Evidence for natural antisense transcript-mediated inhibition of microRNA function
1 Department of Neuroscience, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA
2 Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA
3 T-6, Los Alamos National Laboratory Los Alamos National Laboratory, Los Alamos, NM 87545, USA
4 Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
5 Miami Institute for Human Genomics, Miller School of Medicine, 1501 NW 10th Ave, Miami, FL 33101, USA
6 Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, NIH, Bldg 35, 9000 Rockville Pike, Bethesda, MA 20892, USA
7 Department of Biology, Brown University, 244 Thayer Street, Providence, RI 02912, USA
Genome Biology 2010, 11:R56 doi:10.1186/gb-2010-11-5-r56Published: 27 May 2010
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.