Natural Antisense Inhibition Results in Transcriptional De-Repression and Gene Upregulation

By F. Modarresi, M. Faghihi, Miguel A Lopez-Toledano, Roya Pedram Fatemi, Marco Magistri, S. Brothers, M. P. van der Brug, Claes Wahlestedt. Nature Biotechnology, 2012

626 citations recorded by the source corpus.

The ability to specifically upregulate genes in vivo holds great therapeutic promise. Here we show that inhibition or degradation of natural antisense transcripts (NATs) by single-stranded oligonucleotides or siRNAs can transiently and reversibly upregulate locus-specific gene expression. Brain-derived neurotrophic factor (BDNF) is normally repressed by a conserved noncoding antisense RNA transcript, BDNF-AS. Inhibition of this transcript upregulates BDNF mRNA by two- to sevenfold, alters chromatin marks at the BDNF locus, leads to increased protein levels and induces neuronal outgrowth and differentiation both in vitro and in vivo. We also show that inhibition of NATs leads to increases in glial-derived neurotrophic factor (GDNF) and ephrin receptor B2 (EPHB2) mRNA. Our data suggest that pharmacological approaches targeting NATs can confer locus-specific gene upregulation effects.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da52c8fee95e1e85e0980090ed05a9f690acdc56

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Citations in the corpus

Long noncoding RNAs: Cellular address codes in development and disease (2013, positive): “Aberrant lncRNAs can be knocked down in vivo using oligonucleotide ‘‘drugs’’ (Modarresi et al., 2012; Wheeler et al., 2012), which should spur advance in lncRNA genetics and therapeutics.”
MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions (2016, background): “The recognition by the miRNA seed region of a perfectly matching sequence within a non-coding promoter transcript would recruit a nuclear RISC and induce cleavage of the antisense non-coding tr nscript, removal of chromatin effectors and derepression of the corresponding sense transcription [96,97] ”
Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer (2016, background): “Antisense targeting of natural antisense lncRNAs, or ‘‘antagoNATs”, provides a very specific way for gene upregulation [126,127].”
MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures (2015, neutral): “Input signal [0–39]”