MicroRNAs and Beyond

Abstract

In recent years, microRNAs (miRs) have caused a true revolution in the cardiovascular research field. miRs are a class of highly conserved, small noncoding RNAs. They are transcribed from “normal” genes, and their precursor transcripts are enzymatically processed to a mature and active form by Drosha/Dgcr8 and Dicer enzyme complexes.1–3 miRs fine tune the expression of 30% to 50% of the protein-coding genes by binding to partly complementary base pairs in 3′ untranslated regions (UTRs) of mRNAs and thereby interfering with translation; targeted mRNAs are either degraded or temporarily silenced.4,5 In this way, miRs add another level of complexity to the highly regulated eukaryotic interactome, and their actions (partly) explain why mRNA expression so often does not agree with protein expression levels. So far, >700 human and 500 mouse miR genes have been included in the miRBase (www.microrna.sanger.ac.uk), the primary source of miR data, and computational analyses predict that these numbers will increase.6 The complexity of miR regulation of protein expression is illustrated by the fact that several miRs can target 1 gene, whereas several genes can be targeted by 1 miR.5,7 Bioinformatical tools to predict gene targets of a given miR exist, and their accuracy increases. Identifying the relevant miR-targeted genes and building new miR-gene networks is a challenge that lies ahead of us. The expression of miRs is tightly controlled and highly tissue, developmental stage, and disease specific. The heart expresses 2 unique miR families under the control of cardiogenic transcription factors like the serum response factor and myocyte enhancer factor 2: miR-1 and miR-133a (Figure 1 and please see the online Data Supplement at http://hyper.ahajournals.org for Table S1).8–11 miRs -1-1 and -1-2 represent 40% of all of the expressed miRs in the heart12 and are encoded from bicistronic units together with …