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Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

View ORCID ProfileMichael S. Haney, View ORCID ProfileArchana Shankar, Ian Hsu, Masashi Miyauchi, View ORCID ProfileRóbert Pálovics, Hwei Minn Khoo, Kyomi J. Igarashi, Joydeep Bhadury, Christy Munson, Paul K. Mack, Tze-Kai Tan, View ORCID ProfileTony Wyss-Coray, Hiromitsu Nakauchi, View ORCID ProfileAdam C. Wilkinson
doi: https://doi.org/10.1101/2022.07.22.501030
Michael S. Haney
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford, CA, USA
2Wu Tsai Neurosciences Institute, Stanford University; Stanford, CA, USA
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Archana Shankar
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford, CA, USA
2Wu Tsai Neurosciences Institute, Stanford University; Stanford, CA, USA
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Ian Hsu
3MRC Weatherall Institute of Molecular Medicine, University of Oxford; Oxford, UK
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Masashi Miyauchi
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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Róbert Pálovics
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford, CA, USA
2Wu Tsai Neurosciences Institute, Stanford University; Stanford, CA, USA
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Hwei Minn Khoo
3MRC Weatherall Institute of Molecular Medicine, University of Oxford; Oxford, UK
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Kyomi J. Igarashi
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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Joydeep Bhadury
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
6Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg; Gothenburg, Sweden
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Christy Munson
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford, CA, USA
2Wu Tsai Neurosciences Institute, Stanford University; Stanford, CA, USA
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Paul K. Mack
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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Tze-Kai Tan
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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Tony Wyss-Coray
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford, CA, USA
2Wu Tsai Neurosciences Institute, Stanford University; Stanford, CA, USA
7ChEM-H, Stanford University; Stanford, CA, USA
8Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine; Stanford, CA, USA
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  • For correspondence: adam.wilkinson@imm.ox.ac.uk nakauchi@stanford.edu twc@stanford.edu
Hiromitsu Nakauchi
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
9Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo; Tokyo, Japan
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  • For correspondence: adam.wilkinson@imm.ox.ac.uk nakauchi@stanford.edu twc@stanford.edu
Adam C. Wilkinson
3MRC Weatherall Institute of Molecular Medicine, University of Oxford; Oxford, UK
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA
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  • ORCID record for Adam C. Wilkinson
  • For correspondence: adam.wilkinson@imm.ox.ac.uk nakauchi@stanford.edu twc@stanford.edu
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ABSTRACT

The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To address this knowledge gap, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform to enable the genetic interrogation of hematopoiesis and broad aspects of immune cell function in vivo. Targeting ∼7000 genes with this methodology, we discovered SAGA complex members Tada2b and Taf5l as key regulators of HSC lineage commitment. Loss of Tada2b or Taf5l inhibited hematopoiesis in vivo and was associated with upregulation of interferon response gene expression. SAGA complex member expression is significantly reduced in aged HSCs and upregulated with heterochronic parabiosis, suggesting a novel mechanism of age-associated hematopoietic decline and rejuvenation. Our study provides a rich functional genetics resource of hematopoiesis regulators accessible through a public interactive database (www.hematopoiesiscrisprscreens.com), a novel mechanism regulating age-related decline of hematopoiesis, and a new methodology with broad applications to systematically probe the development and functions of the lymphohematopoietic system.

Competing Interest Statement

H.N. is a co-founder and shareholder in ReproCELL, Megakaryon, and Century Therapeutics.

Footnotes

  • ↵‡ Co-senior authors

  • https://www.hematopoiesiscrisprscreens.com

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 22, 2022.
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Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging
Michael S. Haney, Archana Shankar, Ian Hsu, Masashi Miyauchi, Róbert Pálovics, Hwei Minn Khoo, Kyomi J. Igarashi, Joydeep Bhadury, Christy Munson, Paul K. Mack, Tze-Kai Tan, Tony Wyss-Coray, Hiromitsu Nakauchi, Adam C. Wilkinson
bioRxiv 2022.07.22.501030; doi: https://doi.org/10.1101/2022.07.22.501030
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Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging
Michael S. Haney, Archana Shankar, Ian Hsu, Masashi Miyauchi, Róbert Pálovics, Hwei Minn Khoo, Kyomi J. Igarashi, Joydeep Bhadury, Christy Munson, Paul K. Mack, Tze-Kai Tan, Tony Wyss-Coray, Hiromitsu Nakauchi, Adam C. Wilkinson
bioRxiv 2022.07.22.501030; doi: https://doi.org/10.1101/2022.07.22.501030

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