2. Academic Validation
  3. Multimodal cell maps as a foundation for structural and functional genomics

Multimodal cell maps as a foundation for structural and functional genomics

  • Nature. 2025 Jun;642(8066):222-231. doi: 10.1038/s41586-025-08878-3.
Leah V Schaffer # 1,  Mengzhou Hu # 1,  Gege Qian 1 2,  Kyung-Mee Moon 3,  Abantika Pal 4,  Neelesh Soni 4,  Andrew P Latham 4,  Laura Pontano Vaites 5,  Dorothy Tsai 1,  Nicole M Mattson 1,  Katherine Licon 1,  Robin Bachelder 1,  Anthony Cesnik 6,  Ishan Gaur 6,  Trang Le 6,  William Leineweber 6,  Aji Palar 4,  Ernst Pulido 6,  Yue Qin 1 7,  Xiaoyu Zhao 1,  Christopher Churas 1,  Joanna Lenkiewicz 1,  Jing Chen 1,  Keiichiro Ono 1,  Dexter Pratt 1,  Peter Zage 8,  Ignacia Echeverria 9 10,  Andrej Sali 4 10 11,  J Wade Harper 5,  Steven P Gygi 5,  Leonard J Foster 3,  Edward L Huttlin 12,  Emma Lundberg 13 14 15 16,  Trey Ideker 17 18 19
Affiliations

Affiliations

  • 1 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 2 Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, USA.
  • 3 Department of Biochemistry & Molecular Biology, Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
  • 5 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Bioengineering, Stanford University, Palo Alto, CA, USA.
  • 7 Broad Institute of MIT and Harvard, Boston, MA, USA.
  • 8 Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, USA.
  • 9 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • 10 Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
  • 11 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
  • 12 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. edward_huttlin@hms.harvard.edu.
  • 13 Department of Bioengineering, Stanford University, Palo Alto, CA, USA. emmalu@stanford.edu.
  • 14 Department of Pathology, Stanford University, Palo Alto, CA, USA. emmalu@stanford.edu.
  • 15 Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden. emmalu@stanford.edu.
  • 16 Chan Zuckerberg Biohub, San Francisco, CA, USA. emmalu@stanford.edu.
  • 17 Department of Medicine, University of California San Diego, La Jolla, CA, USA. tideker@ucsd.edu.
  • 18 Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA. tideker@ucsd.edu.
  • 19 Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. tideker@ucsd.edu.
  • # Contributed equally.
PMID: 40205054 DOI: 10.1038/s41586-025-08878-3
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.

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