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Spatio-temporal transcriptome of the human brain

Nature volume 478, pages 483–489 (2011)Cite this article

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Abstract

Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

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Figure 1: Global spatio-temporal dynamics of gene expression.
Figure 2: Sex-biased gene expression.
Figure 3: Sex-biased differential exon usage.
Figure 4: Global co-expression networks and gene modules.
Figure 5: Trajectories of genes associated with neurodevelopmental processes.
Figure 6: Association between SNPs and gene expression.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Exon array have been deposited in the NCBI Gene Expression Omnibus under accession number GSE25219 and genotyping data have been deposited in the NCBI database of Genotypes and Phenotypes under accession number phs000406.v1.p1.

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Acknowledgements

We thank A. Belanger, V. Imamovic, R. Johnson, P. Larton, S. Lindsay, B. Poulos, J. Rajan, D. Rimm and R. Zielke for assistance with tissue acquisition, D. Singh for technical assistance, I. Kostovic and Z. Petanjek for dendrite measurements, P. Levitt for suggesting the inclusion of ITC in the study, and D. Karolchik and A. Zweig for help in creating tracks for the UCSC Genome Browser. We also thank A. Beckel-Mitchener, M. Freund, M. Gerstein, D. Geschwind, T. Insel, M. Judas, J. Knowles, E. Lein, P. Levitt, N. Parikshak and members of the Sestan laboratory for discussions and criticism. Tissue was obtained from several sources including the Human Fetal Tissue Repository at the Albert Einstein College of Medicine, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Laboratory of Developmental Biology at the University of Washington (supported by grant HD000836 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development) and the Joint MRC/Wellcome Trust Human Developmental Biology Resource (http://hdbr.org) at the IHG, Newcastle Upon Tyne (UK funding awards G0700089 and GR082557). Support for predoctoral fellowships was provided by the China Scholarship Council (Y.Z.), the Portuguese Foundation for Science and Technology (A.M.M.S.), the Samsung Scholarship Foundation (Y.S.), a Fellowship of the German Academic Exchange Service – DAAD (S. Mayer) and NIDA grant DA026119 (T.G.). This work was supported by grants from the US National Institutes of Health (MH081896, MH089929, NS054273), the Kavli Foundation and NARSAD, and by a James S. McDonnell Foundation Scholar Award (N.S.).

Author information

Author notes

  1. Hyo Jung Kang, Yuka Imamura Kawasawa, Feng Cheng, Ying Zhu, Xuming Xu and Mingfeng Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Hyo Jung Kang, Yuka Imamura Kawasawa, Feng Cheng, Ying Zhu, Xuming Xu, Mingfeng Li, André M. M. Sousa, Mihovil Pletikos, Kyle A. Meyer, Goran Sedmak, Yurae Shin, Matthew B. Johnson, Željka Krsnik, Simone Mayer, Sofia Fertuzinhos & Nenad Šestan

  2. Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal,

    André M. M. Sousa

  3. Graduate Program in Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia,

    Mihovil Pletikos & Goran Sedmak

  4. Department of Biostatistics, Virginia Commonwealth University, Richmond, 23298, Virginia, USA

    Tobias Guennel & Mark Reimers

  5. MSc/PhD Molecular Biology Program, International Max Planck Research School for Molecular Biology, 37077 Göttingen, Germany,

    Simone Mayer

  6. Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Sheila Umlauf & Shrikant Mane

  7. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK,

    Steven N. Lisgo

  8. Department of Pathology, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Alexander Vortmeyer & Anita Huttner

  9. Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Daniel R. Weinberger, Thomas M. Hyde & Joel E. Kleinman

  10. The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, 21205, Maryland, USA

    Thomas M. Hyde

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  1. Hyo Jung Kang
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Contributions

H.J.K., Y.I.K., A.M.M.S., M.P., K.A.M., G.S., Y.S., M.B.J., Z.K., S. Mayer, S.F., S.U., S. Mane and N.S. performed and analysed the experiments. F.C., Y.Z., X.X., M.L., T.G. and M.R. analysed the data. Z.K., A.M.M.S., M.P., G.S., S.N.L, A.V., D.R.W., T.M.H., A.H., J.E.K. and N.S. participated in tissue procurement and examination. N.S. designed the study and wrote the manuscript, which all authors commented and edited.

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Correspondence to Nenad Šestan.

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Supplementary Information

This file contains Supplementary Text, Data and Methods (1-9 ) - see Contents for full details, (10 ) Supplementary References, (11) Legends for Supplementary Tables 1-17 (see separate excel file for tables), and (12) Supplementary Figures 1-25 with legends. (PDF 7421 kb)

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Kang, H., Kawasawa, Y., Cheng, F. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011). https://doi.org/10.1038/nature10523

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