Silencing the host : the role of intronic microRNAs

Abstract

Fifteen years ago lin-4 was reported to be the first endogenous small non-coding, but interfering RNA structure involved in developmental timing in C. elegans. First thought not, or only rarely, to occur in mammals, microRNAs are now among the major players in up-to-date genomic research. The mature molecules are ~22 nucleotides in length and, by targeting predominantly the 3' UTR of mRNAs, lead to translational repression or degradation of the target message, hence controlling important cellular mechanisms, including division, differentiation and death. This key role makes them excellent targets for cancer research. In fact they have been shown to have a major impact on cancer development in many cases. However, miRNAs are not a homogeneous class and can be sub classified into intragenic and intergenic, depending on their genomic position. Whereas intergenic miRNAs are expected to be independent transcriptional units, intragenic miRNAs are commonly believed to be regulated through their host gene. Despite of the growing knowledge on how miRNAs integrate into cellular regulatory networks, our current knowledge about the specific role of intragenic miRNAs is rather limited. In this work we integrated current miRNA knowledge bases, ranging from miRNA sequence and genomic localization information to target prediction, with biochemical pathway information and publicly available expression data to investigate functional properties of intragenic miRNAs and their relationship to their host genes. To the best of our knowledge, we are the first to show in a large-scale analysis that intragenic miRNAs seem to act as negative feedback regulators on multiple levels. We furthermore investigated the impact of this model on the potential role of intronic miRNAs in cancer pathogenesis.