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      A comparative encyclopedia of DNA elements in the mouse genome.

      1 , 2 , 3 , 4 , 5 , 6 , 4 , 2 , 7 , 6 , 8 , 3 , 3 , 4 , 4 , 4 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 7 , 7 , 7 , 7 , 7 , 3 , 3 , 3 , 10 , 11 , 11 , 12 , 13 , 13 , 14 , 8 , 8 , 8 , 8 , 8 , 15 , 15 , 15 , 16 , 5 , 5 , 5 , 5 , 5 , 5 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 17 , 2 , 18 , 2 , 18 , 18 , 2 , 18 , 19 , 20 , 20 , 20 , 21 , 22 , 23 , 18 , 19 , 24 , 3 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 25 , 25 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 4 , 26 , 27 , 28 , 28 , 28 , 4 , 29 , 30 , 31 , 30 , 32 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 38 , 39 , 40 , 40 , 40 , 40 , 40 , 40 , 9 , 11 , 17 , 21 , 4 , 2 , 3 , 7 , 6 , 5 , 23 , 8
      Nature
      Springer Nature
          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.

          Abstract

          The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, 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 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
                Nature
                Nature
                Springer Nature
                1476-4687
                0028-0836
                Nov 20 2014
                : 515
                : 7527
                Affiliations
                [1 ] 1] Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. [2] Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
                [2 ] Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA.
                [3 ] Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, 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, Pennsylvania 16802, USA.
                [6 ] Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA.
                [7 ] Functional Genomics, Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, New York 11724, USA.
                [8 ] Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA.
                [9 ] Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
                [10 ] 1] Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain. [2] Department of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Waehringerstrasse 17/3/303, A-1090 Vienna, Austria.
                [11 ] Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA.
                [12 ] 1] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. [2] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
                [13 ] Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
                [14 ] 1] Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [2] Department of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA.
                [15 ] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA.
                [16 ] 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
                [17 ] Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697, USA.
                [18 ] Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz (UCSC), Santa Cruz, California 95064, USA.
                [19 ] Departments of Obstetrics/Gynecology and Pathology, and Center for Reproductive Sciences, University of California San Francisco, San Francisco, California 94143, USA.
                [20 ] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
                [21 ] Yale University, Department of Genetics, PO Box 208005, 333 Cedar Street, New Haven, Connecticut 06520-8005, USA.
                [22 ] Computer &Information Sciences &Engineering, University of Florida, Gainesville, Florida 32611, USA.
                [23 ] McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, BRB 573 Baltimore, Maryland 21205, USA.
                [24 ] 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
                [25 ] Department of Biological Structure, University of Washington, HSB I-516, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
                [26 ] MRC Molecular Haemotology Unit, University of Oxford, Oxford OX3 9DS, UK.
                [27 ] Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
                [28 ] HHMI and Ludwig Center at Memorial Sloan Kettering Cancer Center, Immunology Program, Memorial Sloan Kettering Cancer Canter, New York, New York 10065, USA.
                [29 ] Dana Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts 02138, USA.
                [30 ] University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, Iowa 52242, USA.
                [31 ] Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
                [32 ] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
                [33 ] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
                [34 ] Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA.
                [35 ] Bioinformatics and Genomics program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
                [36 ] Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
                [37 ] 1] Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. [2] Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
                [38 ] Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
                [39 ] Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
                [40 ] NHGRI, National Institutes of Health, 5635 Fishers Lane, Bethesda, Maryland 20892-9307, USA.
                Article
                nature13992 NIHMS638072
                10.1038/nature13992
                4266106
                25409824
                0e4af456-1689-46db-96a4-c7dc7d6c9b7e
                History

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