The most well-studied sequences in the human genome are those of protein-coding genes. However, the coding exons of these genes account for only 1.5% of the genome, a proportion that increases to 2% if untranslated regions (UTRs) are considered 1 . In recent years, it has become increasingly apparent that the non-proteincoding portion of the genome is of crucial functional importance: for normal development and physiology and for disease 2 . The functional relevance of the nonprotein-coding genome is particularly evident for a class of small non-coding RNAs (ncRNAs) called microRNAs (miRNAs) . In human diseases, particularly cancer, it has been shown that epigenetic and genetic defects in miRNAs and their processing machinery are a common hallmark of disease . However, miRNAs are just the tip of the iceberg, and other ncRNAs, such as transcribed ultraconserved regions (T-UCRs), small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), large intergenic non-coding RNAs (lincRNAs) and, overall, the heterogeneous group of long non-coding RNAs (lncRNAs), might also contribute to the development of many different human disorders 2 .Here, I focus on the genetic and epigenetic events that disrupt ncRNA loci and their related proteins in the context of cancer and other human diseases, such as neurological, cardiovascular, autoimmune, imprinting and monogenic disorders. I also discuss the emerging opportunities for targeting these disruptions of ncRNAs using novel therapeutic approaches. The role of miRNAs in cancer has recently been reviewed in detail elsewhere , and so it is only briefly recapped here. By contrast, this Review considers in more depth the emerging evidence for roles of other ncRNAs in cancer and for both miRNAs and other ncRNAs in other types of disease.
Types of ncRNA and their functions
The discovery that many genomic sequences in complex organisms are transcribed in a developmental-and tissue-regulated fashion 9,10 has fuelled a race to characterize all of the different types of ncRNAs that are transcribed in human cells. Although most of the work has focused on short RNAs, such as miRNAs, lncRNAs are also gaining prominence. In the case of lncRNAs, they are classified as those ncRNAs that are longer than 200 nucleotides on the basis of RNA purification protocols that exclude small RNAs 10 . Although there is not necessarily a clear delineation between ncRNA classes, for the purpose of simplicity, in this Review, I discuss ncRNAs by division into the following categories: miRNAs, piRNAs, snoRNAs, lncRNAs (for example, homeobox (HOX) transcript antisense RNA (HOTAIR), lincRNAs and T-UCRs) and other types of ncRNAs. TABLE summarizes the different types of ncRNAs that are discussed, and FIG. illustrates the biogenesis machineries of the most well-characterized ncRNAs.miRNAs. The most widely studied class of ncRNAs are miRNAs, which are small ncRNAs of ~22 nucleotides (nt) that, in animals, mediate post-transcriptional gene silencing by controlling the translation of mRNA into proteins . miRNAs are estimated to regulate the translation of more than 60% of protein-coding genes. They are involved in regulating many processes, including proliferation, differentiation, apoptosis and