Multimodal cell maps as a foundation for structural and functional genomics

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 Bachelder, Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, Aji Palar, Ernst Pulido, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, Jing Chen, Keiichiro Ono, Dexter Pratt, Peter Zage, Ignacia Echeverria, Andrej Sali, J. Wade Harper, Steven P. Gygi, Leonard J. Foster, Edward L. Huttlin (), Emma Lundberg () and Trey Ideker ()
Additional contact information
Leah V. Schaffer: University of California San Diego
Mengzhou Hu: University of California San Diego
Gege Qian: 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
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
Andrej Sali: 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
Trey Ideker: University of California San Diego

Nature, 2025, vol. 642, issue 8066, 222-231

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08878-3

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