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Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system

Nature Neuroscience volume 27, pages 2278–2291 (2024)Cite this article

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Abstract

Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to consider during study design and implementation as well as limitations and pitfalls.

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Fig. 1: Schematics for building a multimodal molecular atlas.
Fig. 2: Methods for establishing temporal relationships between cells.

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Acknowledgements

We thank R. Awatramani, H. S. Bateup, B. Bonev, C. R. Cadwell, E. Caglayan, G. Castelo-Branco, F. Chen, J. L. Chen, S. Codeluppi, R. Corces, J. Fan, J. Gillis, G. Green, M. Heiman, K. Harris, F. Inoue, M. Kampmann, M. Kellis, F. Krienen, M. Monje, M. R. O’Dea, R. Patani, A. Pollen, A. Levine, M. Lotfollahi, C. Luo, E. Macosko, S. Marsh, K. R. Maynard, M. Nitzan, F. J. Quintana, V. Ramani, R. Satijia, M. Scavuzzo, L. Schirmer, M. Schmitz, Y. Shen, S. Sloan, N. Sun, P. Tesar, F. Theis, J. Tollkuhn, M. A. Tosches, M. E. Urbanek, X. Wang, J. D. Welch, J. Werner, H. Zeng, B. Tasic and T. Kaya for insightful feedback on this work and J. Kuhl for the illustrations in Fig. 2. G.K. is a Jon Heighten Scholar in Autism Research and holds the Townsend Distinguished Chair in Research on Autism Spectrum Disorders at UT Southwestern. G.K. was partially supported by the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition Scholar Award (220020467), the Simons Foundation for Autism Research Award (947591), and NIH grants (NS126143, HG011641, MH126481, MH134809, NS115821). D.G. was partially supported by NIH funding (R01AG078713). S.A.L. is supported by the NIH (R01EY033353), the Carol and Gene Ludwig Family Foundation, the Collaborative Center for XDP through Massachusetts General Hospital and the Cure Alzheimer’s Fund. Q.M. is a professor and the Chief of the Bioinformatics and Computational Biology Section in the Department of Biomedical Informatics at Ohio State University. This work was partially supported by awards R01GM131399, R21HG012482 and U54AG075931 from the National Institutes of Health. This work was also supported by the Pelotonia Institute of Immuno-Oncology. I.A. is a professor and the Department Chair at the Department of Neuroimmunology at the Center for Brain Research at the Medical University of Vienna, Austria and is a group leader at the Karolinska Institutet in Stockholm, Sweden. I.A. was supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, ERC Synergy Grant KILL-OR-DIFFERENTIATE (856529, ERC-2019-SyG), the Austrian Science Fund (FWF) and EMBO Young Investigator Grants, an Alex’s Lemonade Stand Foundation Crazy 8 Initiative Award, the Paradifference Foundation and Cancerfonden. Q.L. is an assistant professor of Neuroscience and Genetics, and J.Y. is a postdoctoral scholar at Washington University in St. Louis School of Medicine. This work was partially supported by the Whitehall Foundation (2021-08-003), a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation and NIH grant R01AG078512 to Q.L. and the German Research Foundation ImmunoSensation (EXC2151-390873048 to O.G.). This work was partially supported by awards R00NS111731 to A.B. and T32GM008243 and a CIRM-BSCRC Postdoctoral Fellowship to P.N., the Esther A. and Joseph Klingenstein Fund (to T.J.N.), the Shurl and Kay Curci Foundation (T.J.N.) and the Sontag Foundation (to T.J.N.) and a gift from the William K. Bowes Jr Foundation. T.J.N. is a New York Stem Cell Foundation Robertson Neuroscience Investigator. C.N.K. is supported by the UCSF Discovery Fellowship. This work was supported by the NIH Director’s New Innovator Award 1DP2 NS127705-01 to M.G.F. T.B. thanks the founder of the Allen Institute, Paul G. Allen, for his vision, encouragement and support. The work was supported by grants from an NDCN Chan Zuckerberg Initiative grant (to O.G.); C.A.W. was supported by the NINDS (NS03245) and the Allen Discovery Center program, a Paul G. Allen Frontiers Group-advised program of the Paul G. Allen Family Foundation. C.A.W. is an investigator at the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Igor Adameyko

  2. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Igor Adameyko

  3. Allen Institute for Brain Science, Seattle, WA, USA

    Trygve Bakken

  4. Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Aparna Bhaduri & Patricia Nano

  5. Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany

    Chintan Chhatbar & Marco Prinz

  6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital, Boston, MA, USA

    Mariella G. Filbin

  7. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    David Gate

  8. Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel

    Hannah Hochgerner

  9. Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

    Chang Nam Kim & Tomasz J. Nowakowski

  10. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA

    Chang Nam Kim & Tomasz J. Nowakowski

  11. Department of Biomedical Informatics, College of Medicine, the Ohio State University, Columbus, OH, USA

    Jordan Krull & Qin Ma

  12. Pelotonia Institute for Immuno-Oncology, the James Comprehensive Cancer Center, the Ohio State University, Columbus, OH, USA

    Jordan Krull & Qin Ma

  13. Laboratory of Neurodevelopmental Systems Biology, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Gioele La Manno

  14. Department of Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Qingyun Li & Jin Yang

  15. Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Qingyun Li & Jin Yang

  16. Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Sten Linnarsson

  17. Max Planck Institute for Biological Intelligence, Martinsried, Germany

    Christian Mayer

  18. Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University, New York, NY, USA

    Vilas Menon

  19. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

    Marco Prinz

  20. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Steve Quake

  21. Department of Applied Physics, Stanford University, Stanford, CA, USA

    Steve Quake

  22. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Steve Quake

  23. Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA

    Christopher A. Walsh

  24. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Christopher A. Walsh

  25. Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA

    Christopher A. Walsh

  26. Wellcome Sanger Institute, Hinxton, UK

    Omer Ali Bayraktar

  27. Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, Bonn, Germany

    Ozgun Gokce

  28. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Ozgun Gokce

  29. The Edmond and Lily Safra Center for Brain Sciences, the Hebrew University of Jerusalem, Jerusalem, Israel

    Naomi Habib

  30. Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA

    Genevieve Konopka

  31. Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA

    Genevieve Konopka

  32. Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  33. Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  34. Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  35. Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  36. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

  37. Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

  38. The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

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Corresponding authors

Correspondence to Omer Ali Bayraktar, Ozgun Gokce, Naomi Habib, Genevieve Konopka, Shane A. Liddelow or Tomasz J. Nowakowski.

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Adameyko, I., Bakken, T., Bhaduri, A. et al. Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system. Nat Neurosci 27, 2278–2291 (2024). https://doi.org/10.1038/s41593-024-01827-9

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