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Single Cell Proteomics Reveal that Temporal Changes in Transcription Factors Determine Cell-Fate

62 Pages Posted: 5 Nov 2018 Sneak Peek Status: Under Review

See all articles by Carmen G. Palii

Carmen G. Palii

University of Ottawa - Sprott Center for Stem Cell Research

Qian Cheng

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Mark A. Gillespie

Institute for Systems Biology

Michalina Mazurczyk

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Giorgio Napolitani

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Jeffrey A. Ranish

Institute for Systems Biology

Edward Morrissey

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Douglas R. Higgs

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Marjorie Brand

University of Ottawa - Sprott Center for Stem Cell Research

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Abstract

Hematopoiesis provides an accessible system for studying the principles underlying cell-fate decisions in stem cells. Proposed models of hematopoiesis suggest that quantitative changes in lineage-specific transcription factors (LS-TFs) underlie cell-fate decisions. However, evidence for such models is lacking as TFs levels are typically measured via RNA expression rather than by analysing protein abundance. Here, we used single-cell mass-cytometry and absolute quantification by mass-spectrometry to capture the temporal dynamics of TF protein expression in individual cells during human erythropoiesis. We found that LS-TFs from alternate lineages are co-expressed, as proteins, in individual early progenitor cells and quantitative changes of LF-TFs occur gradually, rather than abruptly to direct cell-fate decisions. Importantly, upregulation of a megakaryocytic TF in early progenitors is sufficient to deviate cells from an erythroid to a megakaryocyte trajectory showing that quantitative changes in protein abundance of LS-TFs in progenitors can determine alternate cell-fates.

Keywords: Hematopoietic stem/progenitor cells, cell fate decisions, single-cell proteomics, mass cytometry, transcription factors, KLF1, FLI1, bipotential progenitors, hematopoiesis, erythropoiesis, CyTOF

Suggested Citation

Palii, Carmen G. and Cheng, Qian and Gillespie, Mark A. and Mazurczyk, Michalina and Napolitani, Giorgio and Ranish, Jeffrey A. and Morrissey, Edward and Higgs, Douglas R. and Brand, Marjorie, Single Cell Proteomics Reveal that Temporal Changes in Transcription Factors Determine Cell-Fate (November 2, 2018). Available at SSRN: https://ssrn.com/abstract=3277362 or http://dx.doi.org/10.2139/ssrn.3277362
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Carmen G. Palii

University of Ottawa - Sprott Center for Stem Cell Research

Ottawa, Ontario
Canada

Qian Cheng

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Mark A. Gillespie

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Michalina Mazurczyk

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Giorgio Napolitani

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Jeffrey A. Ranish

Institute for Systems Biology

401 Terry Ave N.
Seattle, WA 98109
United States

Edward Morrissey

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Douglas R. Higgs

Weatherall Institute of Molecular Medicine - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Marjorie Brand (Contact Author)

University of Ottawa - Sprott Center for Stem Cell Research ( email )

Ottawa, Ontario
Canada