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Chromatin state barriers enforce an irreversible mammalian cell fate decision

M. Andrés Blanco, David B. Sykes, Lei Gu, Mengjun Wu, Ricardo Petroni, Rahul Karnik, Mathias Wawer, Joshua Rico, Haitao Li, William D. Jacobus, Ashwini Jambhekar, Sihem Cheloufi, Alexander Meissner, Konrad Hochedlinger, David T. Scadden, Yang Shi
doi: https://doi.org/10.1101/2021.05.12.443709
M. Andrés Blanco
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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  • For correspondence: yang.shi@ludwig.ox.ac.uk david_scadden@harvard.edu ablanco@vet.upenn.edu
David B. Sykes
6Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 02138, USA
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Lei Gu
2Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
15Department of Cell Biology, Harvard Medical School, Boston, MA 02215 USA
17Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
18Cardiopulmonary Institute (CPI), 61231 Bad Nauheim, Germany
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Mengjun Wu
2Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
4The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
15Department of Cell Biology, Harvard Medical School, Boston, MA 02215 USA
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Ricardo Petroni
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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Rahul Karnik
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 02138, USA
9Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
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Mathias Wawer
10Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Joshua Rico
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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Haitao Li
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
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William D. Jacobus
2Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
12Kansas City University, Kansas City, MO 64106, USA
15Department of Cell Biology, Harvard Medical School, Boston, MA 02215 USA
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Ashwini Jambhekar
2Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
15Department of Cell Biology, Harvard Medical School, Boston, MA 02215 USA
11Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
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Sihem Cheloufi
5Department of Biochemistry, Stem Cell Center, University of California, Riverside, Riverside, CA 92521, USA
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Alexander Meissner
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 02138, USA
9Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
13Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Konrad Hochedlinger
6Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
7Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 02138, USA
14Department of Molecular Biology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114,USA
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David T. Scadden
6Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 02138, USA
9Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
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  • For correspondence: yang.shi@ludwig.ox.ac.uk david_scadden@harvard.edu ablanco@vet.upenn.edu
Yang Shi
2Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
3Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, UK
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  • For correspondence: yang.shi@ludwig.ox.ac.uk david_scadden@harvard.edu ablanco@vet.upenn.edu
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Summary

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogated determinants of this ‘point of no return’ in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identifies potential avenues for manipulating cell identity.

Highlights

  • There exists a point of irreversible commitment in granulocytic differentiation

  • Chromatin state dynamics establish the transition from self-renewal to differentiation commitment

  • Reduced chromatin accessibility underlies an irreversible loss of regulatory site access

  • Restoration of a transcription factor feedback loop alters the differentiation commitment point

Competing Interest Statement

DBS is a co-founder and holds equity in Clear Creek Bio and SAFI Biosolutions. He is a consultant for Keros Therapeutics. DTS is a co-founder and equity holder in Fate Therapeutics, Clear Creek Bio and LifeVault Bio; he is a director co-founder and equity holder in Magenta Therapeutics, he is a director and equity holder in Agios Pharmaceuticals and Editas Medicine, he is a consultant for FOG Pharma and VCanBio, a DSMB member for Alexion and a sponsored research recipient from Novartis. YS is a co-founder and holds equity in Constellation Pharmaceuticals, Inc, Athelas Therapeutics, Inc and K36 Therapeutics, Inc. YS also holds equity in Imago Biosciences Inc, and is a consultant for Active Motif, Inc.

Footnotes

  • ↵† Lead contact: M. Andrés Blanco

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Chromatin state barriers enforce an irreversible mammalian cell fate decision
M. Andrés Blanco, David B. Sykes, Lei Gu, Mengjun Wu, Ricardo Petroni, Rahul Karnik, Mathias Wawer, Joshua Rico, Haitao Li, William D. Jacobus, Ashwini Jambhekar, Sihem Cheloufi, Alexander Meissner, Konrad Hochedlinger, David T. Scadden, Yang Shi
bioRxiv 2021.05.12.443709; doi: https://doi.org/10.1101/2021.05.12.443709
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Chromatin state barriers enforce an irreversible mammalian cell fate decision
M. Andrés Blanco, David B. Sykes, Lei Gu, Mengjun Wu, Ricardo Petroni, Rahul Karnik, Mathias Wawer, Joshua Rico, Haitao Li, William D. Jacobus, Ashwini Jambhekar, Sihem Cheloufi, Alexander Meissner, Konrad Hochedlinger, David T. Scadden, Yang Shi
bioRxiv 2021.05.12.443709; doi: https://doi.org/10.1101/2021.05.12.443709

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