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.


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


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