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Multimodal cell maps as a foundation for structural and functional genomics

Author

Listed:
  • Leah V. Schaffer

    (University of California San Diego)

  • Mengzhou Hu

    (University of California San Diego)

  • Gege Qian

    (University of California San Diego
    University of California San Diego)

  • Kyung-Mee Moon

    (University of British Columbia)

  • Abantika Pal

    (University of California San Francisco)

  • Neelesh Soni

    (University of California San Francisco)

  • Andrew P. Latham

    (University of California San Francisco)

  • Laura Pontano Vaites

    (Harvard Medical School)

  • Dorothy Tsai

    (University of California San Diego)

  • Nicole M. Mattson

    (University of California San Diego)

  • Katherine Licon

    (University of California San Diego)

  • Robin Bachelder

    (University of California San Diego)

  • Anthony Cesnik

    (Stanford University)

  • Ishan Gaur

    (Stanford University)

  • Trang Le

    (Stanford University)

  • William Leineweber

    (Stanford University)

  • Aji Palar

    (University of California San Francisco)

  • Ernst Pulido

    (Stanford University)

  • Yue Qin

    (University of California San Diego
    Broad Institute of MIT and Harvard)

  • Xiaoyu Zhao

    (University of California San Diego)

  • Christopher Churas

    (University of California San Diego)

  • Joanna Lenkiewicz

    (University of California San Diego)

  • Jing Chen

    (University of California San Diego)

  • Keiichiro Ono

    (University of California San Diego)

  • Dexter Pratt

    (University of California San Diego)

  • Peter Zage

    (University of California San Diego)

  • Ignacia Echeverria

    (University of California San Francisco
    University of California San Francisco)

  • Andrej Sali

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • J. Wade Harper

    (Harvard Medical School)

  • Steven P. Gygi

    (Harvard Medical School)

  • Leonard J. Foster

    (University of British Columbia)

  • Edward L. Huttlin

    (Harvard Medical School)

  • Emma Lundberg

    (Stanford University
    Stanford University
    KTH Royal Institute of Technology
    Chan Zuckerberg Biohub)

  • Trey Ideker

    (University of California San Diego
    University of California San Diego
    University of California San Diego)

Abstract

Human cells consist of a complex hierarchy of components, many of which remain unexplored1,2. Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10−8 to 10−5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models3. We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag–Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes4, identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.

Suggested Citation

  • Leah V. Schaffer & Mengzhou Hu & Gege Qian & Kyung-Mee Moon & Abantika Pal & Neelesh Soni & Andrew P. Latham & Laura Pontano Vaites & Dorothy Tsai & Nicole M. Mattson & Katherine Licon & Robin Bacheld, 2025. "Multimodal cell maps as a foundation for structural and functional genomics," Nature, Nature, vol. 642(8066), pages 222-231, June.
    • Handle: RePEc:nat:nature:v:642:y:2025:i:8066:d:10.1038_s41586-025-08878-3
    DOI: 10.1038/s41586-025-08878-3
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