Establishment of a Cell-Type-Specific Genetic Network by the Mediator Complex Component Med1

Abstract

ABSTRACT The intense physiologic demand to generate vast numbers of red blood cells requires the establishment of a complex genetic network by the master regulatory transcription factor GATA-1 and its coregulators. This network dictates the genesis of enucleated erythrocytes by orchestrating the survival, proliferation, and differentiation of progenitor cells. In addition to the crucial GATA-1 coregulator Friend of GATA-1 (FOG-1), a component of the Mediator complex, Med1, facilitates GATA-1-dependent transcription at select target genes and controls erythropoiesis. It is not known to what extent Med1 contributes to GATA-1 function or whether Med1 controls a large or restricted cohort of genes that are not regulated by GATA-1. Using a genetic complementation assay in GATA-1-null erythroid cells, we demonstrate that Med1 and another Mediator component, Med25, regulate a restricted cohort of genes that are predominantly not controlled by GATA-1. Most of these genes were not regulated by Med1 in fibroblasts. Loss-of-function analyses with GATA-1-independent Med1 target genes indicate that Rrad , which encodes a small GTPase induced during human erythropoiesis, conferred erythroid cell survival. Thus, while Med1 is a context-dependent GATA-1 coregulator, it also exerts specialized functions in erythroid cells to control GATA-1-independent, cell-type-specific genes, which include candidate regulators of erythroid cell development and function.