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The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity

Yiming Guo, Fei Ji, View ORCID ProfileJernej Murn, David Frankhouser, M Andres Blanco, Carmen Chiem, MiHyun Jang, Ruslan Sadreyev, View ORCID ProfileRussel C. Rockne, David B. Sykes, Konrad Hochedlinger, View ORCID ProfileSihem Cheloufi
doi: https://doi.org/10.1101/2020.10.22.350447
Yiming Guo
1Department of Biochemistry, Stem Cell Center, University of California, Riverside, 900 University Ave. Boyce Hall 4411, Riverside, CA 92521-0129
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Fei Ji
2Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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Jernej Murn
1Department of Biochemistry, Stem Cell Center, University of California, Riverside, 900 University Ave. Boyce Hall 4411, Riverside, CA 92521-0129
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David Frankhouser
3Department of Population Sciences and Department of Diabetes Complications & Metabolism, City of Hope, National Medical Center, Duarte, CA, United States
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M Andres Blanco
4Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Carmen Chiem
1Department of Biochemistry, Stem Cell Center, University of California, Riverside, 900 University Ave. Boyce Hall 4411, Riverside, CA 92521-0129
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MiHyun Jang
5Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, City of Hope National Medical Center, Duarte, CA, United States
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Ruslan Sadreyev
2Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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Russel C. Rockne
5Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, City of Hope National Medical Center, Duarte, CA, United States
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David B. Sykes
6Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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Konrad Hochedlinger
2Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
6Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
7Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
8Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA
9Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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Sihem Cheloufi
1Department of Biochemistry, Stem Cell Center, University of California, Riverside, 900 University Ave. Boyce Hall 4411, Riverside, CA 92521-0129
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  • For correspondence: cheloufi@ucr.edu
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Abstract

During hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBPα and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.

Competing Interest Statement

The authors have declared no competing interest.

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Posted October 22, 2020.
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The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity
Yiming Guo, Fei Ji, Jernej Murn, David Frankhouser, M Andres Blanco, Carmen Chiem, MiHyun Jang, Ruslan Sadreyev, Russel C. Rockne, David B. Sykes, Konrad Hochedlinger, Sihem Cheloufi
bioRxiv 2020.10.22.350447; doi: https://doi.org/10.1101/2020.10.22.350447
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The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity
Yiming Guo, Fei Ji, Jernej Murn, David Frankhouser, M Andres Blanco, Carmen Chiem, MiHyun Jang, Ruslan Sadreyev, Russel C. Rockne, David B. Sykes, Konrad Hochedlinger, Sihem Cheloufi
bioRxiv 2020.10.22.350447; doi: https://doi.org/10.1101/2020.10.22.350447

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