Key Points Exosome complex components are endogenous suppressors of erythroid cell maturation. GATA-1 and Foxo3 transcriptionally repress exosome complex components, thus abrogating the erythroid maturation blockade.

The physiological switch in expression of the embryonic, fetal, and adult b-like globin genes has garnered enormous attention from investigators interested in transcriptional mechanisms and the molecular basis of hemoglobinopathies. These efforts have led to the discovery of cell type-specific transcription factors, unprecedented mechanisms of transcriptional coregulator function, genome biology principles, unique contributions of nuclear organization to transcription and cell function, and promising therapeutic targets. Given the vast literature accrued on this topic, this article will focus on the master regulator of erythroid cell development and function GATA-1, its associated proteins, and its frontline role in controlling hemoglobin synthesis. GATA-1 is a crucial regulator of genes encoding hemoglobin subunits and heme biosynthetic enzymes. GATA-1-dependent mechanisms constitute an essential regulatory core that nucleates additional mechanisms to achieve the physiological control of hemoglobin synthesis.

The critical regulator of hematopoiesis GATA-1 recruits diverse coregulators to chromatin, which mediate transcriptional activation and repression. These coregulators include the cell-type-specific multi-zinc finger protein Friend of GATA-1 (FOG-1), the histone acetyltransferase CREB binding protein (CBP), and the key component of the Mediator complex Med1. While FOG-1 is an established GATA-1 coregulator, the importance of interactions between GATA-1 and other coregulators is poorly understood. Furthermore, whether GATA-1 utilizes multiple coregulators at all loci, or if certain coregulators are dedicated to specific loci is unknown. We compared the capacity of GATA-1 to recruit and utilize FOG-1 and Med1 at activated and repressed target genes. Similar to FOG-1, GATA-1 recruited Med1 to activated genes, and the kinetics of FOG-1 and Med1 recruitment were similar. GATA-1 recruited Med1 in Fog1−/− cells, indicating that GATA-1-mediated Med1 recruitment is FOG-1-independent. In contrast to FOG-1, GATA-1 evicted Med1 during transcriptional repression. Whereas knocking-down FOG-1 had catastrophic effects on GATA-1-mediated activation and repression, knocking-down Med1 modestly impaired GATA-1 activity only at select loci. These results illustrate both similarities and differences between GATA-1-mediated recruitment of FOG-1 and Med1 to chromatin, with a fundamental difference being the quantitatively greater requirement for FOG-1.