title: MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A.
abstract: MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34(+) hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3'UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34(+) cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lulli
authors.forename: Paolo
authors.initials: P
authors.lastname: Romania
authors.forename: Ornella
authors.initials: O
authors.lastname: Morsilli
authors.forename: Paolo
authors.initials: P
authors.lastname: Cianciulli
authors.forename: Marco
authors.initials: M
authors.lastname: Gabbianelli
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marziali
mesh_terms: D017398:Alternative Splicing; D018952:Antigens, CD34 / Q000378:metabolism; D020029:Base Pairing; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics*; D059368:RNA Isoforms; D012097:Repressor Proteins; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; C486563:BCL11A protein, human; D002352:Carrier Proteins; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D059368:RNA Isoforms; D012097:Repressor Proteins; D055545:gamma-Globins; D005319:Fetal Hemoglobin