The non-protein-coding genome is gaining prominence in biology and medicine. The most well-studied non-coding RNAs (ncRNAs) are microRNAs (miRNAs), but many other types of ncRNAs also have major roles in cellular homeostasis and disease.
These additional ncRNAs include PIWI-interacting RNAs (piRNAs), ncRNAs that are associated with transcription start sites, small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs), such as large intergenic non-coding RNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs). The list is not exclusive, and in many instances there is no clear molecular distinction between the classes, in part because many ncRNAs have unknown functions. However, there are some well-studied lncRNAs, such as homeobox (HOX) transcript antisense RNA (HOTAIR) and X-inactivation specific transcript (XIST), which are involved in transcriptional regulation.
The recognition of the role of ncRNAs in disease has been derived from the existence of aberrant miRNA expression profiles in human cancer, where these transcripts, and their processing machineries, undergo genetic and epigenetic disruption. Other ncRNAs, such as T-UCRs and lncRNAs, are show aberrant expression levels in transformed cells.
Cancer showed the way, but ncRNAs are involved in most human diseases, from neurological disorders to cardiovascular problems. Specific miRNAs are disrupted in intellectual disabilities and neurodegerative syndromes and contribute to atherosclerosis, and snoRNA and lncRNA functions are impaired in imprinting syndromes.
These alterations of ncRNA expression and/or function in disease suggest that therapies targeting these molecules might be useful. Most of these approaches usually involve antisense oligonucleotides directed against miRNAs, but small molecule drugs that act on the miRNA machinery are also an interesting alternative pathway to explore, and similar strategies can also target other ncRNAs.
A key challenge comes from the little basic knowledge that exists about the normal function of some ncRNAs, particularly lncRNAs. The alliance between 'wet' laboratory scientists (that is, molecular and cellular biomedical researchers) and 'dry' laboratory scientists (that is, bioinformaticians) promises to be decisive in solving this exciting puzzle.
The relevance of the non-coding genome to human disease has mainly been studied in the context of the widespread disruption of microRNA (miRNA) expression and function that is seen in human cancer. However, we are only beginning to understand the nature and extent of the involvement of non-coding RNAs (ncRNAs) in disease. Other ncRNAs, such as PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), transcribed ultraconserved regions (T-UCRs) and large intergenic non-coding RNAs (lincRNAs) are emerging as key elements of cellular homeostasis. Along with microRNAs, dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases. There is great interest in therapeutic strategies to counteract these perturbations of ncRNAs.
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The author thanks members of his laboratory for helpful discussions. He acknowledges support from the European Research Council Advanced Grant EPINORC, Fondo de Investigaciones Sanitarias Grant PI08-1345, Dr. Josef Steiner Cancer Research Foundation Award and the Health Department of the Catalan Government (Generalitat de Catalunya). The author is an Institucio Catalana de Recerca i Estudis Avançats (ICREA) Research Professor.
The author declares no competing financial interests.
The epigenetic marking of a gene on the basis of parental origin, which in somatic tissues results in monoallelic expression.
- Argonaute protein
A type of protein that binds to small RNAs and is the defining component of the RNA-induced silencing complex (RISC). Proteins of this type have an ssRNA-binding domain (PAZ) and a ribonuclease domain (PIWI). The small RNAs guide Argonaute proteins to target mRNAs in order to mediate post-transcriptional degradation and/or translational silencing.
- Polycomb complex
Originally described in Drosophila melanogaster, polycomb complexes maintain the stable and heritable repression of several genes, including the homeotic genes.
Pairs of single genes in two different species that are descended from the same ancestral gene.
- Fragile regions
Chromosomal loci that appear as regions of decondensed or partially broken mitotic chromosomes under specific karyotyping conditions.
A chemotherapy drug that is used to treat various types of cancers. It was the first member of a class of platinum-containing anti-cancer drugs, which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA, which ultimately triggers apoptosis (programmed cell death).
- Loss of heterozygosity
A loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome mis-segregration.
- CpG island
A genomic region enriched for CpG dinucleotides that often occurs near constitutively active promoters. Mammalian genomes are otherwise depleted of CpGs owing to the preferential deamination of methylated cytosines.
- Sub-G1 peak
On cell staining with a DNA-intercalating dye such as propidium iodide, a DNA profile representing cells in G1, S phase and G2M will be observed with apoptotic cells being represented by a sub-G0/G1 population seen to the left of the G0/G1 peak.
- Dendritic spine
A mushroom-shaped structure on neuronal dendrites that receives synaptic input and has postsynaptic densities. Changes in spine shape are thought to be important for modulating synaptic strength.
Inability to coordinate movement.
The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. If penetrance of a disease allele is 100% then all individuals carrying that allele will express the associated disorder and the genotype is said to be 'completely penetrant'.
- 5q syndrome
A rare disorder caused by loss of part of the long arm (q arm, band 5q31.1) of human chromosome 5.
- Systematic evolution of ligands by exponential enrichment
(SELEX). A set of laboratory procedures that are generally used for the identification of representative sets of ligands for a protein. In the context of RNA, this is a method for identifying consensus-binding sequences on RNA substrates by in vitro selection of short RNAs that bind preferentially to RNA-binding proteins.
- Second-generation sequencing
Used in this Review to refer to sequencing methods that have emerged since 2005 that produce millions of typically short sequence reads (50–400 bases) from amplified DNA clones. It is also often known as next-generation sequencing.
- RNA sequencing
An experimental protocol that uses next-generation sequencing technologies to sequence the RNA molecules within a biological sample in an effort to determine the primary sequence and relative abundance of each RNA.
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Esteller, M. Non-coding RNAs in human disease. Nat Rev Genet 12, 861–874 (2011). https://doi.org/10.1038/nrg3074
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