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Proceedings of the National Academy of Sciences of the United States of America DOI:10.1073/pnas.1018384108

MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13.

Publication TypeJournal Article
Year of Publication2011
AuthorsSankaran, VG, Menne, TF, Šćepanović, D, Vergilio, JA, Ji, P, Kim, J, Thiru, P, Orkin, SH, Lander, ES, Lodish, HF
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published2011/01/25

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.