Erythroid regulatory elements.

Abstract

Erythroid differentiation leads to the production of red blood cells that contain a high level of hemoglobin. This level is mainly regulated by globin gene transcription during development and differentiation. Although numerous cis-acting sequences are involved in transcriptional activity of globin genes, combinations of three motifs, CCACC, SP1 and GATA represent the core elements of their regulatory sequences. These combinations are also found in promoters and/or enhancers of non-globin genes specifically expressed in the late stages of erythroid differentiation. The CCACC and SP1 sequences bind proteins that do not display erythrocytic specificity, and the GATA sequences bind a family of transacting factors recently cloned. The GATA family members are distinctive for a highly homologous DNA binding domain that exists in two zinc fingers reminiscent of those of the glucocorticoid receptor. None of the GATA family members displays only erythroid specificity, but gene disruption followed by rescue indicates that GATA-1 is necessary for terminal erythroid differentiation throughout development. The GATA/SP1 and GATA/CCACC associations are present in positive, negative or inducible regulatory sequences suggesting that other elements control the fine tuning of erythroid gene expression. NF-E2, which is a major transcriptional activator, members of the ets family which are implicated in the early stages of erythropoiesis and finally c-erbA which directly regulates a set of erythroid-specific genes are proteins that bind these latter regulatory motifs.