Abstract
microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date.
Highlights
IntroductionMicroRNAs (miRNAs) are short 20–22 nt long endogenous non-coding RNA molecules that reduce gene expression via degradation of messenger RNA (mRNA) [1] and translational inhibition [2]
Introduction microRNAs are short 20–22 nt long endogenous non-coding RNA molecules that reduce gene expression via degradation of messenger RNA [1] and translational inhibition [2]. These micro managers [3] play essential roles in major biological processes such as cell proliferation and differentiation [4] development [5] and disease [6,7]. miRNAs can tune the expression of multiple genes including complex networks of transcription factors, signaling pathways [8] and other regulatory loops [9]
It is thought that an essential component of miRNA regulation involves the formation of a duplex between the miRNA and the 39 untranslated region (39UTR) of a target messenger RNA (mRNA)
Summary
MicroRNAs (miRNAs) are short 20–22 nt long endogenous non-coding RNA molecules that reduce gene expression via degradation of messenger RNA (mRNA) [1] and translational inhibition [2] These micro managers [3] play essential roles in major biological processes such as cell proliferation and differentiation [4] development [5] and disease [6,7]. It is thought that an essential component of miRNA regulation involves the formation of a duplex between the miRNA and the 39 untranslated region (39UTR) of a target mRNA This duplex is characterized in animals by a perfectly paired seed region at the 59 end of the miRNA and a more loosely paired 39 extremity [10]. A correlation (or inverse correlation) in expression does not necessarily imply a direct functional relationship between two molecules
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