MacroRNA underdogs in a microRNA world: evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA.

The central dogma of molecular biology relegates RNAs to the role of "messengers" of genetic information, with proteins as the end products that perform key roles as regulators and effectors of biological processes. Notable exceptions include non-protein-coding RNAs, which function as adaptors (tRNAs) and ribosomal components (rRNAs) during translation, as well as in splicing (snRNAs) and RNA maturation including editing (snoRNAs). Genome and transcriptome projects have revealed, however, a significant number, rivaling the protein-coding transcripts, of non-protein-coding RNAs not related to these previously characterized transcript classes. Non-protein-coding RNA research has primarily focused on microRNAs, a small subclass of non-protein-coding RNAs, and their regulatory roles in gene expression, and these findings have been reviewed extensively. Here, we turn our attention to the larger, in number and size, long non-coding RNAs (lncRNAs), and review their evolutionary complexity and the growing evidence for their diverse mechanisms of action and functional roles in basic molecular and cellular biology and in human disease. In contrast to the focus on in-silico and expression studies in existing lncRNA literature, we emphasize direct evidence for lncRNA function, presenting experimental approaches and strategies for systematic characterization of lncRNA activities, with applications to known gene regulatory networks and diseases.