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.

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

“…The LR-HSCs (≤ 4 divisions) in old mice contain only fHSCs which still preserve multipotency (with a myeloid bias) and self-renewal potential, whereas the H2B-GFP − non-LR-HSCs (> 4 divisions) represent functionally defective HSCs, intermediate HSCs and lineage-restricted progenitors. Thus, non-LR-HSCs have minimal self-renewal and restricted regenerative capacity [ 81 , 82 ]. Szade’s lab found that Neo1 is a better marker for separating My-bi HSCs from Bala-HSCs.…”

“…Thus, dormant HSCs divide approximately 5 times over the course of mouse’s lifetime. Recent studies suggested that the self-renewal and LT-ML HRC of HSCs are negatively correlated to their divisional history in normal physiological hematopoiesis [ 82 , 91 – 93 ]. Therefore, it is speculated that the major driver of HSC aging is proliferation.…”

“…These include increased methylation on the genomic loci associated with lymphoid and erythroid lineages and reduced methylation on the genomic loci associated with the myeloid lineage [ 159 ]. Although such epigenetic alterations influence changes in gene expression that are associated with self-renewal and myeloid differentiation of aged HSCs, they contribute to an aging-related functional decline and myeloid differentiation skewing of aged HSCs by regulating gene expression in their differentiated progeny [ 71 , 82 , 184 – 186 ]. Compared to young HSCs, there is a reduction in H4K16 Ac levels and a more widespread distribution of H3K4 me [ 3 ] and H3K27 me [ 3 ] in aged HSCs [ 101 ].…”

“…Most importantly, the aging-related epigenetic changes of HSCs are associated with a proliferative history, suggesting a proliferation-driven epigenetic memory loss [ 184 ]. Proliferation drives HSC aging by triggering the switch of HSCs from dormancy and multipotency to cellular activation and lineage priming through inducing an epigenetic switch (for example, a switch from Ezh1-to-Ezh2 PRC2), [ 82 ] downregulating DNA methylation regulators such as Dnmt1, Dnmt3b and 3 Tet enzymes, as well as key chromatin modulators such as Bmi, Suz12, Eed, Kat6b, Jarid1b, Suv39H1 and Sirt1 [ 82 , 92 , 148 , 159 , 187 ]. In addition, mutations in epigenetic modifiers are frequently detected in healthy elderly individuals and these also contribute to epigenetic landscape changes and the physiological process of aging in HSCs [ 187 ].…”

The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation

“…In summary, we have demonstrated that PHF19 depletion increases the dormancy-like HSC state by a mechanism that, at the same time, impairs differentiation and reduces durability upon serial transplants. Several studies have used label dilution models to quantify HSC divisional history, which has allowed a link between low mitotic rate and greatest repopulation ability (30,43). The transcriptional program associated with low divisional history resembles the Phf19-KO expression data ( fig.…”