Systems Biology and Epigenetic Mechanisms in Erythropoiesis

Irreversible rapid cellular decisions are often controlled by network motifs known as bistable switches. We identified a cell-cycle regulated bistable switch that controls activation of the erythroid transcriptional program during early S phase of the last generation of erythroid colony-forming-unit progenitors (CFUe). This switch drives a rapid, multi-layered commitment event that activates GATA-1 transcription, renders the cells dependent on erythropoietin, and brings about chromatin reconfiguration at erythroid gene loci. In addition, it triggers an unusual process of genome-wide DNA demethylation, the first known example of such a process in somatic cell development. Approximately 25 to 30 percent of all methylation marks are lost from essentially all genomic elements during erythroid terminal differentiation. The bistable switch activating erythroid transcription consists of two linked double-negative feedback interactions of the erythroid transcriptional repressor PU.1, which antagonizes both S phase progression, and the erythroid master transcriptional regulator GATA-1. During operation of the switch, a rapid S phase-dependent decline in PU.1 activates GATA-1 transcription. The dependence of this switch on S phase progression coincides with a dramatic change in the nature of S phase itself, which becomes shorter and 50 percent faster. The accelerated intra-S phase DNA synthesis rate is essential for the loss of genome-wide DNA methylation, which in turn is required for the rapid induction of erythroid genes.