LIPCAR

> Only one link of the chain of destiny can be handled at a time .> > — Winston Churchill All proteins are translated from RNA, but only a fraction of RNAs seem to be translated into proteins. Advanced genomics technologies have uncovered noncoding regulatory RNAs exhibiting extraordinary diversity in size, structure, and molecular function. We know a great deal about small (≈20 nucleotides) microRNAs that post-transcriptionally regulate translation of protein from target mRNAs having complementary 3′ sequences. These linear single-stranded nucleotides are transcribed either as independent gene products or as passengers within so-called miRtrons (microRNA-containing introns) of protein-coding genes and then processed and exported from the nucleus where they incorporate into RNA-induced silencing complexes.1 Because some microRNAs exhibit altered expression or differing circulating levels, they are being assessed as diagnostic biomarkers in cardiac disease. As yet, we know far less about the larger (>200 nucleotides) long noncoding RNAs (lncRNAs). lncRNAs are generated as antisense transcripts of protein-coding genes, as sense transcripts from within protein-coding gene introns, or as independent transcripts originating from intergenic regions.2 Unlike short microRNAs, lncRNAs are sufficiently long to develop multiple intramolecular RNA–RNA interactions conferring on them complex 3-dimensional structures. The unique physical configurations of different lncRNAs enable many of them to bind specific sets of proteins. Likewise, openly configured single-strand RNA sequences within lncRNA structures permit them to bind to complementary sequences in the genome. The combination of these 2 characteristics, protein binding and recognition of specific DNA sequences, evokes a characteristic lncRNA functionality: chaperoning transcriptional modulators or chromatin modifiers to specific genomic locations. In this manner, lncRNAs can epigenetically regulate gene expression.3Article, see p 1569Our nascent but growing understanding of lncRNA biology generally assumes that they are produced by, and act on, the nuclear genome. In this issue of Circulation Research …