MicroRNAs (miRNAs, miRs) are a family of small non-coding RNAs that regulate gene expression by targeting mRNAs in a sequence specific manner, inducing translational repression or mRNA degradation. MicroRNAs have been found deeply involved in the control of erythroid differentiation. In human trisomy 13, there is delayed switching and persistence of HbF and elevation of embryonic hemoglobin in newborns (Sankaran et al., 2001). By examining the genes in this region, two microRNAs, miR-15a and miR-16-1, appear as top candidates for the elevated HbF levels. Increased expression of these microRNAs in primary human erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression. The target of these microRNAs was identified in MYB mRNA; interestingly, MYB plays an important role in silencing the fetal and embryonic hemoglobin genes. The microRNA miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3'UTR (Lulli et al., 2013). Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of beta-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced beta-globin expression. The data obtained indicate that BCL11A, one of the major repressor of beta-globin gene expression, is a molecular target of miR-486-3p; accordingly, pharmacological mediated up-regulation of miR-486-3p might lead to BCL11A down-regulation and, consequently activation of the beta-globin gene expression. Other microRNAs found up-regulated in association with beta-globin gene expression were miR-210 (Bianchi et al., 2009), miR-26b (Alijani et al., 2014), miR-451 (Kouhkan et al., 2014). As a first conclusion, the findings that microRNAs are involved in beta-globin anticipate the possibility that their pharmacological alteration might be a key strategy for increase HbF in erythroid cells.
Targeting the MicroRNAs-Transcription Factors Network for Innovative Therapeutic Protocols for ???-Thalassemia and Sickle-cell Anemia
GAMBARI, Roberto
2014
Abstract
MicroRNAs (miRNAs, miRs) are a family of small non-coding RNAs that regulate gene expression by targeting mRNAs in a sequence specific manner, inducing translational repression or mRNA degradation. MicroRNAs have been found deeply involved in the control of erythroid differentiation. In human trisomy 13, there is delayed switching and persistence of HbF and elevation of embryonic hemoglobin in newborns (Sankaran et al., 2001). By examining the genes in this region, two microRNAs, miR-15a and miR-16-1, appear as top candidates for the elevated HbF levels. Increased expression of these microRNAs in primary human erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression. The target of these microRNAs was identified in MYB mRNA; interestingly, MYB plays an important role in silencing the fetal and embryonic hemoglobin genes. The microRNA miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3'UTR (Lulli et al., 2013). Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of beta-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced beta-globin expression. The data obtained indicate that BCL11A, one of the major repressor of beta-globin gene expression, is a molecular target of miR-486-3p; accordingly, pharmacological mediated up-regulation of miR-486-3p might lead to BCL11A down-regulation and, consequently activation of the beta-globin gene expression. Other microRNAs found up-regulated in association with beta-globin gene expression were miR-210 (Bianchi et al., 2009), miR-26b (Alijani et al., 2014), miR-451 (Kouhkan et al., 2014). As a first conclusion, the findings that microRNAs are involved in beta-globin anticipate the possibility that their pharmacological alteration might be a key strategy for increase HbF in erythroid cells.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
