Abstract
micro(mi)RNAs are small non-coding RNAs that negatively regulate expression of most mRNAs. They are powerful regulators of various differentiation stages, and the expression of genes that either negatively or positively correlate with expressed miRNAs is expected to hold information on the biological state of the cell and, hence, of the function of the expressed miRNAs. We have compared the large amount of available gene array data on the steady state system of the NCI60 cell lines to two different data sets containing information on the expression of 583 individual miRNAs. In addition, we have generated custom data sets containing expression information of 54 miRNA families sharing the same seed match. We have developed a novel strategy for correlating miRNAs with individual genes based on a summed Pearson Correlation Coefficient (sPCC) that mimics an in silico titration experiment. By focusing on the genes that correlate with the expression of miRNAs without necessarily being direct targets of miRNAs, we have clustered miRNAs into different functional groups. This has resulted in the identification of three novel miRNAs that are linked to the epithelial-to-mesenchymal transition (EMT) in addition to the known EMT regulators of the miR-200 miRNA family. In addition, an analysis of gene signatures associated with EMT, c-MYC activity, and ribosomal protein gene expression allowed us to assign different activities to each of the functional clusters of miRNAs. All correlation data are available via a web interface that allows investigators to identify genes whose expression correlates with the expression of single miRNAs or entire miRNA families. miRConnect.org will aid in identifying pathways regulated by miRNAs without requiring specific knowledge of miRNA targets.
Highlights
Micro(mi)RNAs are small, 19–22 nucleotide long, non-coding RNAs that regulate gene expression mostly by targeting the 39UTR of mRNAs resulting in reduced translation of proteins or degradation of the mRNAs. miRNAs are fundamental regulators of cell differentiation and developmental processes
We made use of several data sets available for the NCI60 cells (59 cell lines): 1) the expression profile of 208 human miRNAs quantified by real-time PCR [20]; 2) four data sets of human gene expression profiles (STANFORD, GENELOGIC_U95, GENELOGIC_U133 and NOVARTIS) available on the NCI Developmental Therapeutics Program (DTP) server
An advantage of the NCI60 system is the ability of combining individual endogenous miRNA expression in a way represented by correlating gene expression with the expression of an entire miRNA family
Summary
Micro(mi)RNAs are small, 19–22 nucleotide long, non-coding RNAs that regulate gene expression mostly by targeting the 39UTR of mRNAs resulting in reduced translation of proteins or degradation of the mRNAs. miRNAs are fundamental regulators of cell differentiation and developmental processes. They have been recognized to be highly relevant in cancer formation and progression [1]. MiRNAs contain at their 59 end a short stretch of 6–8 nucleotides complementary to the seed match in the target mRNA This complementarity is accessible to computational analysis and multiple algorithms have been developed to predict miRNA targets [5]. Both overexpression and inhibition of miRNAs have caveats [7] and it is not clear whether the observed changes at the mRNA and protein level are the result of direct regulation by miRNAs or are the result of changes downstream of the miRNA-targeted genes
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