Browsing by keyword "cell fate decision"
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Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switchCell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase-dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. Our work suggests that cell cycles with specialized global DNA replication dynamics are integral to the maintenance of specific cell states and to cell fate decisions.
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The Role of S-phase Speed During an Erythroid Transcriptional SwitchThe cell division cycles of differentiating cells are coordinated so as to generate sufficient numbers of mature cells. The cell cycle may also regulate the process of differentiation, in ways that are not well understood. We previously discovered that during erythropoiesis, the cell cycle is synchronized with a specific developmental switch, where erythroid progenitors known as colony-forming-unit-erythroid (CFU-e) transition from a self-renewal state to a state of erythroid terminal differentiation (ETD). This switch takes place during a single cell cycle S phase and is dependent on S-phase progression. My work shows that this S phase is unusual, in that it is shorter than S phase in preceding cycles, as a result of a global increase in replication fork speed. I found that the CDK inhibitor, p57KIP2, negatively regulates replication fork speed in self-renewing CFU-e, and its down-regulation at the switch to ETD results in S-phase shortening. p57KIP2-mediated inhibition of CDK2 is essential for CFU-e self-renewal. It exerts this effect by reducing replication stress and also reducing the probability of transition from CFU-e to ETD, promoting CFU-e self-renewal instead. CDK2 inhibiting drugs that mimic the action of p57KIP2 stimulate erythropoiesis both in vitro and in vivo, through expansion of the CFU-e pool. In addition to p57KIP2, E2f4 also regulates S-phase shortening and the efficiency of the CFU-e to ETD transition. Overall, my work shows that S-phase speed regulates a key erythroid cell fate decision, and suggests a possible translational application of CDK2 inhibiting drugs in the stimulation of erythropoiesis.
