The Role of miRNA in Rheumatoid Arthritis

Abstract

MicroRNAs (miRNAs) are a well-established class of small (~22 nucleotides) endogenous non-coding RNAs that influence the stability and translation of messenger RNA (mRNA) (van Rooij et al., 2007). Hundreds of miRNA have been identified in numerous animal species. The miRNA genes are transcribed by RNA polymerase II as primary miRNA (pri-miRNA). The RNase III enzyme Drosha then processes the nuclear pri-miRNA, to precursor miRNA (pre-miRNA), which is exported from the nucleus with the help of exportin. Maturation of the pre-miRNA into miRNA is then mediated by the cytoplasmic enzyme Dicer, after which the single-stranded mature miRNA is loaded into the RNA-induced silencing complex (RISC). Once loaded, the miRNA guides this complex to the 3′-untranslated region (3′-UTR) of target mRNA (Figure 1). The socalled ‘seed region’ (nucleotides 2–8) of miRNA is most important for target recognition and silencing. miRNA usually binds with imperfect complementarity to its target, which is called the ‘seed sequence’. Association of miRNA with its target mRNA silences expression via at least three mechanisms: inhibition of translation, inhibition of the initiation of translation and destabilization of target mRNA. Recent advances have shown that miRNA expression during development is highly tissuespecific, which suggests that miRNA may be involved in specifying and maintaining tissue identity. Recent studies have shown that a single miRNA can generate a huge impact to the whole profile of protein expression (Selbach et al., 2008; Baek et al., 2008). For most interactions, microRNAs act as ‘rheostats’ to make fine-scale adjustments to protein output (Baek et al., 2008). Several miRNAs have been shown to regulate the 3’-UTR of mRNA that encode transcription factors, and a circuit that sequentially involves miRNA and transcription factors in a mutual negative feedback loop has been described (Tsang et al., 2008). The role of miRNA on protein expression, therefore, is not one-directional: from miRNA to protein. If we consider, however, a simple setting of miRNA and its direct target mRNA, the miRNA upregulated in a particular cell type from patients with specific disease possibly put the cell in short of a group of proteins which are necessary to maintain the physiological homoeostasis by targeting the translation of those proteins. In contrast, the miRNA downregulated in a particular cell type from patients with specific disease might allow the cell to increase translation of a group of proteins that are suppressed at low levels in normal conditions. In 2009, the direct involvement of single nucleotide polymorphisms of a miRNA in human hereditary disease was reported for the first time (Mencia et al., 2009). They found that two different single nucleotide polymorphisms of miR-96 are related the hearing loss found in two families. Their report was the start of a new era, in which the involvement of genetic