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PMID: 20507594 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Evidence for natural antisense transcript-mediated inhibition of microRNA function.

Genome biology ·Vol. 11 ·No. 5 ·2010-00-00 ·Pages R56

Faghihi MA, Zhang M, Huang J, Modarresi F, Van der Brug MP, Nalls MA, Cookson MR, St-Laurent G, Wahlestedt C

Abstract

MicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript. We report here that BACE1-antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1-antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1-antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1-antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1-antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals. Our data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter.

MeSH Terms
Aged Aged, 80 and over Alzheimer Disease/enzymology,genetics Amyloid Precursor Protein Secretases/genetics,metabolism Animals Aspartic Acid Endopeptidases/genetics,metabolism Base Sequence Binding Sites Binding, Competitive/drug effects Brain/drug effects,enzymology,pathology Cell Line High-Throughput Screening Assays Humans Luciferases/metabolism Mice MicroRNAs/genetics,metabolism Molecular Sequence Data Oligonucleotides/pharmacology Open Reading Frames/genetics RNA, Antisense/metabolism RNA, Messenger/genetics,metabolism RNA, Untranslated/genetics,metabolism Reproducibility of Results Sequence Analysis, DNA
Chemicals
MicroRNAs Oligonucleotides RNA, Antisense RNA, Messenger RNA, Untranslated locked nucleic acid Luciferases Amyloid Precursor Protein Secretases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Faghihi Mohammad Ali
Department of Neuroscience, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. [email protected]
Zhang Ming
Huang Jia
Modarresi Farzaneh
Van der Brug Marcel P
Nalls Michael A
Cookson Mark R
St-Laurent Georges
Wahlestedt Claes
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Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
DOI
10.1186/gb-2010-11-5-r56
Email
[email protected]
Published
2010-00-00
Epub
2010-00-27
Pages
R56
Language
English
Region
England
NLM ID
100960660
PMCID
PMC2898074
Subset
IM
Grants
NINDS NIH HHS · R01 NS063974 · United States
NINDS NIH HHS · R01 NS063974-03 · United States
NIA NIH HHS · 1RC2 AG036596 · United States
External Links
PubMed source DOI: 10.1186/gb-2010-11-5-r56 PMC Full Text View journal details
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