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Single-Cell Genomics Unravels Brain Cell-Type Complexity

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Neuroepigenomics in Aging and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((PMISB,volume 978))

Abstract

The brain is the most complex tissue in terms of cell types that it comprises, to the extent that it is still poorly understood. Single cell genome and transcriptome profiling allow to disentangle the neuronal heterogeneity, enabling the categorization of individual neurons into groups with similar molecular signatures. Herein, we unravel the current state of knowledge in single cell neurogenomics. We describe the molecular understanding of the cellular architecture of the mammalian nervous system in health and in disease; from the discovery of unrecognized cell types to the validation of known ones, applying these state-of-the-art technologies.

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References

  1. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Holmberg J, Perlmann T. Maintaining differentiated cellular identity. Nat Rev Genet. 2012;13:429–39.

    Article  CAS  PubMed  Google Scholar 

  3. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.

    Google Scholar 

  4. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature. 2003;425:917–25.

    Article  CAS  PubMed  Google Scholar 

  5. Frumkin D, Wasserstrom A, Itzkovitz S, Harmelin A, Rechavi G, Shapiro E. Amplification of multiple genomic loci from single cells isolated by laser micro-dissection of tissues. BMC Biotechnol. 2008;8:17.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Reece A, Xia B, Jiang Z, Noren B, McBride R, Oakey J. Microfluidic techniques for high throughput single cell analysis. Curr Opin Biotechnol. 2016;40:90–6.

    Article  CAS  PubMed  Google Scholar 

  7. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161:1202–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Waters J, Leung ML, Unruh A, Roh W, Shi X, et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature. 2014;512:155–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dean FB, Nelson JR, Giesler TL, Lasken RS. Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. Genome Res. 2001;11:1095–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spits C, Le Caignec C, De Rycke M, Van Haute L, Van Steirteghem A, Liebaers I, et al. Whole-genome multiple displacement amplification from single cells. Nat Protoc. 2006;1:1965–70.

    Article  CAS  PubMed  Google Scholar 

  11. Garmendia C, Bernad A, Esteban JA, Blanco L, Salas M. The bacteriophage phi 29 DNA polymerase, a proofreading enzyme. J Biol Chem. 1992;267:2594–9.

    CAS  PubMed  Google Scholar 

  12. Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, Arnheim N. Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci U S A. 1992;89:5847–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheung VG, Nelson SF. Whole genome amplification using a degenerate oligonucleotide primer allows hundreds of genotypes to be performed on less than one nanogram of genomic DNA. Proc Natl Acad Sci U S A. 1996;93:14676–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Troutt AB, McHeyzer-Williams MG, Pulendran B, Nossal GJ. Ligation-anchored PCR: a simple amplification technique with single-sided specificity. Proc Natl Acad Sci U S A. 1992;89:9823–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zong C, Lu S, Chapman AR, Xie XS. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012;338:1622–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Bourcy CFA, De Vlaminck I, Kanbar JN, Wang J, Gawad C, Quake SR. A quantitative comparison of single-cell whole genome amplification methods. PLoS One. Public Library of Science; 2014;9:e105585.

    Google Scholar 

  17. Huang L, Ma F, Chapman A, Lu S. Xie XS. Methodology and Applications: Single-Cell Whole-Genome Amplification and Sequencing; 2015.

    Google Scholar 

  18. Tang F, Barbacioru C, Wang Y, Nordman E, Lee C, Xu N, et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods. 2009;6:377–82.

    Article  CAS  PubMed  Google Scholar 

  19. Ramsköld D, Luo S, Wang Y-C, Li R, Deng Q, Faridani OR, et al. Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat Biotechnol. 2012;30:777–82.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Picelli S, Björklund ÅK, Faridani OR, Sagasser S, Winberg G, Sandberg R. smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat Methods. 2013 Nov;10:1096–8.

    Article  CAS  PubMed  Google Scholar 

  21. Islam S, Kjällquist U, Moliner A, Zajac P, Fan J-B, Lönnerberg P, et al. Highly multiplexed and strand-specific single-cell RNA 5′ end sequencing. Nat Protoc. 2012;7:813–28.

    Article  CAS  PubMed  Google Scholar 

  22. Hashimshony T, Wagner F, Sher N, Yanai I. CEL-Seq: Single-Cell RNA-Seq by Multiplexed Linear Amplification. Cell Rep. 2012;2:666–73.

    Article  CAS  PubMed  Google Scholar 

  23. Hashimshony T, Senderovich N, Avital G, Klochendler A, de Leeuw Y, Anavy L, et al. CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. Genome Biol. [Internet]. 2016 [cited 2016 Nov 14];17:77. Available from: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0938-8

  24. Jaitin DA, Kenigsberg E, Keren-Shaul H, Elefant N, Paul F, Zaretsky I, et al. Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types. Science. 2014;343:776–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sasagawa Y, Nikaido I, Hayashi T, Danno H, Uno KD, Imai T, et al. Quartz-Seq: a highly reproducible and sensitive single-cell RNA sequencing method, reveals non-genetic gene-expression heterogeneity. Genome Biol. 2013;14:R31.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Islam S, Zeisel A, Joost S, La Manno G, Zajac P, Kasper M, et al. Quantitative single-cell RNA-seq with unique molecular identifiers. Nat Meth.; 2014;11:163–6.

    Google Scholar 

  27. Baker SC, Bauer SR, Beyer RP, Brenton JD, Bromley B, Burrill J, et al. The External RNA Controls Consortium: a progress report. Nat Methods. 2005;2:731–4.

    Article  CAS  PubMed  Google Scholar 

  28. Guo H, Zhu P, Wu X, Li X, Wen L, Tang F. Single-cell methylome landscapes of mouse embryonic stem cells and early embryos analyzed using reduced representation bisulfite sequencing. Genome Res. 2013;23:2126–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, et al. Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods. 2014;11:817–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Farlik M, Sheffield NC, Nuzzo A, Datlinger P, Schnegger A, Klughammer J, et al. Single-Cell DNA Methylome Sequencing and Bioinformatic Inference of Epigenomic Cell-State Dynamics. Cell Rep. 2015;10:1386–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rotem A, Ram O, Shoresh N, Sperling RA, Goren A, Weitz DA, et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol. 2015;33:1165–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML, Snyder MP, et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature. 2015;523:486–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cusanovich DA, Daza R, Adey A, Pliner HA, Christiansen L, Gunderson KL, et al. Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing. Science. 2015;348:910–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nagano T, Lubling Y, Yaffe E, Wingett SW, Dean W, Tanay A, et al. Single-cell Hi-C for genome-wide detection of chromatin interactions that occur simultaneously in a single cell. Nat Protoc. 2015;10:1986–2003.

    Article  CAS  PubMed  Google Scholar 

  35. Nagano T, Lubling Y, Stevens TJ, Schoenfelder S, Yaffe E, Dean W, et al. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature. 2013;502:59–64.

    Article  CAS  PubMed  Google Scholar 

  36. Macaulay IC, Haerty W, Kumar P, Li YI, Hu TX, Teng MJ, et al. G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. Nat Methods. 2015;12:519–22.

    Article  CAS  PubMed  Google Scholar 

  37. Angermueller C, Clark SJ, Lee HJ, Macaulay IC, Teng MJ, Hu TX, et al. Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nat Methods. 2016;13:229–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Treutlein B, Brownfield DG, Wu AR, Neff NF, Mantalas GL, Espinoza FH, et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature. 2014;509:371–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Muraro MJ, Dharmadhikari G, Grün D, Groen N, Dielen T, Jansen E, et al. A Single-Cell Transcriptome Atlas of the Human Pancreas. Cell Syst. 2016;3:385–394.e3.

    Google Scholar 

  40. Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347:1138–42.

    Article  CAS  PubMed  Google Scholar 

  41. Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 2016;19:335–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harris JA, Hirokawa KE, Sorensen SA, Gu H, Mills M, Ng LL, et al. Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation. Front Neural Circuits. 2014;8

    Google Scholar 

  43. Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci. 2015;201520760

    Google Scholar 

  44. Goddard CA, Butts DA, Shatz CJ. Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci. 2007;104:6828–33.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pollen AA, Nowakowski TJ, Shuga J, Wang X, Leyrat AA, Lui JH, et al. Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex. Nat Biotechnol. 2014;32:1053–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A. 2015;112:7285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Poulin J-F, Zou J, Drouin-Ouellet J, Kim K-YA, Cicchetti F, Awatramani RB. Defining Midbrain Dopaminergic Neuron Diversity by Single-Cell Gene Expression Profiling. Cell Rep. 2014;9:930–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. La Manno G, Gyllborg D, Codeluppi S, Nishimura K, Salto C, Zeisel A, et al. Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells. Cell 2016;167:566–580.e19.

    Google Scholar 

  49. Abraira VE, Ginty DD. The Sensory Neurons of Touch. Neuron. 2013;79:618–39.

    Article  CAS  PubMed  Google Scholar 

  50. Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Publ Gr. 2014;18

    Google Scholar 

  51. Niimura Y, Nei M. Comparative evolutionary analysis of olfactory receptor gene clusters between humans and mice. Gene. 2005;346:13–21.

    Article  CAS  PubMed  Google Scholar 

  52. Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32:381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hanchate NK, Kondoh K, Lu Z, Kuang D, Ye X, Qiu X, et al. Single-cell transcriptomics reveals receptor transformations during olfactory neurogenesis. Science. 2015;350:1251–5.

    Article  CAS  PubMed  Google Scholar 

  54. Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcao A, Xiao L, et al. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science. 2016;352:1326–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Grünblatt E, Riederer P. Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease. J Neural Transm. 2016;123:83–90.

    Article  PubMed  Google Scholar 

  56. Barrow TR. Cell replacement therapy in Parkinson’s disease. Biosci. Horizons. Oxford University Press. 2015;8:hzv002-hzv002.

    Google Scholar 

  57. Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, et al. Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions. Cell Rep. 2012;1:703–14.

    Article  CAS  PubMed  Google Scholar 

  58. van den Bos H, Spierings DCJ, Taudt A, Bakker B, Porubský D, Falconer E, et al. Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons. Genome Biol. 2016;17:116.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Alizadeh AA, Aranda V, Bardelli A, Blanpain C, Bock C, Borowski C, et al. Toward understanding and exploiting tumor heterogeneity. Nat Med. 2015;21:846–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21:2683–710.

    Article  CAS  PubMed  Google Scholar 

  61. Francis JM, Zhang C-Z, Maire CL, Jung J, Manzo VE, Adalsteinsson VA, et al. EGFR Variant Heterogeneity in Glioblastoma Resolved through Single-Nucleus Sequencing. Cancer Discov. 2014;4:956–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539:309–13.

    Article  PubMed  Google Scholar 

  64. Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci. 2008;9:557–68.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra (UPF), Parc Científic de Barcelona – Torre I, Baldiri Reixac, 4, Barcelona, Catalonia, 08028, Spain

    Amy Guillaumet-Adkins Ph.D.

  2. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), National Centre for Genomic Analysis (CNAG), Parc Científic de Barcelona – Torre I, Baldiri Reixac, 4, Barcelona, Catalonia, 08028, Spain

    Holger Heyn Ph.D.

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  1. Amy Guillaumet-Adkins Ph.D.
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  2. Holger Heyn Ph.D.
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Correspondence to Holger Heyn Ph.D. .

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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), CATALONIA, Spain

    Raul Delgado-Morales

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Guillaumet-Adkins, A., Heyn, H. (2017). Single-Cell Genomics Unravels Brain Cell-Type Complexity. In: Delgado-Morales, R. (eds) Neuroepigenomics in Aging and Disease. Advances in Experimental Medicine and Biology(), vol 978. Springer, Cham. https://doi.org/10.1007/978-3-319-53889-1_20

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