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A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA), small non-messenger RNA (snmRNA), functional RNA (fRNA). The term small RNA (sRNA) is often used for bacteria. The DNA sequence from which a non-coding RNA is transcribed as the end product is often called an RNA gene or non-coding RNA gene.

Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNA (tRNA) and ribosomal RNA (rRNA), as well as RNAs such as snoRNAs, microRNAs, siRNAs and piRNAs and lastly long ncRNAs that include examples such as Xist and HOTAIR (see here for a more complete list of ncRNAs). The number of ncRNAs encoded within the human genome is unknown, however recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs.¹²³ Since most of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional.⁴

Biological roles of ncRNA

Noncoding RNAs are a diverse group of genes involved in many cellular processes. These range from ncRNAs of central importance that are conserved across all or most cellular life through to more transient ncRNAs specific to one or a few closely related species. The more conserved ncRNAs are thought to be molecular fossils or relics from LUCA and the RNA world.⁵⁶⁷

ncRNAs in translation

Many of the very well conserved, essential and abundant ncRNAs are involved in translation. Ribonucleoprotein (RNP) particles called ribosomes are the 'factories' where translation takes place in the cell. The ribosome consists of more than 60% ribosomal RNA, these are made up of 3 ncRNAs in prokaryotes and 4 ncRNAs in eukaryotes. Ribosomal RNAs catalyse the translation of nucleotide sequences to protein. Transfer RNAs form an 'adaptor molecule' between mRNA and protein. The snoRNAs and RNase MRP are involved in the maturation of rRNA. The snoRNAs guide covalent modifications of rRNA, tRNA and snRNAs, RNase MRP cleaves the internal transcribed spacer 1 between 18S and 5.8S rRNAs. RNase P, an evolutionary relative of RNase MRP, is involved in the maturation of tRNA. The RNase P generates mature 5'-ends of tRNAs by cleaving the 5'-leader elements of precursor-tRNAs. Another RNP called SRP recognizes and transports specific nascent proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes. In bacteria Transfer-messenger RNA (tmRNA) is an RNP is involved in rescuing stalled ribosomes, tagging incomplete polypeptides and promoting the degradation of aberrant mRNA.

ncRNAs in RNA splicing

The spliceosome performs the splicing reactions essential for the formation of mature mRNA. The spliceosome is another RNP often also known as the snRNP. There are two different forms of the spliceosome, the major and minor forms. The ncRNA components of the major spliceosome are U1, U2, U4 and U5. The ncRNA components of the minor spliceosome are U11, U12, U5, U4atac and U6atac.

There are two main groups of self-splicing RNAs, these are the group I catalytic intron and group II catalytic intron. These RNAs catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms.

ncRNAs in gene regulation

trans-acting ncRNAs

In higher eukaryotes MicroRNAs regulate gene expression. A single miRNA can reduce the expression levels of hundreds of genes. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to down-regulate gene expression.

It has been shown that human nuclear RNase P is required for the normal and efficient transcription of various ncRNAs transcribed by RNA polymerase III, including tRNA, 5S rRNA, SRP RNA and U6 snRNA genes. RNase P exerts its role in transcription through association with Pol III and chromatin of active tRNA and 5S rRNA genes.⁹

A bacterial ncRNA, 6S RNA, specifically associates with RNA polymerase holoenzyme containing the sigma70 specificity factor. This interaction represses expression from a sigma70-dependent promoter during stationary phase.

Another bacterial ncRNA, OxyS RNA represses translation by binding to Shine-Dalgarno sequences thereby occluding ribosome binding. OxyS RNA is induced in response to oxidative stress in Escherichia coli.

The B2 RNA is a small noncoding RNA polymerase III transcript that represses mRNA transcription in response to heat shock in mouse cells. B2 RNA inhibits transcription by binding to core Pol II. Through this interaction, B2 RNA assembles into preinitiation complexes at the promoter and blocks RNA synthesis. ¹⁰

cis-acting ncRNAs

A number of ncRNAs are embedded in the 5' UTRs of protein coding genes and influence their expression in various ways. For example, a riboswitch can directly bind a small target molecule, the binding of the target affects the gene's activity.

RNA leader sequences are found upstream of of the first gene of in amino acid biosynthetic operons. These RNA elements form one of two possible structures in regions encoding very short peptide sequences that are rich in the end product amino acid of the operon. A terminator structure forms when there is an excess of the regulatory amino acid and ribosome movement over the leader transcript is not impeded. When there is a deficiency of the charged tRNA of the regulatory amino acid the ribosome translating the leader peptide stalls and the antiterminator structure forms. This allows RNA polymerase to transcribe the operon. Known RNA leaders are Histidine operon leader, Leucine operon leader, Threonine operon leader and the Tryptophan operon leader.

Iron response elements (IRE) is bound by iron response proteins. The IRE is found in UTRs (Untranslated Regions) of various mRNAs whose products are involved in iron metabolism. When iron concentration is low, IRPs bind the ferritin mRNA IRE leading to translation repression.

ncRNAs and Genome defense

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are repeats found in the DNA of many bacteria and archaea. The repeats are separated by spacers of similar length. It has been demonstrated that these spacers can be derived from phage and subsequently help protect the cell from infection.

ncRNAs and chromosome structure

Telomerase is an RNP enzyme that adds specific DNA sequence repeats ("TTAGGG" in vertebrates) to telomeric regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes. The enzyme is a reverse transcriptase that carries Telomerase RNA, which is used as a template when it elongates telomeres, which are shortened after each replication cycle.

ncRNAs and disease

As with proteins, mutations or imbalances in the ncRNA repertoire within the body can cause a variety of diseases.

ncRNAs and cancer

Many ncRNAs show abnormal expression patterns in cancerous tissues. These include miRNAs,¹¹ long mRNA-like ncRNAs¹²¹³, Telomerase RNA and Y RNAs.¹⁴ The miRNAs are involved in the large scale regulation of many protein coding genes,¹⁵¹⁶ the Y RNAs are important for the initiation of DNA replication¹⁷, telomerase RNA that serves as a primer for telomerase, an RNP that extends telomeric regions at chromosome ends (see telomeres and disease for more information). The direct function of the long mRNA-like ncRNAs is less clear.

ncRNAs and Prader-Willi syndrome

The deletion of the 48 copies of the C/D box snoRNA SNORD116 has been shown to be the primary cause of Prader-Willi syndrome.¹⁸¹⁹²⁰ Prader-Willi is a developmental disorder associated with over-eating and learning difficulties. The targets of SNORD116 are unknown, however a bioinformatic screen located 23 possible targets within protein coding genes, of these a large fraction were found to be alternatively spliced, suggesting a role of SNORD116 in the regulation of alternative splicing.²¹

ncRNAs and Alzheimer's disease

The antisense RNA, BACE1-AS is transcribed from the opposite strand to BACE1 and is upregulated in patients with Alzheimer's disease. ²² BACE1-AS regulates the expression of BACE1 by increasing BACE1 mRNA stability and generating additional BACE1 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations are elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. Showing that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease–associated pathophysiology.

Distinction between functional RNA (fRNA) and ncRNA

The term ncRNA has been used, in addition to its above definition, to describe regions of mRNA that are functional at the RNA level, i.e. they have a biological function other than coding for protein even though they are on a protein-coding mRNA, for example riboswitches and the SECIS element.

They may even overlap with protein-coding sequence and are thus dual-functional: at the RNA level and at the protein level (e.g. SgrS RNA and RNAIII). However, these conflict with the Sequence Ontology's definition of ncRNA, which requires that a RNA does not contain any protein-coding sequence in order to be labeled ncRNA.

Several publications²³²⁴²⁵ have started using the term functional RNA (fRNA), as opposed to ncRNA, to describe regions functional at the RNA level that may or may not be stand-alone RNA transcripts. Therefore, every ncRNA is a fRNA, but there exist fRNA (such as riboswitches, SECIS elements, and other cis-regulatory regions) that are not ncRNA. Yet the term fRNA could also include mRNA as this is RNA coding for protein and hence is functional. Additionally artificially evolved RNAs also fall under the fRNA umbrella term. Some publications²⁶ state that the terms ncRNA and fRNA are nearly synonymous.

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