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S phase and Cell fate

The switch from self-renewal to differentiation in erythroid progenitors: a cell fate decision orchestrated by the cell cycle

Cogwheels self-renewalErythroid progenitors known as 'CFUe' (colony-forming unit erythroid) go through several rounds of self renewal before undergoing a cell fate decision that activates the erythroid transcriptional program. This decision commits CFUe progenitors to an Epo-dependent process of differentiation, which consists of a small number (3 to 5) of 'differentiation divisions', following which they exit the cycle, enucleate and become new red cells. Using the mouse fetal liver model, which is rich in erythroid progenitors, we found that the critical switch from self-renewal to differentiation takes place at the transition of CFUe from the S0 subset (CD71low/medium Ter119neg) to S1 (CD71highTer119neg) (see flow cytometry; [1]). Remarkably, cells undergoing this transition are synchronized in early S phase of a specific cell cycle, corresponding to the last generation of CFUe progenitors (see figure). Further, S phase progression at this time is essential for a number of simultaneous and rapid events that commit cells to the differentiated state, including a conformational switch in chromatin at erythroid gene loci, the onset of dependence on the hormone erythropoietin (Epo), and activation of the erythroid master transcriptional regulator, GATA1. Conversely, the smooth progression of these differentiation events is essential for S phase progression. Our laboratory is investigating the wiring circuits responsible for the inter-dependent cell cycle and differentiation events at the S0/S1 transition. The regulators we identified to date include the cyclin-dependent kinase inhibitor, p57KIP2, and the erythroid transcriptional repressor, PU.1.

s-phase

In addition to being S phase dependent, the S0 to S1 transition involves a fundamental change in cell cycle regulation and the genome replication program. We found that S phase progression at this time is 50% faster, and S phase duration is shorter, than in previous cycles. This accelerated, shorter S phase is essential for triggering the process of global DNA demethylation (see DNA methylation [2]) and in turn, essential for rapid erythroid gene transcription. We are investigating the molecular basis for the S phase acceleration and how it may relate to cell fate commitment. We are using a number of approaches including DNA combing, a single DNA fiber technique that allows direct examination of DNA replication origins and fork progression rates.


References:

1. Pop, R., Shearstone, J.R., Shen, Q., Liu, Y., Hallstrom, K., Koulnis, M., Gribnau, J., and Socolovsky, M. (2010). A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. PLoS Biol 8.

2. Shearstone, J.R., Pop, R., Bock, C., Boyle, P., Meissner, A., and Socolovsky, M. (2011). Global DNA demethylation during mouse erythropoiesis in vivo. Science 334, 799-802.