Department 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.
Nucleic Acids Res. 2014 Jan;42(1):442-57. doi: 10.1093/nar/gkt848. Epub 2013 Sep 18.
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.
转录网络协调复杂的发育过程，而这些网络通常由发育的主调控因子引发。到目前为止，在阐明控制红细胞发育的 GATA 因子依赖性遗传网络方面已经取得了相当大的进展。在这里，我们报道 GATA-1 和 GATA-2 共同调控两个 microRNA 基因，microRNA-27a 和 microRNA-24 的表达，它们在调节红细胞分化中起着关键作用。一般来说，GATA-2 占据 miR-27a≈24 启动子并抑制未成熟红细胞祖细胞中的转录。随着红细胞生成的进行，GATA-1 直接激活 miR-27a≈24 转录，这涉及 GATA-1 介导的 GATA-2 从染色质上的置换，这一过程称为“GATA 转换”。此外，成熟的 miR-27a 和 miR-24 协同抑制 GATA-2 翻译，并有利于从 GATA-2 到 GATA-1 的占据开关，从而完成促进红细胞成熟的正反馈循环。与 GATA 因子的重要作用一致，miR-27a 或 miR-24 的异位表达促进了人类原代 CD34+造血祖细胞和小鼠中的红细胞生成，而减弱的 miR-27 或 miR-24 水平导致造血祖细胞和斑马鱼中的红细胞表型受损。总之，这些数据将 micro RNA 表达和功能整合到 GATA 因子协调的网络中，并为包含 GATA1/2 转换和 miR-27a/24 的红细胞生成的调控回路提供了机制见解。
