MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13
Name
Sankaran-2011-Jan-MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13.pdf
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1.16 MB
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Author(s)
Sankaran, Vijay G.
Menne, Tobias F.
Scepanovic, Danilo
Vergilio, Jo-Anne
Ji, Peng
Kim, Jinkuk
Thiru, Prathapan
Orkin, Stuart H.
Lander, Eric Steven
Lodish, Harvey F
Date Issued
January 2011
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Sankaran, V. G. et al. “MicroRNA-15a and -16-1 Act via MYB to Elevate Fetal Hemoglobin Expression in Human Trisomy 13.” Proceedings of the National Academy of Sciences 108.4 (2011) : 1519-1524. ©2011 by the National Academy of Sciences.
Version
Final published version
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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1073/pnas.1018384108
