The noncoding RNAs: a genomic symphony of transcripts

Abstract

Imagine you are playing a piano. Your fingers sequentially move from one end of the keyboard to the other. Now imagine there is another person, playing the same keys in the opposite direction. Add yet another set of hands, which start and stop playing different keys within the center of the keyboard. Now imagine the room has many pianos, each with thousands of keys, and imagine each piano with thousands of players. The sound delicately balanced in sequence, with some melodies played very loud and others played very softly. So too, are the many transcripts of the genome, especially those of the class of noncoding RNAs (ncRNAs). The regulation of protein production has many more checks and balances than previously imagined. At the heart of this control lies the ncRNAs, which include the familiar tRNAs and rRNAs as well as the more recently discovered microRNAs (miRNAs) and piRNAs (Table 1). The transcriptome has proven to be much more complex than the initial sequencing estimates of approximately 20,000 protein-coding genes in the human genome. Studies have estimated that almost all of the transcriptional output of the human genome is RNAs that do not encode proteins (Mattick 2005). The articles in this issue focus on many aspects of the regulation and functions of miRNAs and other ncRNAs in the mammalian genome. Table 1 General classes of short noncoding RNAs in mammals. The miRNA genes Since the first identification of miRNAs by Victor Ambros and colleagues (Lee et al. 1993), a novel mechanism for controlling translation was discovered. MiRNAs are a group of small ncRNA molecules that are distinct from, but related to, small interfering RNAs (siRNAs) and that have been identified in a variety of organisms (Ambros 2003; Bartel 2004; He and Hannon 2004). These small 19–24 nucleotides (nt) RNAs are transcribed as parts of longer molecules, several kilobases (kb) in length, which are then capped and polyadenylated. These pri-miRNA transcripts are processed in the nucleus into hairpin RNAs of 70–100 nt by the ribonuclease Drosha and the RNA binding protein Pasha (Cullen 2004; Gregory et al. 2004). The hairpin RNAs are transported to the cytoplasm via an exportin-5 dependent mechanism; there they are digested by the double-strand-specific ribonuclease, Dicer. In animals, single-stranded miRNA binds specific messenger RNA (mRNA) through sequences that are complementary to the target mRNA, mainly to the 3’ untranslated region (3’ UTR). By a mechanism that is not fully characterized, the bound mRNA remains untranslated, resulting in reduced levels of the corresponding protein; alternatively, if the sequence match between the microRNA and its target is exact, the bound mRNA can be degraded, resulting in reduced levels of both the corresponding transcript and its encoded protein.