期刊
BLOOD
卷 113, 期 6, 页码 1340-1349出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-08-174854
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资金
- National Basic Research Program of China [2007CB947003]
- National Natural Science Foundation of China [30525019, 30771185]
- Hundred Scholars Award of the Chinese Academy of Sciences
- Shanghai PUJIANG [06PJ14104]
- Knowledge Innovation Program of the Chinese Academy of Sciences [KSCX2-YW-R03]
- Chinese National High Tech Program 863 [2006AA02A405]
- Key Discipline Program of Shanghai Municipal Education Commission [Y0201, 06BZ013]
Precise transcriptional control of developmental stage-specific expression and switching of alpha- and beta-globin genes is significantly important to understand the general principles controlling gene expression and the pathogenesis of thalassemia. Although transcription factors regulating beta-globin genes have been identified, little is known about the microRNAs and trans-acting mechanism controlling alpha-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 alpha-globin, but not embryonic beta-globin, gene expression, through physiologically targeting klfd, an erythroid-specific Kruppel-like transcription factor. Klfd selectively binds to the CACCC boxes in the promoters of both alpha-globin and miR-144 genes to activate their transcriptions, thus forming a negative feedback circuitry to fine-tune the expression of embryonic alpha-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. (Blood. 2009; 113: 1340-1349)
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