title: MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13.
abstract: Many human aneuploidy syndromes have unique phenotypic consequences, but in most instances it is unclear whether these phenotypes are attributable to alterations in the dosage of specific genes. In human trisomy 13, there is delayed switching and persistence of fetal hemoglobin (HbF) and elevation of embryonic hemoglobin in newborns. Using partial trisomy cases, we mapped this trait to chromosomal band 13q14; by examining the genes in this region, two microRNAs, miR-15a and -16-1, appear as top candidates for the elevated HbF levels. Indeed, increased expression of these microRNAs in primary human erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression. Moreover, we show that a direct target of these microRNAs, MYB, plays an important role in silencing the fetal and embryonic hemoglobin genes. Thus we demonstrate how the developmental regulation of a clinically important human trait can be better understood through the genetic and functional study of aneuploidy syndromes and suggest that miR-15a, -16-1, and MYB may be important therapeutic targets to increase HbF levels in patients with sickle cell disease and β-thalassemia.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.forename: Tobias F
authors.initials: TF
authors.lastname: Menne
authors.forename: Danilo
authors.initials: D
authors.lastname: Šćepanović
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Vergilio
authors.forename: Peng
authors.initials: P
authors.lastname: Ji
authors.forename: Jinkuk
authors.initials: J
authors.lastname: Kim
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000465:Algorithms; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020014:K562 Cells; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D011990:Receptors, Transferrin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014314:Trisomy
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D020598:Proto-Oncogene Proteins c-myb; D011990:Receptors, Transferrin; D005319:Fetal Hemoglobin