| Summary |
MicroRNAs (miRNAs) are small endogenous, non-coding RNAs that control genes at post-transcriptional level. They are essential for development and tissue differentiation, and altered miRNA expression patterns are linked to the pathogenesis of inflammation and cancer. There is evidence that miRNA expression is genetically controlled similar to the transcription of protein-coding genes and previous studies identified quantitative trait loci (QTL) for miRNA expression in the liver. So far, little attention has been paid to miRNA expression in the skin. Moreover, there is no data on epistatic control of miRNA expression.
In this study, we statistically linked cutaneous miRNA expression patterns to SNP (single nucleotide polymorphism) markers in an advanced murine intercross line (AIL) of three strains (BxD2, NZM and MRL) that are known to be prone to develop autoimmune diseases as well as the wild-derived strain CAST/EiJ.
In particular, we screened 100 murine samples for 609 different miRNAs and identified 42 eQTL controlling the expression of 38 cutaneous miRNAs. As a result, we identified two chromosomal hot-spots on chromosome 2 and 8 that control the expression of multiple miRNAs. Moreover, for eight miRNAs, an interacting effect of pairs of SNP was observed. Combining the constraints on genes from the statistical interaction of their loci and further using curated protein interaction networks narrowed down the number of candidate genes controlling miRNAs to a set of several genes. Among the resulting interaction pairs were the genes COMMD3 and COPS5 found to regulate the expression of miR-501-5p.
Independently, a network analysis based on co-expression of miRNAs was performed using WGCNA (weighted gene co-expression analysis) to identify clusters (modules) of co-expressed miRNAs. One of these modules significantly correlated with the onset and severity of epidermolysis bullosa acquisita, a cutaneous autoimmune skin blistering disease induced by autoantibodies to type VII collagen. The key miRNAs identified from this analysis were miR-379 and miR-223.This work shows strong evidence for a genetic control of cutaneous miRNA expression.
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