MicroRNAs (miRs) are a group of non-coding RNAs of ~22 nucleotides in length, which post-transcriptionally regulate the expression of their target genes as well as chromatin-remodeling, proliferation, differentiation and apoptosis. These single stranded molecules form a miRNA-mediated silencing complex (miRISC) complex with other proteins which bind to the 3´ untranslated region (UTR) of their target mRNAs so as to prevent their translation in cytoplasm. They have a great impact on cell functions in this way, and are thought to regulate homeostatic and pathologic conditions of various diseases, particularly hematologic, infectious and endometrial disorders as well as different types of cancer.

Hemoglobinopathies are the most common type of blood disorders caused by genetic mutations in human β globin gene (HBB) that result in abnormal hemoglobin structure. Sickle cell disease (SCD) and β-thalassemia are considered as two prevalent forms of these disorders. Increasing fetal hemoglobin (HbF) is a significant therapeutic tool to overcome anemia and ineffective hematopoiesis. This type of Hb has high levels in the fetus and produced at low level in some adults. By balancing the ratio of pathological chains of α/β, the accumulation of α globin chains in erythroid precursors is reduced and thus inhibits ineffective erythropoiesis, therefore improving the oxygen supply to tissues and relieving clinical symptoms.

Different approaches including hydroxyurea, epigenetic modifications and miR-based regulation are used for induction of γ globin which may be used for therapeutic purposes in SCD and β-thalassemia patients. In this review, we discuss changes of miR expression in β-thalassemia and SCD as two common hemoglobinopathies and also illustrate their roles in expression of globin chains so as to introduce new therapies for patients by inducing HbF.

Thalassemia is a hereditary blood disorder, caused by more than 200 autosomal mutations in globin genes resulting in a failure to produce normal globin chains, which shows different phenotypes due to severity of anemia and clinical complications. α and β-thalassemia resulting from different mutations in the α and β globin genes respectively, lead to chronic anemia and ineffective erythropoiesis in these patients . In β-thalassemia, excess α chain accumulates in erythrocytes due to insufficient expression of β globin chains inducing hemolysis and ineffective hematopoiesis. Repeated blood transfusions and HbF synthesis are ways to achieve therapeutic goals in these patients. Given that miRs are involved in the expression of globin genes and also transcriptionally regulate erythroid-specific genes [e.g. Kruppel-like transcription factor D (KLFD)], it can be envisaged that changes in expression of these small RNAs is effective in reducing clinical complications in thalassemic patients.

Accumulation of a globin chains destroy the erythrocyte membrane in thalassemic cells. Most of miRs which inhibit α gene expression, improve hemolytic anemia. MiR-144 as a erythroid-specific miR, prevents cell lysis with direct targeting of erythroid-specific KLFD (21). KLFD, by interacting with CACCC sites in miR-144 and the α globin gene promoter, acts as a co-regulator of both genes. It has been shown that the level of miR-144 expression negatively controls α/β globin gene expression in children with β-thalassemia major. This regulation of gene expression provides the primary basis of β-thalassemia major treatment in which preventing accumulation of excessive α globin may reduce clinical complications in patients with thalassemia. MiR-150 is another candidate for suppressing the α globin gene expression. This miR has various roles in erythroid, lymphocyte and megakaryocyte cell types. Although it has reduced expression during erythroid differentiation, it shows much lower amounts in polycythemia vera. Control of erythroid progenitor cell fate as well as suppression of α globin gene expression is other functions of this miR along with targeting myeloblastosis oncogene.

Decreased expression of miR-503 which regulates cell cycle arrest and apoptosis was found in cells with β-thalassemia mutations. Cell division cycle 25A (CDC25A), a target gene for this miR, is involved in cell cycle and DNA damage responses. Thalassemic cells show 1000-fold CDC25A over-expression due to low levels of this miR which is an important factor for ineffective hematopoiesis occurring in such patients. Induction of miR-503, miR322/424 or other factors which are dependent on hypoxia such as miR-21 and cyclin-dependent kinase inhibitor p21, suppress CDC25A and prevent growth in erythroid progenitor thalassemic cells and cancer cells respectively.

Another erythroid-specific miR is miR-451 which induces erythroid differentiation from CD133+ cells and also during erythropoiesis, has extra expressio, however, in β-thalassemia/HbE cells; miR-451 is significantly over-expressed and is associated with ineffective hematopoiesis, chronic hemolytic anemia and generally thalassemia severity. Over expression of miR-451 is associated with decreasing levels of α chain, glycophorin-A and GATA1 transcripts and is also observed in thalassemic cells which have lower hemoglobin levels and more reticulocytes. MiR-451 over expression is more effective on raising expression of α and β globin genes than γ globin. Increased expression of this miR is also present in other hemoglobinopathies and polycythemia vera where erythropoiesis takes place at a higher level.

Overall, according to the significance of miRs in controlling expression of globin genes, reactivation of these genes, which may change the status of thalassemic cells and improve the pathophysiology and clinical symptoms of hemoglobinopathies, would make it possible to use these small non-coding RNA as new therapeutic targets.

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