Detection of a microRNA signal in an in vivo expression set of mRNAs.
BACKGROUND
microRNAs (miRNAs) are approximately 21 nucleotide non-coding transcripts capable of regulating gene expression. The most widely studied mechanism of regulation involves binding of a miRNA to the target mRNA. As a result, translation of the target mRNA is inhibited and the mRNA may be destabilized. The inhibitory effects of miRNAs have been linked to diverse cellular processes including malignant proliferation, apoptosis, development, differentiation, and metabolic processes. We asked whether endogenous fluctuations in a set of mRNA and miRNA profiles contain correlated changes that are statistically distinguishable from the many other fluctuations in the data set.


RESULTS
RNA was extracted from 12 human primary brain tumor biopsies. These samples were used to determine genome-wide mRNA expression levels by microarray analysis and a miRNA profile by real-time reverse transcription PCR. Correlation coefficients were determined for all possible mRNA-miRNA pairs and the distribution of these correlations compared to the random distribution. An excess of high positive and negative correlation pairs were observed at the tails of these distributions. Most of these highest correlation pairs do not contain sufficiently complementary sequences to predict a target relationship; nor do they lie in physical proximity to each other. However, by examining pairs in which the significance of the correlation coefficients is modestly relaxed, negative correlations do tend to predict targets and positive correlations tend to predict physically proximate pairs. A subset of high correlation pairs were experimentally validated by over-expressing or suppressing a miRNA and measuring the correlated mRNAs.


CONCLUSIONS
Sufficient information exists within a set of tumor samples to detect endogenous correlations between miRNA and mRNA levels. Based on the validations the causal arrow for these correlations is likely to be directed from the miRNAs to the mRNAs. From these data sets, we inferred and validated a tumor suppression pathway linked to miR-181c.
Liu
Tsunglin
T
Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California, United States of America; Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California, United States of America.
Papagiannakopoulos
Thales
T
Puskar
Kathy
K
Qi
Shuping
S
Santiago
Fernando
F
Clay
William
W
Lao
Kaiqin
K
Lee
Yohan
Y
Nelson
Stanley F
SF
Kornblum
Harley I
HI
Doyle
Frank
F
Petzold
Linda
L
Shraiman
Boris
B
Kosik
Kenneth S
KS
D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D035683:MicroRNAs; D012333:RNA, Messenger