Non-coding RNA: Difference between revisions

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A '''non-coding RNA''' ('''ncRNA''') is a functional [[RNA]] molecule that is not [[Translation (genetics)|translated]] into a [[protein]]. The [[DNA]] sequence from which a functional non-coding RNA is transcribed is often called an RNA [[gene]]. Abundant and functionally important [[list of RNAs|types of non-coding RNAs]] include [[transfer RNA]]s (tRNAs) and [[ribosomal RNA]]s (rRNAs), as well as small RNAs such as [[microRNA]]s, [[siRNA]]s, [[piRNA]]s, [[snoRNA]]s, [[snRNA]]s, [[Extracellular RNA|exRNAs]], [[scaRNAs]] and the [[long noncoding RNA|long ncRNA]]s such as [[Xist]] and [[HOTAIR]].

The number of non-coding RNAs within the human genome is unknown; however, recent [[Transcriptomics|transcriptomic]] and [[Bioinformatics|bioinformatic]] studies suggest that there are thousands of non-coding transcripts.<ref name="pmid15790807">{{cite journal | vauthors = Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, Long J, Stern D, Tammana H, Helt G, Sementchenko V, Piccolboni A, Bekiranov S, Bailey DK, Ganesh M, Ghosh S, Bell I, Gerhard DS, Gingeras TR | display-authors = 6 | title = Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution | journal = Science | volume = 308 | issue = 5725 | pages = 1149–1154 | date = May 2005 | pmid = 15790807 | doi = 10.1126/science.1108625 | s2cid = 13047538 | bibcode = 2005Sci...308.1149C }}</ref><ref name="pmid17571346" /><ref name="Thind">{{cite journal | vauthors = Thind AS, Monga I, Thakur PK, Kumari P, Dindhoria K, Krzak M, Ranson M, Ashford B | display-authors = 6 | title = Demystifying emerging bulk RNA-Seq applications: the application and utility of bioinformatic methodology | journal = Briefings in Bioinformatics | volume = 22 | issue = 6 | date = November 2021 | article-number = bbab259 | pmid = 34329375 | doi = 10.1093/bib/bbab259 }}</ref><ref name="pmid17568003">{{cite journal | vauthors = Washietl S, Pedersen JS, Korbel JO, Stocsits C, Gruber AR, Hackermüller J, Hertel J, Lindemeyer M, Reiche K, Tanzer A, Ucla C, Wyss C, Antonarakis SE, Denoeud F, Lagarde J, Drenkow J, Kapranov P, Gingeras TR, Guigó R, Snyder M, Gerstein MB, Reymond A, Hofacker IL, Stadler PF | display-authors = 6 | title = Structured RNAs in the ENCODE selected regions of the human genome | journal = Genome Research | volume = 17 | issue = 6 | pages = 852–864 | date = June 2007 | pmid = 17568003 | pmc = 1891344 | doi = 10.1101/gr.5650707 }}</ref><ref name= MorrisKV>{{cite book | veditors = Morris KV | year=2012 | title=Non-coding RNAs and Epigenetic Regulation of Gene Expression: Drivers of Natural Selection | publisher=[[Caister Academic Press]] | isbn= 978-1-904455-94-3}}</ref><ref name="Shahrouki P 2012">{{cite journal | vauthors = Shahrouki P, Larsson E | title = The non-coding oncogene: a case of missing DNA evidence? | journal = Frontiers in Genetics | volume = 3 | pages = 170 | date = 2012 | pmid = 22988449 | pmc = 3439828 | doi = 10.3389/fgene.2012.00170 | doi-access = free }}</ref><!--^{but see}--><ref>{{cite journal | vauthors = van Bakel H, Nislow C, Blencowe BJ, Hughes TR | title = Most "dark matter" transcripts are associated with known genes | journal = PLOS Biology | volume = 8 | issue = 5 | pages = e1000371 | date = May 2010 | pmid = 20502517 | pmc = 2872640 | doi = 10.1371/journal.pbio.1000371 | veditors = Eddy SR | doi-access = free }}</ref>

Many of the newly identified ncRNAs have unknown functions, if any.<ref name="pmid15851066">{{cite journal | vauthors = Hüttenhofer A, Schattner P, Polacek N | title = Non-coding RNAs: hope or hype? | journal = Trends in Genetics | volume = 21 | issue = 5 | pages = 289–297 | date = May 2005 | pmid = 15851066 | doi = 10.1016/j.tig.2005.03.007 }}</ref>

There is no consensus on how much of non-coding transcription is functional: some believe most ncRNAs to be non-functional "junk RNA", spurious transcriptions,<ref name="waste">{{cite journal | vauthors = Brosius J | title = Waste not, want not--transcript excess in multicellular eukaryotes | journal = Trends in Genetics | volume = 21 | issue = 5 | pages = 287–288 | date = May 2005 | pmid = 15851065 | doi = 10.1016/j.tig.2005.02.014 }}</ref><ref name="PalazzoLee2015">{{cite journal | vauthors = Palazzo AF, Lee ES | title = Non-coding RNA: what is functional and what is junk? | journal = Frontiers in Genetics | volume = 6 | pages = 2 | year = 2015 | pmid = 25674102 | pmc = 4306305 | doi = 10.3389/fgene.2015.00002 | doi-access = free }}</ref> while others expect that many non-coding transcripts have functions to be discovered.<ref>{{cite book | vauthors = Mattick J, Amaral P |title=RNA, The Epicenter of Genetic Information : A New Understanding of Molecular Biology |date=2022 |publisher=CRC Press |isbn= 9780367623920}}</ref><ref>{{cite journal | vauthors = Lee H, Zhang Z, Krause HM | title = Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners? | journal = Trends in Genetics | volume = 35 | issue = 12 | pages = 892–902 | date = December 2019 | pmid = 31662190 | doi = 10.1016/j.tig.2019.09.006 | s2cid = 204975291 | doi-access = free }}</ref>

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In mammals it has been found that snoRNAs can also regulate the [[alternative splicing]] of mRNA, for example snoRNA [[Small nucleolar RNA SNORD115|HBII-52]] regulates the splicing of [[5-HT2C receptor|serotonin receptor 2C]].<ref name=Kishore>{{cite journal | vauthors = Kishore S, Stamm S | title = The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C | journal = Science | volume = 311 | issue = 5758 | pages = 230–232 | date = January 2006 | pmid = 16357227 | doi = 10.1126/science.1118265 | s2cid = 44527461 | doi-access = free | bibcode = 2006Sci...311..230K }}</ref>

In nematodes, the [[SmY]] ncRNA appears to be involved in mRNA [[trans-splicing]].<ref>{{Cite journal |last1=Jones |first1=Thomas A. |last2=Otto |first2=Wolfgang |last3=Marz |first3=Manja |last4=Eddy |first4=Sean R. |last5=Stadler |first5=Peter F. |date=2009 |title=A survey of nematode SmY RNAs |url=https://pubmed.ncbi.nlm.nih.gov/19106623/ |journal=RNA Biology |volume=6 |issue=1 |pages=5–8 |doi=10.4161/rna.6.1.7634 |issn=1555-8584 |pmid=19106623}}</ref>

===In DNA replication===

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''Bifunctional RNAs'', or ''dual-function RNAs'', are RNAs that have two distinct functions.<ref name="pmid18042713">{{cite journal | vauthors = Wadler CS, Vanderpool CK | title = A dual function for a bacterial small RNA: SgrS performs base pairing-dependent regulation and encodes a functional polypeptide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 51 | pages = 20454–20459 | date = December 2007 | pmid = 18042713 | pmc = 2154452 | doi = 10.1073/pnas.0708102104 | doi-access = free | bibcode = 2007PNAS..10420454W }}</ref><ref name="pmid19043537">{{cite journal | vauthors = Dinger ME, Pang KC, Mercer TR, Mattick JS | title = Differentiating protein-coding and noncoding RNA: challenges and ambiguities | journal = PLOS Computational Biology | volume = 4 | issue = 11 | pages = e1000176 | date = November 2008 | pmid = 19043537 | pmc = 2518207 | doi = 10.1371/journal.pcbi.1000176 | veditors = McEntyre J | doi-access = free | bibcode = 2008PLSCB...4E0176D }}</ref> The majority of the known bifunctional RNAs are mRNAs that encode both a protein and ncRNAs. However, a growing number of ncRNAs fall into two different ncRNA categories; e.g., [[snoRNA|H/ACA box snoRNA]] and [[miRNA]].<ref name="pmid19043559">{{cite journal | vauthors = Saraiya AA, Wang CC | title = snoRNA, a novel precursor of microRNA in Giardia lamblia | journal = PLOS Pathogens | volume = 4 | issue = 11 | pages = e1000224 | date = November 2008 | pmid = 19043559 | pmc = 2583053 | doi = 10.1371/journal.ppat.1000224 | veditors = Goldberg DE | doi-access = free }}</ref><ref name="pmid19026782">{{cite journal | vauthors = Ender C, Krek A, Friedländer MR, Beitzinger M, Weinmann L, Chen W, Pfeffer S, Rajewsky N, Meister G | display-authors = 6 | title = A human snoRNA with microRNA-like functions | journal = Molecular Cell | volume = 32 | issue = 4 | pages = 519–528 | date = November 2008 | pmid = 19026782 | doi = 10.1016/j.molcel.2008.10.017 | doi-access = free }}</ref>

Two well known examples of bifunctional RNAs are [[SgrS RNA]] and [[RNAIII]]. However, a handful of other bifunctional RNAs are known to exist (e.g., steroid receptor activator/SRA,<ref name="pmid17710122">{{cite journal | vauthors = Leygue E | title = Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer | journal = Nuclear Receptor Signaling | volume = 5 | pages = e006 | date = August 2007 | article-number = nrs.05006 | pmid = 17710122 | pmc = 1948073 | doi = 10.1621/nrs.05006 }}</ref> VegT RNA,<ref name="pmid9012531">{{cite journal | vauthors = Zhang J, King ML | title = Xenopus VegT RNA is localized to the vegetal cortex during oogenesis and encodes a novel T-box transcription factor involved in mesodermal patterning | journal = Development | volume = 122 | issue = 12 | pages = 4119–4129 | date = December 1996 | pmid = 9012531 | doi = 10.1242/dev.122.12.4119 | s2cid = 28462527 }}</ref><ref name="pmid16000384">{{cite journal | vauthors = Kloc M, Wilk K, Vargas D, Shirato Y, Bilinski S, Etkin LD | title = Potential structural role of non-coding and coding RNAs in the organization of the cytoskeleton at the vegetal cortex of Xenopus oocytes | journal = Development | volume = 132 | issue = 15 | pages = 3445–3457 | date = August 2005 | pmid = 16000384 | doi = 10.1242/dev.01919 | doi-access = free }}</ref>

Oskar RNA,<ref name="pmid16835436">{{cite journal | vauthors = Jenny A, Hachet O, Závorszky P, Cyrklaff A, Weston MD, Johnston DS, Erdélyi M, Ephrussi A | display-authors = 6 | title = A translation-independent role of oskar RNA in early Drosophila oogenesis | journal = Development | volume = 133 | issue = 15 | pages = 2827–2833 | date = August 2006 | pmid = 16835436 | doi = 10.1242/dev.02456 | doi-access = free }}</ref> [[ENOD40]],<ref name="pmid17452360">{{cite journal | vauthors = Gultyaev AP, Roussis A | title = Identification of conserved secondary structures and expansion segments in enod40 RNAs reveals new enod40 homologues in plants | journal = Nucleic Acids Research | volume = 35 | issue = 9 | pages = 3144–3152 | year = 2007 | pmid = 17452360 | pmc = 1888808 | doi = 10.1093/nar/gkm173 }}</ref> p53 RNA<ref name="pmid19160491">{{cite journal | vauthors = Candeias MM, Malbert-Colas L, Powell DJ, Daskalogianni C, Maslon MM, Naski N, Bourougaa K, Calvo F, Fåhraeus R | display-authors = 6 | title = P53 mRNA controls p53 activity by managing Mdm2 functions | journal = Nature Cell Biology | volume = 10 | issue = 9 | pages = 1098–1105 | date = September 2008 | pmid = 19160491 | doi = 10.1038/ncb1770 | s2cid = 5122088 }}</ref> [[SR1 RNA]],<ref>{{cite journal | vauthors = Gimpel M, Preis H, Barth E, Gramzow L, Brantl S | title = SR1--a small RNA with two remarkably conserved functions | journal = Nucleic Acids Research | volume = 40 | issue = 22 | pages = 11659–11672 | date = December 2012 | pmid = 23034808 | pmc = 3526287 | doi = 10.1093/nar/gks895 }}</ref> and [[Spot 42 RNA]].<ref name="pmid35239441">{{cite journal | vauthors = Aoyama JJ, Raina M, Zhong A, Storz G | title = Dual-function Spot 42 RNA encodes a 15-amino acid protein that regulates the CRP transcription factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 10 | pagesarticle-number = e2119866119 | date = March 2022 | pmid = 35239441 | pmc = 8916003 | doi = 10.1073/pnas.2119866119 | doi-access = free | bibcode = 2022PNAS..11919866A }}</ref>) Bifunctional RNAs were the subject of a 2011 special issue of [[Biochimie]].<ref>{{cite journal | vauthors = Francastel C, Hubé F | title = Coding or non-coding: Need they be exclusive? | journal = Biochimie | volume = 93 | issue = 11 | pages = vi-vii | date = November 2011 | pmid = 21963143 | doi = 10.1016/S0300-9084(11)00322-1 | url = https://zenodo.org/record/889579 }}</ref>

=== As a hormone ===

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The [[p53]] tumor suppressor is arguably the most important agent in preventing tumor formation and progression. The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. In addition to its crucial role in cancer, p53 has been implicated in other diseases including diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Studies have suggested that p53 expression is subject to regulation by non-coding RNA.<ref name="MorrisKV"/>

Another example of non-coding RNA dysregulated in cancer cells is the long non-coding RNA Linc00707. Linc00707 is upregulated and sponges miRNAs in human bone marrow-derived mesenchymal stem cells,<ref>{{cite journal | vauthors = Jia B, Wang Z, Sun X, Chen J, Zhao J, Qiu X | title = Long noncoding RNA LINC00707 sponges miR-370-3p to promote osteogenesis of human bone marrow-derived mesenchymal stem cells through upregulating WNT2B | journal = Stem Cell Research & Therapy | volume = 10 | issue = 1 | pagesarticle-number = 67 | date = February 2019 | pmid = 30795799 | pmc = 6387535 | doi = 10.1186/s13287-019-1161-9 | doi-access = free }}</ref> gastric cancer<ref>{{cite journal | vauthors = Xie M, Ma T, Xue J, Ma H, Sun M, Zhang Z, Liu M, Liu Y, Ju S, Wang Z, De W | display-authors = 6 | title = The long intergenic non-protein coding RNA 707 promotes proliferation and metastasis of gastric cancer by interacting with mRNA stabilizing protein HuR | journal = Cancer Letters | volume = 443 | pages = 67–79 | date = February 2019 | pmid = 30502359 | doi = 10.1016/j.canlet.2018.11.032 | s2cid = 54611497 }}</ref> or breast cancer,<ref>{{cite journal | vauthors = Li T, Li Y, Sun H | title = MicroRNA-876 is sponged by long noncoding RNA LINC00707 and directly targets metadherin to inhibit breast cancer malignancy | journal = Cancer Management and Research | volume = 11 | pages = 5255–5269 | date = 2019-06-06 | pmid = 31239777 | pmc = 6559252 | doi = 10.2147/cmar.s210845 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yuan RX, Bao D, Zhang Y | title = Linc00707 promotes cell proliferation, invasion, and migration via the miR-30c/CTHRC1 regulatory loop in breast cancer | journal = European Review for Medical and Pharmacological Sciences | volume = 24 | issue = 9 | pages = 4863–4872 | date = May 2020 | pmid = 32432749 | doi = 10.26355/eurrev_202005_21175 | s2cid = 218759508 }}</ref> and thus promotes osteogenesis, contributes to hepatocellular carcinoma progression, promotes proliferation and metastasis, or indirectly regulates expression of proteins involved in cancer aggressiveness, respectively.

===Prader–Willi syndrome===

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==Distinction between functional RNA (fRNA) and ncRNA==

Scientists have started to distinguish ''functional RNA'' (''fRNA'') from ncRNA, to describe regions functional at the RNA level that may or may not be stand-alone RNA transcripts.<ref>{{cite journal | vauthors = Carter RJ, Dubchak I, Holbrook SR | title = A computational approach to identify genes for functional RNAs in genomic sequences | journal = Nucleic Acids Research | volume = 29 | issue = 19 | pages = 3928–3938 | date = October 2001 | pmid = 11574674 | pmc = 60242 | doi = 10.1093/nar/29.19.3928 }}</ref><ref>{{cite journal | vauthors = Pedersen JS, Bejerano G, Siepel A, Rosenbloom K, Lindblad-Toh K, Lander ES, Kent J, Miller W, Haussler D | display-authors = 6 | title = Identification and classification of conserved RNA secondary structures in the human genome | journal = PLOS Computational Biology | volume = 2 | issue = 4 | pages = e33 | date = April 2006 | pmid = 16628248 | pmc = 1440920 | doi = 10.1371/journal.pcbi.0020033 | doi-access = free | bibcode = 2006PLSCB...2...33P }}</ref><ref>{{cite journal | vauthors = Thomas JM, Horspool D, Brown G, Tcherepanov V, Upton C | title = GraphDNA: a Java program for graphical display of DNA composition analyses | journal = BMC Bioinformatics | volume = 8 | pagesarticle-number = 21 | date = January 2007 | pmid = 17244370 | pmc = 1783863 | doi = 10.1186/1471-2105-8-21 | doi-access = free }}</ref> This implies that fRNA (such as riboswitches, [[SECIS element]]s, and other cis-regulatory regions) is not ncRNA. Yet fRNA could also include [[Messenger RNA|mRNA]], as this is RNA coding for protein, and hence is functional. Additionally [[Systematic Evolution of Ligands by Exponential Enrichment|artificially evolved RNAs]] also fall under the fRNA umbrella term. Some publications<ref name="Edd01" /> state that ''ncRNA'' and ''fRNA'' are nearly synonymous, however others have pointed out that a large proportion of annotated ncRNAs likely have no function.<ref name="waste"/><ref name="PalazzoLee2015"/> It also has been suggested to simply use the term ''RNA'', since the distinction from a protein coding RNA ([[messenger RNA]]) is already given by the qualifier ''mRNA''.<ref>{{cite journal | vauthors = Brosius J, Raabe CA | title = What is an RNA? A top layer for RNA classification | journal = RNA Biology | volume = 13 | issue = 2 | pages = 140–144 | date = February 2015 | pmid = 26818079 | pmc = 4829331 | doi = 10.1080/15476286.2015.1128064 }}</ref> This eliminates the ambiguity when addressing a gene "encoding a non-coding" RNA. Besides, there may be a number of ncRNAs that are misannoted in published literature and datasets.<ref>{{cite journal | vauthors = Ji Z, Song R, Regev A, Struhl K | title = Many lncRNAs, 5'UTRs, and pseudogenes are translated and some are likely to express functional proteins | journal = eLife | volume = 4 | pagesarticle-number = e08890 | date = December 2015 | pmid = 26687005 | pmc = 4739776 | doi = 10.7554/eLife.08890 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tosar JP, Rovira C, Cayota A | title = Non-coding RNA fragments account for the majority of annotated piRNAs expressed in somatic non-gonadal tissues | language = En | journal = Communications Biology | volume = 1 | issue = 1 | pagesarticle-number = 2 | date = 2018-01-22 | pmid = 30271890 | pmc = 6052916 | doi = 10.1038/s42003-017-0001-7 }}</ref><ref>{{cite journal | vauthors = Housman G, Ulitsky I | title = Methods for distinguishing between protein-coding and long noncoding RNAs and the elusive biological purpose of translation of long noncoding RNAs | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1859 | issue = 1 | pages = 31–40 | date = January 2016 | pmid = 26265145 | doi = 10.1016/j.bbagrm.2015.07.017 }}</ref>

== See also ==