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PMID: 22446693 Published · epublish English Journal Article Research Support, N.I.H., Extramural

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

Nature biotechnology ·Vol. 30 ·No. 5 ·2012-03-25 ·Pages 453-9

Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, van der Brug MP, Wahlestedt C

Abstract

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.

MeSH Terms
Animals Cell Line Chromatin/chemistry,metabolism Exons Gene Expression Profiling Genomics Glial Cell Line-Derived Neurotrophic Factor/biosynthesis HEK293 Cells Humans Mice Models, Genetic Oligonucleotides, Antisense/antagonists & inhibitors RNA, Messenger/metabolism RNA, Small Interfering/metabolism Receptor, EphB2/biosynthesis Sequence Analysis, DNA Transcription, Genetic Up-Regulation
Chemicals
Chromatin Glial Cell Line-Derived Neurotrophic Factor Oligonucleotides, Antisense RNA, Messenger RNA, Small Interfering Receptor, EphB2
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Modarresi Farzaneh
Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Faghihi Mohammad Ali
Lopez-Toledano Miguel A
Fatemi Roya Pedram
Magistri Marco
Brothers Shaun P
van der Brug Marcel P
Wahlestedt Claes
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.2158
Published
2012-03-25
Epub
2012-00-25
Pages
453-9
Language
English
Region
United States
NLM ID
9604648
PMCID
PMC4144683
Subset
IM
Grants
NINDS NIH HHS · R01 NS063974-05 · United States
NIA NIH HHS · RC2 AG036596-01 · United States
NINDS NIH HHS · R01 NS063974-01A1 · United States
NINDS NIH HHS · R01 NS063974 · United States
NINDS NIH HHS · 5R01NS063974 · United States
NIA NIH HHS · RC2 AG036596-02 · United States
NIA NIH HHS · 5RC2AG036596 · United States
NINDS NIH HHS · R01 NS063974-04 · United States
NIA NIH HHS · RC2 AG036596 · United States
NINDS NIH HHS · R01 NS063974-02 · United States
NIA NIH HHS · RC2 AG036596-03 · United States
NINDS NIH HHS · R01 NS063974-03 · United States
Corrections
CommentIn
PMID: 22803202
External Links
PubMed source DOI: 10.1038/nbt.2158 PMC Full Text View journal details
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