The let-7 microRNA interfaces extensively with the translation machinery to regulate cell differentiation.
MicroRNAs (miRNAs) are noncoding RNAs that regulate numerous target genes through a posttranscriptional mechanism and thus control major developmental pathways. The phylogenetically conserved let-7 miRNA regulates cell proliferation and differentiation, thus functioning as a key regulator of developmental timing in C. elegans and a tumor suppressor gene in humans. Using a reverse genetic screen, we have identified genetic interaction partners of C. elegans let-7, including known and novel potential target genes. Initial identification of several translation initiation factors as suppressors of a let-7 mutation led us to systematically examine genetic interaction between let-7 and the translational machinery, which we found to be widespread. In the presence of wild-type let-7, depletion of the translation initiation factor eIF3 resulted in precocious cell differentiation, suggesting that developmental timing is translationally regulated, possibly by let-7. As overexpression of eIF3 in humans promotes translation of mRNAs that are also targets of let-7-mediated repression, we suggest that eIF3 may directly or indirectly oppose let-7 activity. This might provide an explanation for the opposite functions of let-7 and eIF3 in regulating tumorigenesis.
Ding
Xavier C
XC
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Slack
Frank J
FJ
Grosshans
Helge
H
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism; D017238:Genes, Helminth; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D014176:Protein Biosynthesis / Q000235:genetics*
D039621:Eukaryotic Initiation Factor-3; D035683:MicroRNAs; C474488:let-7 microRNA, C elegans