The Emerging Role of Long Noncoding RNAs in Human Disease

Only a small fraction of the human genome corresponds to protein-coding genes. Historically, the vast majority of genomic sequence was dismissed as transcriptionally silent, but recent large-scale investigations have instead revealed a rich array of functionally significant elements, including non-protein-coding transcripts, within the noncoding regions of the human genome. Long noncoding RNAs (lncRNAs), a class of noncoding transcripts with lengths >200 nucleotides, are pervasively transcribed in the genome, and have been shown to bind DNA, RNA, and protein. LncRNAs exert effects through a variety of mechanisms that include guiding chromatin-modifying complexes to specific genomic loci, providing molecular scaffolds, modulating transcriptional programs, and regulating miRNA expression. An increasing number of experimental studies are providing evidence that lncRNAs mediate disease pathogenesis, thereby challenging the concept that protein-coding genes are the sole contributors to the development of human disease. Researchers from the Translational Genomics Research Institute highlight recent findings linking lncRNAs with human diseases of complex etiology, including hepatocellular carcinoma, Alzheimer’s disease, and diabetes.

Mechanistic categories of lncRNAs

(a) Decoy lncRNA, (b) Signal lncRNA, (c) Scaffold lncRNA, and (d) Guide lncRNA. Hairpin loops represent lncRNAs; black arrows represent transcriptional start sites; blue and green circles depict transcription factors and chromatin modifying complex, respectively; yellow burst indicates developmental or environmental signal. Plus and minus signs depict transcriptional activation or repression, respectively.