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MicroRNA-directed transcriptional gene silencing in mammalian cells

  1. Daniel H. Kim*,?,
  2. P?l S?trom?,§,
  3. Ola Sn?ve, Jr.?, and
  4. John J. Rossi*,?
  1. *Graduate School of Biological Sciences and Division of Molecular Biology, Beckman Research Institute of the City of Hope, 1450 E. Duarte Road, Duarte, CA 91010;
  2. ?Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology and Interagon AS, Laboratoriesenteret, NO-7489 Trondheim, Norway; and
  3. §Department of Computer and Information Science, Norwegian University of Science and Technology, Sem S?lands vei 7-9, NO-7491 Trondheim, Norway
  1. Communicated by Arthur D. Riggs, Beckman Research Institute of the City of Hope, Duarte, CA, September 5, 2008 (received for review June 3, 2008)

Abstract

MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level in the cytoplasm, but recent findings suggest additional roles for miRNAs in the nucleus. To address whether miRNAs might transcriptionally silence gene expression, we searched for miRNA target sites proximal to known gene transcription start sites in the human genome. One conserved miRNA, miR-320, is encoded within the promoter region of the cell cycle gene POLR3D in the antisense orientation. We provide evidence of a cis-regulatory role for miR-320 in transcriptional silencing of POLR3D expression. miR-320 directs the association of RNA interference (RNAi) protein Argonaute-1 (AGO1), Polycomb group (PcG) component EZH2, and tri-methyl histone H3 lysine 27 (H3K27me3) with the POLR3D promoter. Our results suggest the existence of an epigenetic mechanism of miRNA-directed transcriptional gene silencing (TGS) in mammalian cells.

Footnotes

  • ?To whom correspondence should be addressed. E-mail: jrossi{at}coh.org
  • Author contributions: D.H.K. and J.J.R. designed research; D.H.K., P.S., and O.S. performed research; P.S. and O.S. contributed new reagents/analytic tools; D.H.K., P.S., O.S., and J.J.R. analyzed data; and D.H.K. and J.J.R. wrote the paper.

  • ??Present address: Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, 185 Cambridge St., Boston, MA 02114.

  • The authors declare no conflict of interest.

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