The role of specialized cell cycles during erythroid lineage development: insights from single-cell RNA sequencing

Abstract

Early erythroid progenitors known as CFU-e undergo multiple self-renewal cell cycles. The CFU-e developmental stage ends with the onset of erythroid terminal differentiation (ETD). The transition from CFU-e to ETD is a critical cell fate decision that determines erythropoietic rate. Here we review recent insights into the regulation of this transition, garnered from flow cytometric and single-cell RNA sequencing studies. We find that the CFU-e/ETD transition is a rapid S phase-dependent transcriptional switch. It takes place during an S phase that is much shorter than in preceding or subsequent cycles, as a result of globally faster replication forks. Furthermore, it is preceded by cycles in which G1 becomes gradually shorter. These dramatic cell cycle and S phase remodeling events are directly linked to regulation of the CFU-e/ETD switch. Moreover, regulators of erythropoietic rate exert their effects by modulating cell cycle duration and S phase speed. Glucocorticoids increase erythropoietic rate by inducing the CDK inhibitor p57 KIP2 , which slows replication forks, inhibiting the CFU-e/ETD switch. Conversely, erythropoietin promotes induction of ETD by shortening the cycle. S phase shortening was reported during cell fate decisions in non-erythroid lineages, suggesting a fundamentally new developmental role for cell cycle speed.

RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation

“…The downregulation of genes involved in the cell cycle in SUPT5H-edited cells led us to ask whether the cell cycle is altered in SUPT5H-edited cells during the transition from progenitors to precursors. Consistent with previous studies describing cell cycle remodeling during murine erythropoiesis (Socolovsky 2022;Hwang et al 2017), we observed a rapid increase in the Sphase cell population, and a reciprocal decrease in the G0/G1 population, in control cells (Figure 5A-B). By contrast, in SUPT5H-edited cells, we observed a prolonged shift in cell cycle dynamics with a higher percentage of cells in G0/G1 (58±2% vs 45±3%) and a lower percentage in S (39±1% vs 52±2%) relative to control cells (Figure 5A-C, S5D).…”

Human erythroid progenitors express antigen presentation machinery

“…We filtered this dataset to remove non-erythroid contaminants, then re-clustered the data (Figure 1A) and identified clusters via surface markers and transcription factors differentially expressed throughout erythropoiesis (Supplemental Figure 1; Figure 1C). Committed erythroid progenitors (BFU-E, CFU-E, and proerythroblasts) are transcriptionally distinct from erythroid precursors 52 . Surprisingly, we found that erythroid progenitors express antigen presentation machinery that is typically restricted to professional antigen presenting immune cells.…”

Pas de deux: the coordinated coupling of erythroid differentiation with the cell cycle

“…Two broad progenitor categories exist: earlier progenitors that form ’bursts’ (the burst-forming-unit-erythroid, ’BFU-e’) and later progenitors that give rise to smaller colonies (colony-forming-unit-erythroid, ’CFU-e’). The progenitor phase is followed by erythroid terminal differentiation (ETD), a phase in which morphologically-identifiable erythroblasts (also known as erythroid precursors) undergo three to five maturational cell divisions, culminating in enucleation and the formation of immature red blood cells (reticulocytes) [2].…”