Memory of Divisional History Directs the Continuous Process of Primitive Hematopoietic Lineage Commitment

Jeffrey M Bernitz; Katrina Rapp; Michael G Daniel; Dmitrii Shcherbinin; Ye Yuan; Andreia Gomes; Avinash Waghray; Ran Brosh; Alexander Lachmann; Avi Ma'ayan; Dmitri Papatsenko; Kateri A Moore

doi:10.1016/j.stemcr.2020.03.005

Memory of Divisional History Directs the Continuous Process of Primitive Hematopoietic Lineage Commitment

Stem Cell Reports. 2020 Apr 14;14(4):561-574. doi: 10.1016/j.stemcr.2020.03.005. Epub 2020 Apr 2.

Authors

Affiliations

¹ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; The Graduate School of Biomedical Sciences; Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
² Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
³ Skoltech Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow 121205, Russia; Institute of Biomedical Chemistry (IBMC), Moscow 119121, Russia.
⁴ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Doctoral Programme in Experimental Biology and Biomedicine, University of Coimbra, 3004-517 Coimbra, Portugal.
⁵ Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Skoltech Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow 121205, Russia.
⁷ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA. Electronic address: kateri.moore@mssm.edu.

Abstract

Hematopoietic stem cells (HSCs) exist in a dormant state and progressively lose regenerative potency as they undergo successive divisions. Why this functional decline occurs and how this information is encoded is unclear. To better understand how this information is stored, we performed RNA sequencing on HSC populations differing only in their divisional history. Comparative analysis revealed that genes upregulated with divisions are enriched for lineage genes and regulated by cell-cycle-associated transcription factors, suggesting that proliferation itself drives lineage priming. Downregulated genes are, however, associated with an HSC signature and targeted by the Polycomb Repressive Complex 2 (PRC2). The PRC2 catalytic subunits Ezh1 and Ezh2 promote and suppress the HSC state, respectively, and successive divisions cause a switch from Ezh1 to Ezh2 dominance. We propose that cell divisions drive lineage priming and Ezh2 accumulation, which represses HSC signature genes to consolidate information on divisional history into memory.

Keywords: cell heterogeneity; divisional history; epigenetics; hematopoietic stem cells; leukemia; memory; polycomb repressive complex.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Division* / genetics
Cell Lineage* / genetics
Cell Self Renewal
Chromatin / metabolism
Enhancer of Zeste Homolog 2 Protein / metabolism
Female
Gene Expression Regulation
Hematopoiesis* / genetics
Hematopoietic Stem Cells / cytology*
Homeostasis
Male
Mice, Inbred C57BL
Models, Biological
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism

Substances

Chromatin
Enhancer of Zeste Homolog 2 Protein
Ezh1 protein, mouse
Ezh2 protein, mouse
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding