Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

Diana Mahdessian; Anthony J. Cesnik; Christian Gnann; Frida Danielsson; Lovisa Stenström; Muhammad Arif; Cheng Zhang; Trang Le; Fredric Johansson; Rutger Shutten; Anna Bäckström; Ulrika Axelsson; Peter Thul; Nathan H. Cho; Oana Carja; Mathias Uhlén; Adil Mardinoglu; Charlotte Stadler; Cecilia Lindskog; Burcu Ayoglu; Manuel D. Leonetti; Fredrik Pontén; Devin P. Sullivan; Emma Lundberg

doi:10.1038/s41586-021-03232-9

Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

Diana Mahdessian, Anthony J. Cesnik, Christian Gnann, Frida Danielsson, Lovisa Stenström, Muhammad Arif, Cheng Zhang, Trang Le, Fredric Johansson, Rutger Shutten, Anna Bäckström, Ulrika Axelsson, Peter Thul, Nathan H. Cho, Oana Carja, Mathias Uhlén, Adil Mardinoglu, Charlotte Stadler, Cecilia Lindskog, Burcu AyogluManuel D. Leonetti, Fredrik Pontén, Devin P. Sullivan, Emma Lundberg^*

^*Corresponding author for this work

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

98 Citations (Scopus)

Abstract

The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer^1–3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

Original language	English
Pages (from-to)	649-654
Number of pages	6
Journal	Nature
Volume	590
Issue number	7847
DOIs	https://doi.org/10.1038/s41586-021-03232-9
Publication status	Published - 25 Feb 2021

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Mahdessian, D., Cesnik, A. J., Gnann, C., Danielsson, F., Stenström, L., Arif, M., Zhang, C., Le, T., Johansson, F., Shutten, R., Bäckström, A., Axelsson, U., Thul, P., Cho, N. H., Carja, O., Uhlén, M., Mardinoglu, A., Stadler, C., Lindskog, C., ... Lundberg, E. (2021). Spatiotemporal dissection of the cell cycle with single-cell proteogenomics. Nature, 590(7847), 649-654. https://doi.org/10.1038/s41586-021-03232-9

@article{94d83a04d3134a5795c75fe2a33ae597,

title = "Spatiotemporal dissection of the cell cycle with single-cell proteogenomics",

abstract = "The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer1–3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.",

author = "Diana Mahdessian and Cesnik, {Anthony J.} and Christian Gnann and Frida Danielsson and Lovisa Stenstr{\"o}m and Muhammad Arif and Cheng Zhang and Trang Le and Fredric Johansson and Rutger Shutten and Anna B{\"a}ckstr{\"o}m and Ulrika Axelsson and Peter Thul and Cho, {Nathan H.} and Oana Carja and Mathias Uhl{\'e}n and Adil Mardinoglu and Charlotte Stadler and Cecilia Lindskog and Burcu Ayoglu and Leonetti, {Manuel D.} and Fredrik Pont{\'e}n and Sullivan, {Devin P.} and Emma Lundberg",

note = "Funding Information: Acknowledgements We acknowledge the entire staff of the HPA program. We acknowledge S. Ito and H. Masai for providing the stable U2OS FUCCI cell line; the Eukaryotic Single Cell Genomics (ESCG) facility at SciLifeLab for single-cell sequencing; M. Otrocka for access to imaging infrastructure; S. Besson and F. Wong for help with annotating the imaging data using IDR metadata templates (https://idr.openmicroscopy.org); P. Ranefall and C. W{\"a}hlby for providing support for establishing the Cell Profiler pipeline; A. Kundaje for providing support at Stanford University; and L. M. Smith for providing access to computational resources. Funding was provided by the Knut and Alice Wallenberg Foundation (2016.0204) and the Swedish Research Council (2017-05327) to E.L. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = feb,

day = "25",

doi = "10.1038/s41586-021-03232-9",

language = "English",

volume = "590",

pages = "649--654",

journal = "Nature",

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Mahdessian, D, Cesnik, AJ, Gnann, C, Danielsson, F, Stenström, L, Arif, M, Zhang, C, Le, T, Johansson, F, Shutten, R, Bäckström, A, Axelsson, U, Thul, P, Cho, NH, Carja, O, Uhlén, M, Mardinoglu, A, Stadler, C, Lindskog, C, Ayoglu, B, Leonetti, MD, Pontén, F, Sullivan, DP & Lundberg, E 2021, 'Spatiotemporal dissection of the cell cycle with single-cell proteogenomics', Nature, vol. 590, no. 7847, pp. 649-654. https://doi.org/10.1038/s41586-021-03232-9

TY - JOUR

T1 - Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

AU - Mahdessian, Diana

AU - Cesnik, Anthony J.

AU - Gnann, Christian

AU - Danielsson, Frida

AU - Stenström, Lovisa

AU - Arif, Muhammad

AU - Zhang, Cheng

AU - Le, Trang

AU - Johansson, Fredric

AU - Shutten, Rutger

AU - Bäckström, Anna

AU - Axelsson, Ulrika

AU - Thul, Peter

AU - Cho, Nathan H.

AU - Carja, Oana

AU - Uhlén, Mathias

AU - Mardinoglu, Adil

AU - Stadler, Charlotte

AU - Lindskog, Cecilia

AU - Ayoglu, Burcu

AU - Leonetti, Manuel D.

AU - Pontén, Fredrik

AU - Sullivan, Devin P.

AU - Lundberg, Emma

N1 - Funding Information: Acknowledgements We acknowledge the entire staff of the HPA program. We acknowledge S. Ito and H. Masai for providing the stable U2OS FUCCI cell line; the Eukaryotic Single Cell Genomics (ESCG) facility at SciLifeLab for single-cell sequencing; M. Otrocka for access to imaging infrastructure; S. Besson and F. Wong for help with annotating the imaging data using IDR metadata templates (https://idr.openmicroscopy.org); P. Ranefall and C. Wählby for providing support for establishing the Cell Profiler pipeline; A. Kundaje for providing support at Stanford University; and L. M. Smith for providing access to computational resources. Funding was provided by the Knut and Alice Wallenberg Foundation (2016.0204) and the Swedish Research Council (2017-05327) to E.L. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2/25

Y1 - 2021/2/25

N2 - The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer1–3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

AB - The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer1–3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

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U2 - 10.1038/s41586-021-03232-9

DO - 10.1038/s41586-021-03232-9

M3 - Article

C2 - 33627808

AN - SCOPUS:85101540882

SN - 0028-0836

VL - 590

SP - 649

EP - 654

JO - Nature

JF - Nature

IS - 7847

ER -

Spatiotemporal dissection of the cell cycle with single-cell proteogenomics

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