A Key Commitment Step in Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition between PU.1 and S-Phase Progression

Ramona Pop,Merav Socolovsky,Miroslav Koulnis,Jeffrey R Shearstone,Joost Gribnau,Ying Liu,Qichang Shen,Kelly Hallstrom,Margaret A Goodell

doi:10.1371/journal.pbio.1000484

Ramona Pop, Merav Socolovsky + Show 7 more

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https://doi.org/10.1371/journal.pbio.1000484

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Abstract

Author SummaryHematopoietic progenitors that give rise to mature blood cell types execute simultaneous programs of differentiation and proliferation. One well-established link between the cell cycle and differentiation programs takes place at the end of terminal differentiation, when cell cycle exit is brought about by the induction of cyclin -dependent kinase inhibitors. It is unknown, however, whether the cell cycle and differentiation programs are coordinated prior to cell cycle exit. Here, we identify a novel and unique link between the cell cycle clock and the erythroid (red blood cell) differentiation program that takes place several cell division cycles prior to cell cycle exit. It differs from the established link in several respects. First, it takes place at the onset, rather than at the end, of erythroid terminal differentiation, preceding the chromatin changes that enable induction of red cell genes. Second, it is initiated by the suppression, rather than the induction, of a cyclin -dependent kinase inhibitor. It therefore causes the cell to enter S-phase, rather than exit the cell cycle. Specifically, we found that there is an absolute interdependence between S-phase progression at this time in differentiation, and a key commitment step in which, within a short few hours, cells become dependent on the hormone erythropoietin, undergo activating changes in chromatin of red cell genes, and activate GATA-1, the erythroid master transcriptional regulator. Arresting S-phase progression at this time prevents execution of this commitment step and subsequent induction of red cell genes; conversely, arresting differentiation prevents S-phase progression. However, once cells have undergone this key commitment step, there is no longer an interdependence between S-phase progression and the induction of erythroid genes. We identified two regulators that control a “synchromesh” mechanism ensuring the precise locking of the cell cycle clock to the erythroid differentiation program during this key commitment step.

Highlights

Hematopoietic progenitors execute a cell division program in parallel with a differentiation program in which lineage choice is followed by lineage-specific gene expression
The S0 to S1 Transition Is Marked by Downregulation of PU.1 and GATA-2 and Precedes Induction of Erythroid-Specific Genes To investigate the link between S-phase and the erythroid differentiation program, we examined expression of erythroid transcriptional regulators and erythroid-specific genes in freshly sorted fetal liver subsets and in fetal brain (Figure 3A)
We have identified a committal step in erythropoiesis in which the cell cycle clock is precisely synchronized with and coordinates an erythroid differentiation switch

Summary

Introduction

Hematopoietic progenitors execute a cell division program in parallel with a differentiation program in which lineage choice is followed by lineage-specific gene expression. Cell cycle exit, driven by cyclin-dependent kinase inhibitors (CDKI), is a prerequisite for terminal differentiation, establishing a key interaction between the cell cycle and differentiation programs [1,2,3]. It is unclear how the cell cycle and differentiation programs might be linked prior to cell cycle exit. Such links are presumably required to ensure the correct number of differentiated progeny. An intriguing possibility is that the clockwork-like mechanisms regulating orderly cell cycle transitions may be used, in the context of differentiating cells, to coordinate key steps in differentiation

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