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 Schutten, 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 and Emma Lundberg ()
Additional contact information
Diana Mahdessian: KTH - Royal Institute of Technology
Anthony J. Cesnik: KTH - Royal Institute of Technology
Christian Gnann: KTH - Royal Institute of Technology
Frida Danielsson: KTH - Royal Institute of Technology
Lovisa Stenström: KTH - Royal Institute of Technology
Muhammad Arif: KTH - Royal Institute of Technology
Cheng Zhang: KTH - Royal Institute of Technology
Trang Le: KTH - Royal Institute of Technology
Fredric Johansson: KTH - Royal Institute of Technology
Rutger Schutten: KTH - Royal Institute of Technology
Anna Bäckström: KTH - Royal Institute of Technology
Ulrika Axelsson: KTH - Royal Institute of Technology
Peter Thul: KTH - Royal Institute of Technology
Nathan H. Cho: Chan Zuckerberg Biohub, San Francisco
Oana Carja: Stanford University
Mathias Uhlén: KTH - Royal Institute of Technology
Adil Mardinoglu: KTH - Royal Institute of Technology
Charlotte Stadler: KTH - Royal Institute of Technology
Cecilia Lindskog: Uppsala University
Burcu Ayoglu: KTH - Royal Institute of Technology
Manuel D. Leonetti: Chan Zuckerberg Biohub, San Francisco
Fredrik Pontén: Uppsala University
Devin P. Sullivan: KTH - Royal Institute of Technology
Emma Lundberg: KTH - Royal Institute of Technology

Nature, 2021, vol. 590, issue 7847, 649-654

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03232-9

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