Chromatin-state barriers enforce an irreversible mammalian cell fate decision

M Andrés Blanco¹, David B Sykes², Lei Gu³, Mengjun Wu⁴, Ricardo Petroni⁵, Rahul Karnik⁶, Mathias Wawer⁷, Joshua Rico⁵, Haitao Li⁵, William D Jacobus⁴, Ashwini Jambhekar⁴, Sihem Cheloufi⁸, Alexander Meissner⁹, Konrad Hochedlinger¹⁰, David T Scadden¹¹, Yang Shi¹²

Affiliations

¹ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address: ablanco@vet.upenn.edu.
² Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
³ Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Cardiopulmonary Institute (CPI), Bad Nauheim, Germany; Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁴ Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁵ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁷ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Biochemistry, Stem Cell Center, University of California, Riverside, Riverside, CA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
¹⁰ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Molecular Biology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: david_scadden@harvard.edu.
¹² Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford, UK. Electronic address: yang.shi@ludwig.ox.ac.uk.

PMID: 34758323
DOI: 10.1016/j.celrep.2021.109967

Free article

Chromatin-state barriers enforce an irreversible mammalian cell fate decision

M Andrés Blanco et al. Cell Rep. 2021.

Free article

. 2021 Nov 9;37(6):109967.

doi: 10.1016/j.celrep.2021.109967.

Authors

Affiliations

¹ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address: ablanco@vet.upenn.edu.
² Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
³ Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Cardiopulmonary Institute (CPI), Bad Nauheim, Germany; Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁴ Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁵ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁷ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Biochemistry, Stem Cell Center, University of California, Riverside, Riverside, CA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
¹⁰ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Molecular Biology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: david_scadden@harvard.edu.
¹² Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford, UK. Electronic address: yang.shi@ludwig.ox.ac.uk.

PMID: 34758323
DOI: 10.1016/j.celrep.2021.109967

Abstract

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 interrogate 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 identify potential avenues for manipulating cell identity.

Keywords: Hoxa9; acute myeloid leukemia; cell fate; chromatin; development; differentiation; epigenetics; hematopoiesis; lineage commitment.

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Conflict of interest statement

Declaration of interests D.B.S. is a co-founder and holds equity in Clear Creek Bio and SAFI Biosolutions and is a consultant for Keros Therapeutics. D.T.S. 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; a director and equity holder in Agios Pharmaceuticals and Editas Medicine; a consultant for FOG Pharma and VCanBio; a DSMB member for Alexion; and a sponsored research recipient from Novartis. Y.S. is a co-founder and equity holder of K36 Therapeutics, a consultant for Active Motif, and holds equity in Imago Biosciences.

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Chromatin-state barriers enforce an irreversible mammalian cell fate decision

Affiliations

Chromatin-state barriers enforce an irreversible mammalian cell fate decision

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials