Abstract
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 Krüppel-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Apoptosis
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Blotting, Northern
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Blotting, Western
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Computational Biology
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Embryo, Nonmammalian / cytology
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Embryo, Nonmammalian / metabolism*
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Erythroid Precursor Cells / cytology
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Erythroid Precursor Cells / metabolism
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Erythropoiesis / physiology*
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Gene Expression Regulation, Developmental*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Immunoenzyme Techniques
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In Situ Hybridization
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Kruppel-Like Transcription Factors / antagonists & inhibitors
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Kruppel-Like Transcription Factors / physiology
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Oligonucleotides / pharmacology
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Promoter Regions, Genetic / genetics
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription, Genetic
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Zebrafish
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Zebrafish Proteins / antagonists & inhibitors
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
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Zebrafish Proteins / physiology
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alpha-Globins / genetics*
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alpha-Globins / metabolism
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beta-Globins / genetics
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beta-Globins / metabolism
Substances
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Kruppel-Like Transcription Factors
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MicroRNAs
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Oligonucleotides
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RNA, Messenger
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Zebrafish Proteins
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alpha-Globins
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beta-Globins
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enhanced green fluorescent protein
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klf1 protein, zebrafish
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locked nucleic acid
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Green Fluorescent Proteins