Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation

• Published in: Nature biotechnology Vol. 30; no. 5; pp. 453 - 459
• Main Authors: Modarresi, Farzaneh, Faghihi, Mohammad Ali, Lopez-Toledano, Miguel A, Fatemi, Roya Pedram, Magistri, Marco, Brothers, Shaun P, van der Brug, Marcel P, Wahlestedt, Claes
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2012; Nature Publishing Group
• Subjects: 631/337; 631/378/1686; 631/61/191; 631/61/391/1914; Agriculture; Animals; Antisense RNA; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Brain-derived neurotrophic factor; Cell Line; Chromatin - chemistry; Chromatin - metabolism; Exons; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene therapy; Genetic aspects; Genetic regulation; Genetic transcription; Genomics; Glial Cell Line-Derived Neurotrophic Factor - biosynthesis; Growth factors; HEK293 Cells; Humans; Inhibition; Life Sciences; Mice; Models, Genetic; Oligonucleotides, Antisense - antagonists & inhibitors; Physiological aspects; Receptor, EphB2 - biosynthesis; Ribonucleic acid; RNA; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Sequence Analysis, DNA; Transcription, Genetic; Up-Regulation; United States; In vivo; Regulation(control); Messenger RNA; Gene; Transcription; Antisense RNA; Inhibition
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/nbt.2158

Methods for specific gene silencing have advanced as far as clinical trials, but a similar set of tools does not exist for increasing gene expression. Modarresi et al . demonstrate gene-specific upregulation in vivo by treating mice with oligonucleotides that inhibit the function of natural antisense transcripts. 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.