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Abstract
Transcriptional networks orchestrate complex developmental processes, and such networks are commonly instigated by master regulators for development. By now, considerable progress has been made in elucidating GATA factor-dependent genetic networks that control red blood cell development. Here we reported that GATA-1 and GATA-2 co-regulated the expression of two microRNA genes, microRNA-27a and microRNA-24, with critical roles in regulating erythroid differentiation. In general, GATA-2 occupied the miR-27a∼24 promoter and repressed their transcription in immature erythroid progenitor cells. As erythropoiesis proceeded, GATA-1 directly activated miR-27a∼24 transcription, and this involved a GATA-1-mediated displacement of GATA-2 from chromatin, a process termed ‘GATA switch’. Furthermore, the mature miR-27a and miR-24 cooperatively inhibited GATA-2 translation and favoured the occupancy switch from GATA-2 to GATA-1, thus completing a positive feedback loop to promote erythroid maturation. In line with the essential role of GATA factors, ectopic expression of miR-27a or miR-24 promoted erythropoiesis in human primary CD34+ haematopoietic progenitor cells and mice, whereas attenuated miR-27 or miR-24 level led to impaired erythroid phenotypes in haematopoietic progenitor cells and zebrafish. Taken together, these data integrated micro RNA expression and function into GATA factor coordinated networks and provided mechanistic insight into a regulatory circuit that comprised GATA1/2 switch and miR-27a/24 in erythropoiesis.
Highlights
Erythropoiesis is the process by which haematopoietic stem/progenitor cells give rise to lineage-committed erythroid precursors, which terminally differentiate into mature circulating red blood cells
Q-PCR using specific Taqman probes revealed that pri-miR-23a$27a$24-2 and mature miR-27a, miR-24 and miR-23a were increased in EPO-driven erythroid differentiation of primary cultured human CD34+ haematopoietic progenitor cells (HPCs) (Figure 1D)
GATA-1 and GATA-2 often act in opposition on shared sites and co-regulate target genes through a GATA switch during erythropoiesis [22]
Summary
Erythropoiesis is the process by which haematopoietic stem/progenitor cells give rise to lineage-committed erythroid precursors, which terminally differentiate into mature circulating red blood cells. The unique expression patterns of GATA-1 and GATA-2 reflect distinct biological functions; GATA-1 is essential for erythropoiesis, whereas GATA-2 regulates the development and function of haematopoietic progenitor cells (HPCs). GATA-2 is expressed earlier than GATA-1 during erythropoiesis and occupies multiple GATA sites [1,2,3]. As GATA-1 is activated, it competes with and displaces GATA-2 occupancy from chromatin sites [4]. This switch generally causes a change in transcriptional output that leads to terminal erythroid
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