title: HMGA2 Moderately Increases Fetal Hemoglobin Expression in Human Adult Erythroblasts.
abstract: Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with beta-hemoglobin disorders. Previous studies showed that let-7 microRNAs (miRNAs) are highly regulated in erythroid cells during the fetal-to-adult developmental transition, and that targeting let-7 mediated the up-regulation of HbF to greater than 30% of the total globin levels in human adult cultured erythroblasts. HMGA2 is a member of the high-mobility group A family of proteins and a validated target of the let-7 family of miRNAs. Here we investigate whether expression of HMGA2 directly regulates fetal hemoglobin in adult erythroblasts. Let-7 resistant HMGA2 expression was studied after lentiviral transduction of CD34(+) cells. The transgene was regulated by the erythroid-specific gene promoter region of the human SPTA1 gene (HMGA2-OE). HMGA2-OE caused significant increases in gamma-globin mRNA expression and HbF to around 16% of the total hemoglobin levels compared to matched control transductions. Interestingly, no significant changes in KLF1, SOX6, GATA1, ZBTB7A and BCL11A mRNA levels were observed. Overall, our data suggest that expression of HMGA2, a downstream target of let-7 miRNAs, causes moderately increased gamma-globin gene and protein expression in adult human erythroblasts.
authors.affiliation: Molecular Genomics and Therapeutics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jaira F
authors.initials: JF
authors.lastname: de Vasconcellos
authors.affiliation: Molecular Genomics and Therapeutics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Y Terry
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Molecular Genomics and Therapeutics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Colleen
authors.initials: C
authors.lastname: Byrnes
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laxminath
authors.initials: L
authors.lastname: Tumburu
authors.affiliation: Molecular Genomics and Therapeutics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Rabel
authors.affiliation: Molecular Genomics and Therapeutics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Miller
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D025743:HMGA2 Protein; D035683:MicroRNAs; D012333:RNA, Messenger; D014157:Transcription Factors; D055545:gamma-Globins; C487931:mirnlet7 microRNA, human; D005319:Fetal Hemoglobin