Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

The transcriptional landscape of age in human peripheral blood

1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , NABEC/UKBEC Consortium, 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 2 , 3 , 2 , 28 , 29 , 2 , 3 , 30 , 1 , 30 , 1 , 30 , 1 , 1 , 1 , 1 , 1 , 1 , 10 , 31 , 10 , 32 , 33 , 31 , 34 , 32 , 33 , 35 , 36 , 35 , 37 , 35 , 36 , 37 , 38 , 35 , 36 , 35 , 36 , 39 , 5 , 40 , 41 , 5 , 42 , 4 , 4 , 43 , 44 , 45 , 20 , 20 , 20 , 20 , 12 , 46 , 47 , 48 , 49 , 50 , 51 , 51 , 52 , 53 , 10 , 17 , 18 , 17 , 18 , 54 , 55 , 18 , 9 , 56 , 57 , 58 , 58 , 57 , 7 , 58 , 59 , 60 , 60 , 61 , 62 , 62 , 63 , 64 , 65 , 19 , 63 , 19 , 11 , 66 , 15 , 15 , 15 , 67 , 68 , 69 , 70 , 71 , 56 , 72 , 20 , 19 , 57 , 49 , 50 , 12 , 17 , 18 , 73 , 49 , 50 , 15 , 11 , 16 , 13 , 14 , 74 , 10 , 46 , 75 , 76 , 5 , a , 1 , b , 2 , 3

Nature Communications

Nature Pub. Group

Read this article at

Bookmark
      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

      Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

      Abstract

      Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.

      Related collections

      Most cited references 84

      • Record: found
      • Abstract: found
      • Article: not found

      Integrative analysis of 111 reference human epigenomes

      The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Functions of DNA methylation: islands, start sites, gene bodies and beyond.

        DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Human DNA methylomes at base resolution show widespread epigenomic differences.

          DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.
            Bookmark

            Author and article information

            Affiliations
            [1 ]Department of Internal Medicine, Erasmus Medical Centre Rotterdam , Rotterdam 3000CA, The Netherlands
            [2 ]The National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study , Framingham, Massachusetts 01702, USA
            [3 ]Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute , Bethesda, Maryland 20817, USA
            [4 ]Epidemiology and Public Health, University of Exeter Medical School , Exeter EX4 1DB, UK
            [5 ]Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald , Greifswald 17493, Germany
            [6 ]The Charles Bronfman Institute for Personalized Medicine, Genetics of Obesity & Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai , One Gustave L. Levy Place, New York 10029, USA
            [7 ]Department of Human Genetics, School of Medicine, Emory University , Atlanta, Georgia 30301, USA
            [8 ]Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland , St Lucia, Brisbane, Queensland 4000, Australia
            [9 ]The Institute for Molecular Bioscience, University of Queensland , Brisbane, Queensland 4000, Australia
            [10 ]Estonian Genome Center, University of Tartu , Tartu 0794, Estonia
            [11 ]Nathan Shock Center of Excellence in the Basic Biology of Aging, The Jackson Laboratory , Bar Harbor, Maine 04609, USA
            [12 ]Department of Genetics, University Medical Center Groningen, University of Groningen , Groningen 9700RB, The Netherlands
            [13 ]Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health , Neuherberg 85764, Germany
            [14 ]Institute of Human Genetics, Technical University Munich , Munich 85540, Germany
            [15 ]Neuroscience Division, Garvan Institute of Medical Research, Australia and Charles Perkins Centre and School of Molecular Bioscience, The University of Sydney , Sydney, New South Wales 2006, Australia
            [16 ]Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health , Phoenix, Arizona 85001, USA
            [17 ]Institute for Molecular Medicine Finland FIMM, University of Helsinki , Helsinki 00131, Finland
            [18 ]Department of Chronic Disease Prevention, National Institute for Health and Welfare , Helsinki 00131, Finland
            [19 ]Department of Molecular Epidemiology, Leiden University Medical Center , Leiden 2300RC, The Netherlands
            [20 ]Department of Genetics, Texas Biomedical Research Institute , San Antonio, Texas 78201, USA
            [21 ]Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Sciences , Center at Houston, Texas 77001, USA
            [22 ]Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston , Houston, Texas 77001, USA
            [23 ]Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest School of Medicine , Winston-Salem, North Carolina 27101, USA
            [24 ]Computational Medicine Core, Center for Lung Biology, University of Washington , Seattle, Washington 98101, USA
            [25 ]Section of Genetic Medicine, Institute for Genomics and Systems Biology, University of Chicago , Chicago, Illinois 60290, USA
            [26 ]Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02108, USA
            [27 ]Center of Human Development and Aging, New Jersey Medical School , Newark 07101, USA
            [28 ]General Internal Medicine Section, Boston University , Boston, Massachusetts 02108, USA
            [29 ]The Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health , Bethesda, Maryland 20817, USA
            [30 ]Department of Epidemiology, Erasmus Medical Center , Rotterdam 3000CA, The Netherlands
            [31 ]Molecular Pathology, Institute of Biomedicine, University of Tartu , Tartu 0794, Estonia
            [32 ]Department of Cardiovascular Sciences, University of Leicester , Leicester LE1, UK
            [33 ]National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital , Leicester LE1, UK
            [34 ]Institute of Molecular and Cell Biology, Estonian Genome Center, University of Tartu , Tartu 0794, Estonia
            [35 ]Institute of Epidemiologie II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health , Neuherberg 85764, Germany
            [36 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health , Neuherberg 85764, Germany
            [37 ]Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf , Düsseldorf 40593, Germany
            [38 ]Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University , Düsseldorf 40593, Germany
            [39 ]Hannover Unified Biobank, Hannover Medical School , Hannover 30519, Germany
            [40 ]Department of Psychiatry and Psychotherapy, Helios Hospital Stralsund, University Medicine Greifswald , Greifswald 17489, Germany
            [41 ]Institute for Community Medicine, University Medicine Greifswald , Greifswald 17489, Germany
            [42 ]Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, University Medicine Greifswald , Greifswald 17489, Germany
            [43 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
            [44 ]Geriatric Unit, Azienda Sanitaria di Firenze , Florence 50123, Italy
            [45 ]Centre for Genetic Origins of Health and Disease, The University of Western Australia, and Faculty of Health Sciences, Curtin University , Perth, Western Australia 9011, Australia
            [46 ]Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge 02138, USA
            [47 ]Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02108, USA
            [48 ]Partners Center for Personalized Genetic Medicine , Boston, Massachusetts 02108, USA
            [49 ]The Queensland Brain Institute, University of Queensland , Brisbane, Queensland 4000, Australia
            [50 ]University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital , Brisbane, Queensland 4000, Australia
            [51 ]Department of Epidemiology, University of Michigan , Ann Arbor, Michigan 48103, USA
            [52 ]Department of Biosciences, University of Helsinki , Helsinki 00100, Finland
            [53 ]Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare , Helsinki 00100, Finland
            [54 ]Wellcome Trust Sanger Institute , Hinxton, Cambridge CB4, UK
            [55 ]Department of Public Health, Hjelt Institute, University of Helsinki , Helsinki 00100, Finland
            [56 ]QIMR Berghofer Medical Research Institute , Brisbane, Queensland 4000, Australia
            [57 ]Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine , Atlanta, Georgia 30301, USA
            [58 ]Max-Planck Institute of Psychiatry , Munich 80331, Germany
            [59 ]Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina 27101, USA
            [60 ]Department of Epidemiology, University of Washington , Seattle, Washington 98101, USA
            [61 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , Seattle, Washington 98101, USA
            [62 ]Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California 90501, USA
            [63 ]Department of Medical Statistics, Leiden University Medical Center , Leiden 2300RC, The Netherlands
            [64 ]Department of Rheumatology, Leiden University Medical Center , Leiden 2300RC, The Netherlands
            [65 ]Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300RC, The Netherlands
            [66 ]Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02138, USA
            [67 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , Seattle, Washington 98195, USA
            [68 ]Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington , Seattle, Washington 98195, USA
            [69 ]Cardiovascular Health Research Unit, Department of Health Services, University of Washington , Seattle, Washington 98195, USA
            [70 ]Group Health Research Institute, Group Health Cooperative , Seattle, Washington 98195, USA
            [71 ]Department of Pathology, University of Vermont College of Medicine , Colchester, Vermont 98195, USA
            [72 ]Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic , Rochester, Minnesota 55901, USA
            [73 ]Computational Medicine, Institute of Health Sciences, Faculty of Medicine, University of Oulu , Oulu 90570, Finland
            [74 ]Clinical Research Branch, National Institute on Aging , Baltimore, Maryland 21218, USA
            [75 ]Division of Endocrinology, Children's Hospital Boston , Boston, Massachusetts 02108, USA
            [76 ]Department of Genetics, Harvard Medical School , Boston, Massachusetts 02108, USA
            [77 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, Maryland 20817, USA.
            [78 ]Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London WC1N 3BG, UK.
            [79 ]Department of Medical and Molecular Genetics, King's College London, Guy's Hospital , London SE1 9RT, UK.
            [80 ]Research Resources Branch, National Institute on Aging, National Institutes of Health, Bethesda , Maryland 20817, USA.
            [81 ]Department of Neuroscience, Karolinska Institutet , Stockholm 10044, Sweden.
            [82 ]Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh , Edinburgh EH13, UK.
            [83 ]Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health , Baltimore, Maryland 20817, USA.
            [84 ]Department of Genetics, King Faisal Specialist Hospital and Research Centre 11564, Saudi Arabia.
            [85 ]Brain Resource Center, Johns Hopkins University , Baltimore, Maryland 20817, USA.
            [86 ]ITGR Biomarker Discovery Group, Genentech , South San Francisco, California 94101, USA.
            [87 ]NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School , Baltimore, Maryland 2117, USA.
            Author notes
            [*]

            These authors contributed equally to this work.

            [†]

            These authors jointly supervised the work.

            [‡]

            A full list of consortium members appears below.

            Journal
            Nat Commun
            Nat Commun
            Nature Communications
            Nature Pub. Group
            2041-1723
            22 October 2015
            2015
            : 6
            26490707
            4639797
            ncomms9570
            10.1038/ncomms9570
            Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

            This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

            Categories
            Article

            Uncategorized

            Comments

            Comment on this article