Memory of Divisional History Directs the Continuous Process of Primitive Hematopoietic Lineage Commitment
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000463404Publication status
publishedExternal links
Journal / series
Stem Cell ReportsVolume
Pages / Article No.
Publisher
ElsevierSubject
hematopoietic stem cells; divisional history; cell heterogeneity; polycomb repressive complex; epigenetics memory; leukemiaOrganisational unit
03992 - Schroeder, Timm / Schroeder, Timm
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