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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1340-1349.
Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-08-174854.
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RED CELLS, IRON, AND ERYTHROPOIESIS
Mir-144 selectively regulates embryonic  -hemoglobin synthesis during primitive erythropoiesis
Yan-Fang Fu1,*,
Ting-Ting Du1,*,
Mei Dong1,
Kang-Yong Zhu1,
Chang-Bin Jing1,
Yong Zhang1,
Lei Wang1,
Hong-Bo Fan1,
Yi Chen1,
Yi Jin1,
Gui-Ping Yue2,
Sai-Juan Chen1,
Zhu Chen1,
Qiu-Hua Huang1,
Qing Jing2,
Min Deng1,3, and
Ting Xi Liu1,3,4
1 Laboratory of Development and Diseases and State Key Laboratory for Medical Genomics and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, and Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai;
2 Laboratory of Nucleic Acid and Molecular Biomedicine, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai;
3 Shanghai Stem Cell Institute, Shanghai Jiao Tong University School of Medicine, Shanghai; and
4 Model Organism Division, E-Institutes of Shanghai Universities, Shanghai, China
Precise transcriptional control of developmental stage-specific expression and switching of  - and β-globin genes is significantly important to understand the general principles controlling gene expression and the pathogenesis of thalassemia. Although transcription factors regulating β-globin genes have been identified, little is known about the microRNAs and trans-acting mechanism controlling -globin genes transcription. Here, we show that an erythroid lineage-specific microRNA gene, miR-144, expressed at specific developmental stages during zebrafish embryogenesis, negatively regulates the embryonic -globin, but not embryonic β-globin, gene expression, through physiologically targeting klfd, an erythroid-specific Krüppel-like transcription factor. Klfd selectively binds to the CACCC boxes in the promoters of both -globin and miR-144 genes to activate their transcriptions, thus forming a negative feedback circuitry to fine-tune the expression of embryonic -globin gene. The selective effect of the miR-144-Klfd pathway on globin gene regulation may thereby constitute a novel therapeutic target for improving the clinical outcome of patients with thalassemia.
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