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Nucleic Acids Research Advance Access published online on October 24, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm847
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

An RNA targeted to the HIV-1 LTR promoter modulates indiscriminate off-target gene activation

Marc S. Weinberg1, Samantha Barichievy1, Lana Schaffer2, Jiang Han3 and Kevin V. Morris3,*

1Antiviral Gene Therapy Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School, 7 York Rd Parktown 2193, South Africa, 2Biostatistics/informatics DNA Array Core Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037 and 3Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA

*To whom correspondence should be addressed. Tel: 1-858-784-9949; Fax: 1-858-784-2131; Email: kmorris{at}scripps.edu

Received August 31, 2007. Revised September 24, 2007. Accepted September 25, 2007.

Transcriptional gene silencing (TGS) can be achieved by small RNAs targeted to upstream promoter regions. Previously we characterized siRNAs targeted to the HIV-1 long terminal repeat (LTR) promoter at site 247, and found that a 21-base antisense strand of siRNA-247 (LTR-247as) suppressed LTR-mediated expression. To characterize the specificity of LTR-247as, vectors expressing antisense RNAs targeted to a region spanning 50 bases up- and downstream of the 247 target site were generated. LTR-247as+7, a ~22 base antisense RNA that is shifted by only seven bases upstream of LTR-247as, showed a significant increase in LTR-driven reporter gene expression that was independent of cell type and active chromatin methyl-marks. Promoter-targeting siRNAs have been recently shown to induce gene activation. However, here we demonstrate gene activation via a sequence-specific off-target effect. Microarray analysis of LTR-247as+7-treated cultures resulted in the deregulation of ~185 genes. A gene of unknown function, C10orf76, was responsive to inhibition by LTR-247as+7 and the loss of C10orf76 resulted in the upregulation of several genes that were activated by LTR-247as+7. These data suggest caution when using short antisense RNAs or siRNAs designed to target promoter sequences, since promoter-targeted RNAs may have unintended inhibitory effects against factors with suppressive gene activity.


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