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Nucleic Acids Res. 2014 Jan;42(1):442-57. doi: 10.1093/nar/gkt848. Epub 2013 Sep 18.

A regulatory circuit comprising GATA1/2 switch and microRNA-27a/24 promotes erythropoiesis.

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  • 1Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100005, PR China, Zebrafish Core Facility, State Key Laboratory of Medical Molecular Sciences, Institute of Basic Medical Sciences, CAMS & PUMC, Beijing 100005, PR China, Department of Biomedical Engineering, School of Computation and Information Technology, Beijing Jiaotong University, Beijing 100044, PR China, Department of Cardiology, Children's Hospital Boston, Boston, MA 02115, USA, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China and Cancer Center, The General Hospital of the People's Liberation Army, Beijing 100853, PR China.

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.

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