Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors

Franziska Paul; Ya'ara Arkin; Amir Giladi; Diego Adhemar Jaitin; Ephraim Kenigsberg; Hadas Keren-Shaul; Deborah Winter; David Lara-Astiaso; Meital Gury; Assaf Weiner; Eyal David; Nadav Cohen; Felicia Kathrine Bratt Lauridsen; Simon Haas; Andreas Schlitzer; Alexander Mildner; Florent Ginhoux; Steffen Jung; Andreas Trumpp; Bo Torben Porse; Amos Tanay; Ido Amit

doi:10.1016/j.cell.2015.11.013

Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors

Franziska Paul, Ya'ara Arkin, Amir Giladi, Diego Adhemar Jaitin, Ephraim Kenigsberg, Hadas Keren-Shaul, Deborah Winter, David Lara-Astiaso, Meital Gury, Assaf Weiner, Eyal David, Nadav Cohen, Felicia Kathrine Bratt Lauridsen, Simon Haas, Andreas Schlitzer, Alexander Mildner, Florent Ginhoux, Steffen Jung, Andreas Trumpp, Bo Torben PorseAmos Tanay^*, Ido Amit

^*Corresponding author for this work

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

707 Citations (Scopus)

Abstract

Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor sub-populations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.

Original language	English
Pages (from-to)	1663-1677
Number of pages	15
Journal	Cell
Volume	163
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2015.11.013
Publication status	Published - 17 Dec 2015

Funding

We thank members of the Tanay and Amit labs for critical discussions and Genia Brodsky for artwork. Research in I.A. and A. Tanay laboratories is supported by the European Research Council, the I-CORE for chromatin and RNA regulation, and personal grants from the Israel Science foundation (782/11, 1050/12) and the BLUEPRINT FP7 consortium. I.A. is supported by the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, and the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193). A. Tanay is a Kimmel investigator. F.P. is a fellow of the German-Israeli Helmholtz Research School in Cancer Biology. Work in the B.P. laboratory was supported through a center grant from the NovoNordisk Foundation (The Novo Nordisk Foundation section for Stem Cell Biology in Human Disease).

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Paul, F., Arkin, Y., Giladi, A., Jaitin, D. A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., David, E., Cohen, N., Lauridsen, F. K. B., Haas, S., Schlitzer, A., Mildner, A., Ginhoux, F., Jung, S., Trumpp, A., ... Amit, I. (2015). Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors. Cell, 163(7), 1663-1677. https://doi.org/10.1016/j.cell.2015.11.013

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title = "Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors",

abstract = "Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor sub-populations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.",

author = "Franziska Paul and Ya'ara Arkin and Amir Giladi and Jaitin, {Diego Adhemar} and Ephraim Kenigsberg and Hadas Keren-Shaul and Deborah Winter and David Lara-Astiaso and Meital Gury and Assaf Weiner and Eyal David and Nadav Cohen and Lauridsen, {Felicia Kathrine Bratt} and Simon Haas and Andreas Schlitzer and Alexander Mildner and Florent Ginhoux and Steffen Jung and Andreas Trumpp and Porse, {Bo Torben} and Amos Tanay and Ido Amit",

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Paul, F, Arkin, Y, Giladi, A, Jaitin, DA, Kenigsberg, E, Keren-Shaul, H, Winter, D, Lara-Astiaso, D, Gury, M, Weiner, A , David, E, Cohen, N, Lauridsen, FKB, Haas, S, Schlitzer, A, Mildner, A, Ginhoux, F, Jung, S, Trumpp, A, Porse, BT, Tanay, A & Amit, I 2015, 'Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors', Cell, vol. 163, no. 7, pp. 1663-1677. https://doi.org/10.1016/j.cell.2015.11.013

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AU - Kenigsberg, Ephraim

AU - Keren-Shaul, Hadas

AU - Winter, Deborah

AU - Lara-Astiaso, David

AU - Gury, Meital

AU - Weiner, Assaf

AU - David, Eyal

AU - Cohen, Nadav

AU - Lauridsen, Felicia Kathrine Bratt

AU - Haas, Simon

AU - Schlitzer, Andreas

AU - Mildner, Alexander

AU - Ginhoux, Florent

AU - Jung, Steffen

AU - Trumpp, Andreas

AU - Porse, Bo Torben

AU - Tanay, Amos

AU - Amit, Ido

PY - 2015/12/17

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AB - Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor sub-populations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.

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Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors

Abstract

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