Tissue Specificity of Gene Expression


Tissue-specific patterns of gene expression are fundamental to establishing and preserving tissue identity and function, and dysregulation of these patterns underlies a wide range of diseases. Over the past few years, several large-scale efforts driven by the advent of RNA sequencing have established resources of gene expression measurements, across both tissues and individuals, toward building a comprehensive understanding of the specificity and variability of gene expression. We summarize these resources, review insights gained into the tissue specificity of gene expression across transcript classes, including protein-coding and non-coding RNAs, and discuss the developments that will be needed to integrate existing and new resources into a detailed map of gene expression and its regulation across the human body.

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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Nica AC, Parts L, Glass D, Nisbet J, Barrett A, Sekowska M, et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 2011;7:e1002003.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest ARR, Kawaji H, Rehli M, Baillie JK, de Hoon MJL, et al. A promoter-level mammalian expression atlas. Nature. 2014;507:462–70. Presents a detailed map of transcription start sites across human tissues.

  4. 4.

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Article  Google Scholar 

  5. 5.

    •• Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419–9. Describes the largest characterization of the proteome across human tissues conducted to date.

  6. 6.

    •• GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. American Association for the Advancement of Science; 2015;348:648–60. Summarizes initial results from the largest multi-tissue and multi-individual study of gene expression in humans conducted to date.

  7. 7.

    •• Melé M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. The human transcriptome across tissues and individuals. Science. 2015;348:660–5. Initial characterization of the human transcriptome across tissues from the GTEx project.

  8. 8.

    Uhlen M, Hallstrom BM, Lindskog C, Mardinoglu A, Ponten F, Nielsen J. Transcriptomics resources of human tissues and organs. Molecular Systems Biology. 2016;12:862.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Gry M, Oksvold P, Ponten F, Uhlen M. Tissue-specific protein expression in human cells, tissues and organs. J Proteomics Bioinform. 2010;3:283–93.

    Google Scholar 

  10. 10.

    Lin S, Lin Y, Nery JR, Urich MA, Breschi A, Davis CA, et al. Comparison of the transcriptional landscapes between human and mouse tissues. Proc Natl Acad Sci USA. 2014;111:17224–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Schug J, Schuller W-P, Kappen C, Salbaum JM, Bucan M, Stoeckert CJ. Promoter features related to tissue specificity as measured by Shannon entropy. Genome Biol BioMed Central. 2005;6:R33.

  12. 12.

    Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507:455–61.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Aguet F, Brown AA, Castel S, Davis JR, Mohammadi P, Segrè AV, et al. Local genetic effects on gene expression across 44 human tissues. bioRxiv http://www.biorxiv.org/content/early/2016/09/09/074450 2016.

  14. 14.

    Yeo G, Holste D, Kreiman G, Burge CB. Variation in alternative splicing across human tissues. Genome Biol. 2004;5:R74.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    de Hoon M, Shin JW, Carninci P. Paradigm shifts in genomics through the FANTOM projects. Mamm Genome. Springer US; 2015;26:391–402.

  17. 17.

    •• Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47:199–208. Largest compendium of long noncoding RNAs in humans, reporting > 40,000 previously unannotated lncRNAs.

  18. 18.

    Londin E, Loher P, Telonis AG, Quann K, Clark P, Jing Y, et al. Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci USA. 2015;112:E1106–15.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Freedman JE, Gerstein M, Mick E, Rozowsky J. Diverse human extracellular RNAs are widely detected in human plasma. Nature Commun. 2016. doi: 10.1038/ncomms11106.

  20. 20.

    Joehanes R, Johnson AD, Barb JJ, Raghavachari N, Liu P, Woodhouse KA, et al. Gene expression analysis of whole blood, peripheral blood mononuclear cells, and lymphoblastoid cell lines from the Framingham Heart Study. Physiol Genomics. 2012;44:59–75.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469–76.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Byron SA, Van Keuren-Jensen KR, Engelthaler DM, Carpten JD, Craig DW. Translating RNA sequencing into clinical diagnostics: opportunities and challenges. Nature. 2016;17:257–71.

    CAS  Google Scholar 

  23. 23.

    Jung H, Lee D, Lee J, Park D, Kim YJ, Park W-Y, et al. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet. 2015;47:1242–8.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Li YI, van de Geijn B, Raj A, Knowles DA, Petti AA, Golan D, et al. RNA splicing is a primary link between genetic variation and disease. Science. American Association for the. Adv Sci. 2016;352:600–4.

    CAS  Google Scholar 

  25. 25.

    Rivas MA, Pirinen M, Conrad DF, Lek M, Tsang EK, Karczewski KJ, et al. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science. 2015;348:666–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. bioRxiv. http://biorxiv.org/cgi/content/short/074153v1, 2016.

  27. 27.

    • Lovén J, Orlando DA, Sigova AA, Lin CY, Rahl PB, Burge CB, et al. Revisiting Global Gene Expression Analysis. Cell. Elsevier Inc; 2012;151:476–82. Summarizes fundamental between-sample normalization issues in RNA sequence data.

  28. 28.

    Danielsson F, James T, Gomez-Cabrero D, Huss M. Assessing the consistency of public human tissue RNA-seq data sets. Brief Bioinform. Oxford University Press; 2015;16:941–9.

  29. 29.

    •• Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30. Most extensive study of the human epigenome conducted to date.

  30. 30.

    Petryszak R, Keays M, Tang YA, Fonseca NA, Barrera E, Burdett T, et al. Expression Atlas update—an integrated database of gene and protein expression in humans, animals and plants. Nucleic Acids Res. 2016;44:D746–52.

    Article  PubMed  Google Scholar 

  31. 31.

    Buil A, Brown AA, Lappalainen T, Viñuela A, Davies MN, Zheng H-F, et al. Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins. Nat Genet. 2015;47:88–91.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Brown AA, Buil A, Viñuela A, Lappalainen T, Zheng H-F, Richards JB, et al. Genetic interactions affecting human gene expression identified by variance association mapping. eLife. eLife Sciences Publications Limited; 2014;3:e01381–16.

  33. 33.

    Krupp M, Marquardt JU, Sahin U, Galle PR, Castle J, Teufel A. RNA-Seq Atlas–a reference database for gene expression profiling in normal tissue by next-generation sequencing. Bioinformatics. 2012;28:1184–5.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Castle JC, Armour CD, Löwer M, Haynor D, Biery M, Bouzek H, et al. Digital genome-wide ncRNA expression, including SnoRNAs, across 11 human tissues using PolyA-neutral amplification. Creighton C, editor. PLoS One. Public Library of Science; 2010;5:e11779–9.

  35. 35.

    Yu NY-L, Hallström BM, Fagerberg L, Ponten F, Kawaji H, Carninci P, et al. Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. 2015;43:6787–98.

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Correspondence to Kristin G. Ardlie.

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François Aguet and Kristin G. Ardlie declare that they have no conflict of interest.

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Aguet, F., Ardlie, K.G. Tissue Specificity of Gene Expression. Curr Genet Med Rep 4, 163–169 (2016). https://doi.org/10.1007/s40142-016-0105-2

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  • Gene expression
  • Tissue specificity
  • RNA-seq
  • Human transcriptome
  • Genomic resources