Mir-144 selectively regulates embryonic ά-hemoglobin synthesis during primitive erythropoiesis

Abstract

Precise transcriptional control of developmental stage-specific expression and switching of α- 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 micro-RNAs and trans-acting mechanism controlling α-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 α-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 α-globin and miR-144 genes to activate their transcriptions, thus forming a negative feedback circuitry to fine-tune the expression of embryonic α-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. © 2009 by The American Society of Hematology.