Selective blockade of microRNA processing by Lin28.
MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked posttranscriptionally in embryonic stem cells, embryonal carcinoma cells, and primary tumors. Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.
Viswanathan
Srinivas R
SR
Stem Cell Program, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
Daley
George Q
GQ
Gregory
Richard I
RI
D000818:Animals; D018236:Carcinoma, Embryonal; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C513400:Drosha protein, mouse; D043244:Ribonuclease III