Modulating Transcription in human cells using small RNAs
Abstract
RNAi is generally associated with recognition of mRNA and post-transcriptional silencing of gene expression. We have observed that small RNAs complementary to gene promoters or to regions beyond the 3' termini of genes can either activate or inhibit gene expression. The mechanism involves recruitment of argonaute 2 and recognition of noncoding transcripts that overlap gene termini. Inhibition or activation is transient and does not involve DNA methylation. Regulation of gene expression by promoter-targeted RNAs is robust and can be achieved by miRNAs. Our data suggest that RNA-mediated regulation of transcription may contribute to cellular gene regulation.
References
Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Hardy, D., Shames, D. S., Minna, J. D., and Corey D. R. Inhibiting gene expression at transcription start sites in chromosomal DNA by antigene RNAs. Nat. Chem. Biol. 1, 216-222 (2005).
Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Nordsell, R., Shames, D. S., Minna, J. D., and Corey, D. R. Ago1 and Ago2 link mammalian transcriptional silencing with RNAi. Nature Structural Molecular Biology 13, 787-792 (2006).
Janowski, B. A., Younger, S. T., Hardy, D. B., Ram, R., Huffman, K. E., and Corey, D. R. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. 3 166-173 (2007).
Schwartz, J. C., Younger, S. T., Nguyen, N-B., Hardy, D. B., Corey, D. R., and Janowski, B. A. Antisense transcripts are targets for small activating RNAs. Nat. Struct. Mol. Biol. 15, 842-848 (2008).
Younger, S. T., Pertsemlidis, A., and Corey, D. R. A method for predicting potential miRNA target sites within gene promoters. Biorg. Med. Chem. Lett. 19, 2791-3794 (2009).
Yue, X., Schwartz, J. C., Younger, S. T., Chu, Y., Gagnon, K.T., Elbashir, S., Janowski, B. A., Corey, D. R. Regulation of transcription by small RNAs complementary to sequences downstream from the 3’ termini of genes. Nature Chemical Biology 6, 621-629 (2010).
Watts, J. K., Yu, D., Charisse, K., Montaillier, C., Potier, P., Manoharan, M., and Corey, D. R. Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs (agRNAs) that are complementary to gene promoters. Nucl. Acids Res. 38, 5242-5259 (2010).
Chu, Y., Yue, X., Janowski, B. A., Younger S. T., and Corey, D. R. Argonaute proteins and modulation of progesterone receptor expression by promoter-targeted RNAs. Nucl. Acids Res. 38, 7736-7748 (2010).
Matsui et al., Activation of LDL Receptor (LDLR) Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter. Chem. Biol. 17, in press (2010).
