Author(s): Katrien Van Roosbroeck 1 , Jeroen Pollet 2 , George A Calin [*] 3
autoimmune diseases; biomarkers; cancer; cardiovascular diseases; infectious diseases; miRNAs; molecular diagnostics; neurological diseases; noncoding RNAs
Loci harboring protein-coding genes are the best-studied in the human genome, but comprise only less than 2% of it  . The fact that at least 90% of the genome is actively transcribed adds another layer of complexity to the human transcriptome, suggesting that the majority of the transcripts are noncoding RNAs (ncRNAs)  . ncRNAs are transcripts that lack an open-reading frame and, therefore, do not encode proteins. They can be divided into small ncRNAs, of which microRNAs (miRNAs) are the most prominent, and long ncRNA, a very heterogeneous group of ncRNAs that are more than 200 nucleotides in length and that include, among others, long intergenic ncRNAs (lincRNAs), transcribed ultraconserved regions (T-UCRs), pseudogenes and antisense RNAs (reviewed by  ). ncRNAs were originally thought to be only 'transcriptional noise'; however, increasing evidence assigns a major biological role in many physiological processes, and deregulation of ncRNAs is implicated in many human diseases. Although a lot of effort is being put into discovering new ncRNAs and elucidating their roles, both in normal physiology as well as in disease, most of the research so far has focused on miRNAs. Unraveling the roles and mechanisms of action of most other ncRNAs is still in its infancy and remains challenging. Especially, long ncRNAs form a novel, poorly characterized class of ncRNAs, and it is still a key challenge to understand their precise roles in relation to physiology and disease. Nevertheless, the function of many ncRNAs has been elucidated in recent years, pointing to a general role in a plethora of human diseases.
In this article, the authors summarize some emerging new roles for miRNAs and long ncRNAs, and describe mechanisms that cause abnormal expression of ncRNAs. The authors review established and new methods to detect RNAs, and discuss the use of ncRNAs as biomarkers in human diseases, as well as their targeting as new strategies for therapeutic intervention. This review mainly concentrates on, but is not only restricted to, miRNAs and long ncRNAs in cancer; the authors also consider other human disorders including cardiovascular, autoimmune, neurological and infectious diseases. For reviews concerning the use of miRNAs as biomarkers, the reader is redirected to some excellent reviews [4-15] .
Emerging roles for ncRNAs
Since the discovery of miRNAs in 1993 [16,17] and the demonstration of miRNA involvement in human diseases, a lot of research has focused on elucidating their roles in physiology as well as in human diseases. By now, it is common knowledge that miRNAs negatively regulate expression of protein-coding genes at the post-transcriptional and translational level through mRNA cleavage (Figure 1A) or translational repression (Figure 1B), and that miRNAs themselves are regulated by transcription factors. However, recent studies suggest that miRNAs work in a much more sophisticated way than initially assumed and that complex interaction networks exist between miRNAs, other ncRNAs and mRNA from protein-coding genes ...