Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response.
MicroRNAs are important regulators in many cellular processes, including stem cell self-renewal. Recent studies demonstrated their function as pluripotency factors with the capacity for somatic cell reprogramming. However, their role in human embryonic stem (ES) cells (hESCs) remains poorly understood, partially due to the lack of genome-wide strategies to identify their targets. Here, we performed comprehensive microRNA profiling in hESCs and in purified neural and mesenchymal derivatives. Using a combination of AGO cross-linking and microRNA perturbation experiments, together with computational prediction, we identified the targets of the miR-302/367 cluster, the most abundant microRNAs in hESCs. Functional studies identified novel roles of miR-302/367 in maintaining pluripotency and regulating hESC differentiation. We show that in addition to its role in TGF-β signaling, miR-302/367 promotes bone morphogenetic protein (BMP) signaling by targeting BMP inhibitors TOB2, DAZAP2, and SLAIN1. This study broadens our understanding of microRNA function in hESCs and is a valuable resource for future studies in this area.
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
Inna
I
Lipchina
Yechiel
Y
Elkabetz
Markus
M
Hafner
Robert
R
Sheridan
Aleksandra
A
Mihailovic
Thomas
T
Tuschl
Chris
C
Sander
Lorenz
L
Studer
Doron
D
Betel
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C532169:MIRN302A microRNA, human; C568081:MIRN367 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D016212:Transforming Growth Factor beta