Chemically Modified Oligonucleotides Modulate an Epigenetically Varied and Transient Form of Transcription Silencing of HIV-1 in Human Cells

• Published in: Molecular therapy. Nucleic acids Vol. 1; no. 4; p. e16
• Main Authors: Knowling, Stuart, Stapleton, Kenneth, Turner, Anne-Marie W, Uhlmann, Eugen, Lehmann, Thomas, Vollmer, Jörg, Morris, Kevin V
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2012; Elsevier Limited; Nature Publishing Group; Elsevier
• Subjects: Ago-1; antisense non-coding RNA; DNMT3a; epigenetic; HDAC-1; HIV-1; Human immunodeficiency virus 1; Lentivirus; LNA; oligonucleotide; Original; transcription; HIV-1; TGS; transcription; epigenetic; DNMT3a; antisense non-coding RNA; Ago-1; HDAC-1; LNA; oligonucleotide
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1038/mtna.2012.8

Small noncoding RNAs (ncRNAs) have been shown to guide epigenetic silencing complexes to target loci in human cells. When targeted to gene promoters, these small RNAs can lead to long-term stable epigenetic silencing of gene transcription. To date, small RNAs have been shown to modulate transcriptional gene silencing (TGS) of human immunodeficiency virus type 1 (HIV-1) as well as several other disease-related genes, but it has remained unknown as to what extent particular chemistries can be used to generate single-stranded backbone-modified oligonucleotides that are amenable to this form of gene targeting and regulation. Here, we present data indicating that specific combinations of backbone modifications can be used to generate single-stranded antisense oligonucleotides that can functionally direct TGS of HIV-1 in a manner that is however, independent of epigenetic changes at the target loci. Furthermore, this functionality appears contingent on the absence of a 5′ phosphate in the oligonucleotide. These data suggest that chemically modified oligonucleotide based approaches could be implemented as a means to regulate gene transcription in an epigenetically independent manner.