sloan Kettering Cancer Canter, New York, NY 10065, USA
                [28 ]Dana Farber Cancer Institute, Harvard Medical School, Cambridge MA 02138, USA
                [29 ]University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, Iowa, IA 52242, USA
                [30 ]Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
                [31 ]Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
                [32 ]Department of Pathology, University of Washington, Seattle, WA 98195, USA
                [33 ]Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
                [34 ]Bioinformatics and Genomics program, The Pennsylvania State University, The Pennsylvania State University, University Park, PA 16802, USA
                [35 ]Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
                [36 ]Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
                [37 ]NHGRI, National Institutes of Health, 5635 Fishers Lane, Bethesda, Maryland 20892-9307, USA
                Author notes
                [*]

                These authors contributed equally to the work

                Current address for Feng Yue: Department of Biochemistry and Molecular Biology, School of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.

                Current address for Rebecca Lowdon: Washington University in St. Louis, St. Louis, MO 63108

                Current address for Leslie Adams: University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.

                Current address for Weisheng Wu: Bioinformatics Core, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

                Article
                NIHMS638072
                10.1038/nature13992
                4266106
                25409824
                0e4af456-1689-46db-96a4-c7dc7d6c9b7e

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