Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2

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Abstract
How does an emerging transcriptional programme regulate individual genes as stem cells undergo lineage commitment, differentiation and maturation? To answer this, we have analysed the dynamic protein/DNA interactions across 130 kb of chromatin containing the mouse α‐globin cluster in cells representing all stages of differentiation from stem cells to mature erythroblasts. The α‐gene cluster appears to be inert in pluripotent cells, but priming of expression begins in multipotent haemopoietic progenitors via GATA‐2. In committed erythroid progenitors, GATA‐2 is replaced by GATA‐1 and binding is extended to additional sites including the α‐globin promoters. Both GATA‐1 and GATA‐2 nucleate the binding of various protein complexes including SCL/LMO2/E2A/Ldb‐1 and NF‐E2. Changes in protein/DNA binding are accompanied by sequential alterations in long‐range histone acetylation and methylation. The recruitment of polymerase II, which ultimately leads to a rapid increase in α‐globin transcription, occurs late in maturation. These studies provide detailed evidence for the more general hypothesis that commitment and differentiation are primarily driven by the sequential appearance of key transcriptional factors, which bind chromatin at specific, high‐affinity sites.