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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)561-574
Number of pages14
JournalStem Cell Reports
Issue number4
StatePublished - 14 Apr 2020


  • cell heterogeneity
  • divisional history
  • epigenetics
  • hematopoietic stem cells
  • leukemia
  • memory
  • polycomb repressive complex


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