Abstract
The involvement of microRNAs in the control of repressors of human γ-globin gene transcription has been firmly demonstrated, as described for the miR-486-3p mediated down-regulation of BCL11A. On the other hand, we have reported that miR-210 is involved in erythroid differentiation and, possibly, in γ-globin gene up-regulation. In the present study, we have identified the coding sequence of BCL11A as a possible target of miR-210. The following results sustain this hypothesis: (a) interactions between miR-210 and the miR-210 BCL11A site were demonstrated by SPR-based biomolecular interaction analysis (BIA); (b) the miR-210 site of BCL11A is conserved through molecular evolution; (c) forced expression of miR-210 leads to decrease of BCL11A-XL and increase of γ-globin mRNA content in erythroid cells, including erythroid precursors isolated from β-thalassemia patients. Our study suggests that the coding mRNA sequence of BCL11A can be targeted by miR-210. In addition to the theoretical point of view, these data are of interest from the applied point of view, supporting a novel strategy to inhibit BCL11A by mimicking miR-210 functions, accordingly with the concept supported by several papers and patent applications that inhibition of BCL11A is an efficient strategy for fetal hemoglobin induction in the treatment of β-thalassemia.
Highlights
MicroRNAs are a category of conserved, short (19 to 25 nucleotides in length) RNAs that regulate gene expression by targeting specific mRNA sequences [1,2,3], causing a post-transcriptional negative control or mRNA degradation, depending on the level of base-pairing between miRNAs and target RNA sequences [1,4,5]
Considering that a mRNA might contain in its 3 untranslated region (3 UTR), coding DNA sequence (CDS), 5 untranslated region (5 UTR) several sequences for miRNA recognition and that a single miRNA can bind and regulate several mRNAs, it is calculated that more than 60% of human mRNAs are targets of microRNAs [2,4]
MicroRNA expression profiling was performed by Choong et al on ex vivo differentiating erythroid cultures derived from human umbilical cord blood (UCB) CD34+ cells and K562 cells, with the aim of identifying miRNAs involved in erythropoiesis [7]
Summary
MicroRNAs (miRNAs, miRs) are a category of conserved, short (19 to 25 nucleotides in length) RNAs that regulate gene expression by targeting specific mRNA sequences [1,2,3], causing a post-transcriptional negative control or mRNA degradation, depending on the level of base-pairing between miRNAs and target RNA sequences [1,4,5]. Since their discovery and first characterization, the number of validated microRNA sequences enlisted in databases has significantly grown [3]. MiRNAs have been indicated to play roles in normal hematopoiesis [6,7,8,9,10,11,12,13,14,15,16,17,18]
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