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; Trey Ideker

doi:10.1038/s41586-025-08878-3

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 ZhaoChristopher 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, Trey Ideker

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Abstract

Human cells consist of a complex hierarchy of components, many of which remain unexplored^1,2. 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.

Original language	English (US)
Pages (from-to)	222-231
Number of pages	10
Journal	Nature
Volume	642
Issue number	8066
DOIs	https://doi.org/10.1038/s41586-025-08878-3
State	Published - Jun 5 2025

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Schaffer, L. V., Hu, M., Qian, G., Moon, K. M., Pal, A., Soni, N., Latham, A. P., Pontano Vaites, L., Tsai, D., Mattson, N. M., Licon, K., Bachelder, R., Cesnik, A., Gaur, I., Le, T., Leineweber, W., Palar, A., Pulido, E., Qin, Y., ... Ideker, T. (2025). Multimodal cell maps as a foundation for structural and functional genomics. Nature, 642(8066), 222-231. https://doi.org/10.1038/s41586-025-08878-3

Schaffer, LV, Hu, M, Qian, G, Moon, KM, Pal, A, Soni, N, Latham, AP, Pontano Vaites, L, Tsai, D, Mattson, NM, Licon, K, Bachelder, R, Cesnik, A, Gaur, I, Le, T, Leineweber, W, Palar, A, Pulido, E, Qin, Y, Zhao, X, Churas, C, Lenkiewicz, J, Chen, J, Ono, K, Pratt, D, Zage, P, Echeverria, I, Sali, A, Harper, JW, Gygi, SP, Foster, LJ, Huttlin, EL, Lundberg, E & Ideker, T 2025, 'Multimodal cell maps as a foundation for structural and functional genomics', Nature, vol. 642, no. 8066, pp. 222-231. https://doi.org/10.1038/s41586-025-08878-3

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title = "Multimodal cell maps as a foundation for structural and functional genomics",

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.",

author = "Schaffer, {Leah V.} and Mengzhou Hu and Gege Qian and Moon, {Kyung Mee} and Abantika Pal and Neelesh Soni and Latham, {Andrew P.} and {Pontano Vaites}, Laura and Dorothy Tsai and Mattson, {Nicole M.} and Katherine Licon and Robin Bachelder and Anthony Cesnik and Ishan Gaur and Trang Le and William Leineweber and Aji Palar and Ernst Pulido and Yue Qin and Xiaoyu Zhao and Christopher Churas and Joanna Lenkiewicz and Jing Chen and Keiichiro Ono and Dexter Pratt and Peter Zage and Ignacia Echeverria and Andrej Sali and Harper, {J. Wade} and Gygi, {Steven P.} and Foster, {Leonard J.} and Huttlin, {Edward L.} and Emma Lundberg and Trey Ideker",

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doi = "10.1038/s41586-025-08878-3",

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AU - Schaffer, Leah V.

AU - Hu, Mengzhou

AU - Qian, Gege

AU - Moon, Kyung Mee

AU - Pal, Abantika

AU - Soni, Neelesh

AU - Latham, Andrew P.

AU - Pontano Vaites, Laura

AU - Tsai, Dorothy

AU - Mattson, Nicole M.

AU - Licon, Katherine

AU - Bachelder, Robin

AU - Cesnik, Anthony

AU - Gaur, Ishan

AU - Le, Trang

AU - Leineweber, William

AU - Palar, Aji

AU - Pulido, Ernst

AU - Qin, Yue

AU - Zhao, Xiaoyu

AU - Churas, Christopher

AU - Lenkiewicz, Joanna

AU - Chen, Jing

AU - Ono, Keiichiro

AU - Pratt, Dexter

AU - Zage, Peter

AU - Echeverria, Ignacia

AU - Sali, Andrej

AU - Harper, J. Wade

AU - Gygi, Steven P.

AU - Foster, Leonard J.

AU - Huttlin, Edward L.

AU - Lundberg, Emma

AU - Ideker, Trey

PY - 2025/6/5

Y1 - 2025/6/5

N2 - 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.

AB - 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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JO - Nature

JF - Nature

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ER -

Multimodal cell maps as a foundation for structural and functional genomics

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