{{short description|Non-protein coding transcripts longer than 200 nucleotides}} {{cs1 config|name-list-style=vanc|display-authors=6}} thumb|348x348px|Different types of long non-coding RNAs.<ref name="Fernandes_2019">{{cite journal | vauthors = Fernandes JC, Acuña SM, Aoki JI, Floeter-Winter LM, Muxel SM | title = Long Non-Coding RNAs in the Regulation of Gene Expression: Physiology and Disease | journal = Non-Coding RNA | volume = 5 | issue = 1 | page = 17 | date = February 2019 | pmid = 30781588 | pmc = 6468922 | doi = 10.3390/ncrna5010017 | doi-access = free }}</ref> '''Long non-coding RNAs''' ('''long ncRNAs''', '''lncRNA''') are a type of RNA, generally defined as transcripts of more than 200 nucleotides that are not translated into protein.<ref>{{cite journal | vauthors = Perkel JM | title = Visiting "noncodarnia" | journal = BioTechniques | volume = 54 | issue = 6 | pages = 301, 303–301, 304 | date = June 2013 | pmid = 23750541 | doi = 10.2144/000114037 | quote = "We're calling long noncoding RNAs a class, when actually the only definition is that they are longer than 200 bp," says Ana Marques, a Research Fellow at the University of Oxford who uses evolutionary approaches to understand lncRNA function. | type = paper | doi-access = free }}</ref> This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs.<ref name="Ma_2013">{{cite journal | vauthors = Ma L, Bajic VB, Zhang Z | title = On the classification of long non-coding RNAs | journal = RNA Biology | volume = 10 | issue = 6 | pages = 925–933 | date = June 2013 | pmid = 23696037 | pmc = 4111732 | doi = 10.4161/rna.24604 }}</ref> Given that some genuine lncRNAs may encode small proteins, the latest definition of lncRNA is a class of transcripts of over 200 nucleotides that have no or limited coding capacity.<ref>{{Cite journal | vauthors = Ma L, Zhang Z | title = The contribution of databases towards understanding the universe of long non-coding RNAs | journal = Nature Reviews. Molecular Cell Biology | volume = 24 | issue = 9 | pages = 601–602 | date = September 2023 | pmid = 37147495 | doi = 10.1038/s41580-023-00612-z | issn = 1471-0080 | s2cid = 258528357 }}</ref>
The definition of lncRNAs differs from that of other RNAs such as siRNAs, mRNAs, miRNAs, and snoRNAs because it is not connected to the function of the RNA. A lncRNA is any transcript that is not one of the other well-characterized RNAs and is longer than 200-500 nucleotides. Some scientists think that most lncRNAs do not have a biologically relevant function because they are transcripts of junk DNA.<ref name="Palazzo_2015" /><ref name="Ponting&Haerty2022" />
==Abundance== Long non-coding transcripts are found in many species. Large-scale complementary DNA (cDNA) sequencing projects such as FANTOM reveal the complexity of these transcripts in humans.<ref name="Carninci_2005" /> The FANTOM3 project identified ~35,000 non-coding transcripts that bear many signatures of messenger RNAs, including 5' capping, splicing, and poly-adenylation, but have little or no open reading frame (ORF).<ref name="Carninci_2005" /> This number represents a conservative lower estimate, since it omitted many singleton transcripts and non-polyadenylated transcripts (tiling array data shows more than 40% of transcripts are non-polyadenylated).<ref>{{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 | 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 | bibcode = 2005Sci...308.1149C | s2cid = 13047538 }}</ref> Identifying ncRNAs within these cDNA libraries is challenging since it can be difficult to distinguish protein-coding transcripts from non-coding transcripts. It has been suggested through multiple studies that testis,<ref name="Necsulea_2014">{{cite journal | vauthors = Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grützner F, Kaessmann H | title = The evolution of lncRNA repertoires and expression patterns in tetrapods | journal = Nature | volume = 505 | issue = 7485 | pages = 635–640 | date = January 2014 | pmid = 24463510 | doi = 10.1038/nature12943 | bibcode = 2014Natur.505..635N | s2cid = 1179101 | url = http://infoscience.epfl.ch/record/197210 }}</ref> and neural tissues express the greatest amount of long non-coding RNAs of any tissue type.<ref name="Derrien_2012">{{cite journal | vauthors = Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R | title = The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression | journal = Genome Research | volume = 22 | issue = 9 | pages = 1775–1789 | date = September 2012 | pmid = 22955988 | pmc = 3431493 | doi = 10.1101/gr.132159.111 }}</ref> Using FANTOM5, 27,919 long ncRNAs have been identified in various human sources.<ref>{{cite journal | vauthors = Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, Lizio M, Kawaji H, Kasukawa T, Itoh M, Burroughs AM, Noma S, Djebali S, Alam T, Medvedeva YA, Testa AC, Lipovich L, Yip CW, Abugessaisa I, Mendez M, Hasegawa A, Tang D, Lassmann T, Heutink P, Babina M, Wells CA, Kojima S, Nakamura Y, Suzuki H, Daub CO, de Hoon MJ, Arner E, Hayashizaki Y, Carninci P, Forrest AR | title = An atlas of human long non-coding RNAs with accurate 5′ ends | journal = Nature | volume = 543 | issue = 7644 | pages = 199–204 | date = March 2017 | pmid = 28241135 | pmc = 6857182 | doi = 10.1038/nature21374 | bibcode = 2017Natur.543..199H }}</ref>
Quantitatively, these transcripts demonstrate ~10-fold lower abundance than mRNAs,<ref name="Cabili_2011">{{cite journal | vauthors = Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL | title = Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses | journal = Genes & Development | volume = 25 | issue = 18 | pages = 1915–1927 | date = September 2011 | pmid = 21890647 | pmc = 3185964 | doi = 10.1101/gad.17446611 }}</ref><ref>{{cite journal | vauthors = Ravasi T, Suzuki H, Pang KC, Katayama S, Furuno M, Okunishi R, Fukuda S, Ru K, Frith MC, Gongora MM, Grimmond SM, Hume DA, Hayashizaki Y, Mattick JS | title = Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome | journal = Genome Research | volume = 16 | issue = 1 | pages = 11–19 | date = January 2006 | pmid = 16344565 | pmc = 1356124 | doi = 10.1101/gr.4200206 }}</ref> much of which is explained by higher cell-to-cell variation of expression levels of lncRNAs in the individual cells, when compared to protein-coding genes and well-characterized non-coding genes.<ref>{{cite journal | vauthors = Yunusov D, Anderson L, DaSilva LF, Wysocka J, Ezashi T, Roberts RM, Verjovski-Almeida S | title = HIPSTR and thousands of lncRNAs are heterogeneously expressed in human embryos, primordial germ cells and stable cell lines | journal = Scientific Reports | volume = 6 | date = September 2016 | pmid = 27605307 | pmc = 5015059 | doi = 10.1038/srep32753 | article-number = 32753 | bibcode = 2016NatSR...632753Y }}</ref> This is consistent with the idea that many of these transcripts are non-functional spurious transcripts and the transcribed regions are not genes by any standard definition.<ref name="Palazzo_2015" /><ref name="Ponting&Haerty2022" />
In general, the majority (~78%) of lncRNAs are characterized as tissue-specific, as opposed to only ~19% of mRNAs.<ref name="Cabili_2011" /> In addition to higher tissue specificity, lncRNAs are characterized by higher developmental stage specificity,<ref>{{cite journal | vauthors = Yan L, Yang M, Guo H, Yang L, Wu J, Li R, Liu P, Lian Y, Zheng X, Yan J, Huang J, Li M, Wu X, Wen L, Lao K, Li R, Qiao J, Tang F | title = Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 9 | pages = 1131–1139 | date = September 2013 | pmid = 23934149 | doi = 10.1038/nsmb.2660 | s2cid = 29209966 }}</ref> and cell subtype specificity in tissues such as human neocortex<ref>{{cite journal | vauthors = Liu SJ, Nowakowski TJ, Pollen AA, Lui JH, Horlbeck MA, Attenello FJ, He D, Weissman JS, Kriegstein AR, Diaz AA, Lim DA | title = Single-cell analysis of long non-coding RNAs in the developing human neocortex | journal = Genome Biology | volume = 17 | date = April 2016 | pmid = 27081004 | pmc = 4831157 | doi = 10.1186/s13059-016-0932-1 | article-number = 67 | doi-access = free }}</ref> and other parts of the brain, regulating correct brain development and function.<ref>{{cite journal | vauthors = Aliperti V, Skonieczna J, Cerase A | title = Long Non-Coding RNA (lncRNA) Roles in Cell Biology, Neurodevelopment and Neurological Disorders | journal = Non-Coding RNA | volume = 7 | issue = 2 | page = 36 | date = June 2021 | pmid = 34204536 | pmc = 8293397 | doi = 10.3390/ncrna7020036 | doi-access = free }}</ref> In 2022, a comprehensive integration of lncRNAs from existing databases, revealed that there are 95,243 lncRNAs and 323,950 transcripts in humans.<ref>{{Cite journal | vauthors = Li Z, Liu L, Feng C, Qin Y, Xiao J, Zhang Z, Ma L | title = LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations | journal = Nucleic Acids Research | volume = 51 | issue = D1 | pages = D186–D191 | date = 2023-01-06 | pmid = 36330950 | pmc = 9825513 | doi = 10.1093/nar/gkac999 | issn = 1362-4962 }}</ref>
In comparison to mammals relatively few studies have focused on the prevalence of lncRNAs in plants. However an extensive study considering 37 higher plant species and six algae identified ~200,000 non-coding transcripts using an ''in-silico'' approach,<ref>{{cite journal | vauthors = Paytuví Gallart A, Hermoso Pulido A, Anzar Martínez de Lagrán I, Sanseverino W, Aiese Cigliano R | title = GREENC: a Wiki-based database of plant lncRNAs | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D1161–D1166 | date = January 2016 | pmid = 26578586 | pmc = 4702861 | doi = 10.1093/nar/gkv1215 }}</ref> which also established the associated Green Non-Coding Database (GreeNC), a repository of plant lncRNAs.
==Genomic organization== In 2005 the landscape of the mammalian genome was described as numerous 'foci' of transcription that are separated by long stretches of intergenic space.<ref name="Carninci_2005" /> While some long ncRNAs are located within the intergenic stretches, the majority are overlapping sense and antisense transcripts that often include protein-coding genes,<ref name="Kapranov_2007">{{cite journal | vauthors = Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermüller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR | title = RNA maps reveal new RNA classes and a possible function for pervasive transcription | journal = Science | volume = 316 | issue = 5830 | pages = 1484–1488 | date = June 2007 | pmid = 17510325 | doi = 10.1126/science.1138341 | bibcode = 2007Sci...316.1484K | s2cid = 25609839 | url = http://lips.informatik.uni-leipzig.de/?q=node/1519 }}</ref> giving rise to a complex hierarchy of overlapping isoforms.<ref>{{cite journal | vauthors = Kapranov P, Willingham AT, Gingeras TR | title = Genome-wide transcription and the implications for genomic organization | journal = Nature Reviews Genetics | volume = 8 | issue = 6 | pages = 413–423 | date = June 2007 | pmid = 17486121 | doi = 10.1038/nrg2083 | s2cid = 6465064 }}</ref> Genomic sequences within these transcriptional foci are often shared within a number of coding and non-coding transcripts in the sense and antisense directions<ref name="Birney_2007" /> For example, 3012 out of 8961 cDNAs previously annotated as truncated coding sequences within FANTOM2 were later designated as genuine ncRNA variants of protein-coding cDNAs.<ref name="Carninci_2005" /> While the abundance and conservation of these arrangements suggest they have biological relevance, the complexity of these foci frustrates easy evaluation.
The GENCODE consortium has collated and analysed a comprehensive set of human lncRNA annotations and their genomic organisation, modifications, cellular locations and tissue expression profiles.<ref name="Derrien_2012" /> Their analysis indicates human lncRNAs show a bias toward two-exon transcripts.<ref name="Derrien_2012" />
==Translation== There has been considerable debate about whether lncRNAs have been misannotated and do in fact encode proteins. Several lncRNAs have been found to in fact encode for peptides with biologically significant function.<ref>{{cite journal | vauthors = Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, Kasaragod P, Shelton JM, Liou J, Bassel-Duby R, Olson EN | title = A micropeptide encoded by a putative long noncoding RNA regulates muscle performance | journal = Cell | volume = 160 | issue = 4 | pages = 595–606 | date = February 2015 | pmid = 25640239 | pmc = 4356254 | doi = 10.1016/j.cell.2015.01.009 }}</ref><ref>{{cite journal | vauthors = Matsumoto A, Pasut A, Matsumoto M, Yamashita R, Fung J, Monteleone E, Saghatelian A, Nakayama KI, Clohessy JG, Pandolfi PP | title = mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide | journal = Nature | volume = 541 | issue = 7636 | pages = 228–232 | date = January 2017 | pmid = 28024296 | doi = 10.1038/nature21034 | bibcode = 2017Natur.541..228M | s2cid = 205253245 }}</ref><ref>{{cite journal | vauthors = Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, Tsai SQ, Joung JK, Saghatelian A, Schier AF | title = Toddler: an embryonic signal that promotes cell movement via Apelin receptors | journal = Science | volume = 343 | issue = 6172 | date = February 2014 | pmid = 24407481 | pmc = 4107353 | doi = 10.1126/science.1248636 | article-number = 1248636 }}</ref> Ribosome profiling studies have suggested that anywhere from 40% to 90% of annotated lncRNAs are in fact translated,<ref>{{cite journal | vauthors = Ingolia NT, Lareau LF, Weissman JS | title = Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes | journal = Cell | volume = 147 | issue = 4 | pages = 789–802 | date = November 2011 | pmid = 22056041 | pmc = 3225288 | doi = 10.1016/j.cell.2011.10.002 | bibcode = 2011Cell..147..789I }}</ref><ref name="Ji_2015">{{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 | date = December 2015 | pmid = 26687005 | pmc = 4739776 | doi = 10.7554/eLife.08890 | article-number = e08890 | doi-access = free }}</ref> although there is disagreement about the correct method for analyzing ribosome profiling data.<ref>{{cite journal | vauthors = Guttman M, Russell P, Ingolia NT, Weissman JS, Lander ES | title = Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins | journal = Cell | volume = 154 | issue = 1 | pages = 240–251 | date = July 2013 | pmid = 23810193 | pmc = 3756563 | doi = 10.1016/j.cell.2013.06.009 | bibcode = 2013Cell..154..240G }}</ref> Additionally, it is thought that many of the peptides produced by lncRNAs may be highly unstable and without biological function.<ref name="Ji_2015" />
==Conservation== The sequences of most long non-coding transcripts are not conserved, which supports the idea that most of them are spurious transcripts with no biological function. Initial studies into lncRNA conservation noted that some of them were enriched for conserved sequence elements,<ref>{{cite journal | vauthors = Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES | title = Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals | journal = Nature | volume = 458 | issue = 7235 | pages = 223–227 | date = March 2009 | pmid = 19182780 | pmc = 2754849 | doi = 10.1038/nature07672 | bibcode = 2009Natur.458..223G }}</ref> depleted in substitution and insertion/deletion rates<ref>{{cite journal | vauthors = Ponjavic J, Ponting CP, Lunter G | title = Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs | journal = Genome Research | volume = 17 | issue = 5 | pages = 556–565 | date = May 2007 | pmid = 17387145 | pmc = 1855172 | doi = 10.1101/gr.6036807 }}</ref> and depleted in rare frequency variants,<ref>{{cite journal | vauthors = Haerty W, Ponting CP | title = Mutations within lncRNAs are effectively selected against in fruitfly but not in human | journal = Genome Biology | volume = 14 | issue = 5 | date = May 2013 | pmid = 23710818 | pmc = 4053968 | doi = 10.1186/gb-2013-14-5-r49 | article-number = R49 | doi-access = free }}</ref> indicative of purifying selection maintaining lncRNA function. However, further investigations into vertebrate lncRNAs revealed that while some lncRNAs are conserved in sequence, they are not conserved in transcription.<ref>{{cite journal | vauthors = Washietl S, Kellis M, Garber M | title = Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals | journal = Genome Research | volume = 24 | issue = 4 | pages = 616–628 | date = April 2014 | pmid = 24429298 | pmc = 3975061 | doi = 10.1101/gr.165035.113 }}</ref><ref>{{cite journal | vauthors = Kutter C, Watt S, Stefflova K, Wilson MD, Goncalves A, Ponting CP, Odom DT, Marques AC | title = Rapid turnover of long noncoding RNAs and the evolution of gene expression | journal = PLOS Genetics | volume = 8 | issue = 7 | article-number = e1002841 | date = 2012 | pmid = 22844254 | pmc = 3406015 | doi = 10.1371/journal.pgen.1002841 | doi-access = free }}</ref><ref name="Necsulea_2014" /> In other words, even when the sequence of a human lncRNA is conserved in another vertebrate species, there is often no transcription of a lncRNA in the orthologous genomic region. Some argue that these observations suggest non-functionality of the majority of lncRNAs,<ref>{{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>{{cite journal | vauthors = Struhl K | title = Transcriptional noise and the fidelity of initiation by RNA polymerase II | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 2 | pages = 103–105 | date = February 2007 | pmid = 17277804 | doi = 10.1038/nsmb0207-103 | s2cid = 29398526 }}</ref><ref name="Palazzo_2015">{{cite journal | vauthors = Palazzo AF, Lee ES | title = Non-coding RNA: what is functional and what is junk? | journal = Frontiers in Genetics | volume = 6 | page = 2 | date = 2015-01-26 | pmid = 25674102 | pmc = 4306305 | doi = 10.3389/fgene.2015.00002 | doi-access = free }}</ref> while others argue that they may be indicative of rapid species-specific adaptive selection.<ref>{{cite journal | vauthors = Kapusta A, Feschotte C | title = Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implications | journal = Trends in Genetics | volume = 30 | issue = 10 | pages = 439–452 | date = October 2014 | pmid = 25218058 | pmc = 4464757 | doi = 10.1016/j.tig.2014.08.004 }}</ref>
While most long non-coding transcripts are not conserved, it is important to note that still, hundreds of lncRNAs are conserved at the sequence level. There have been several attempts to delineate the different categories of selection signatures seen amongst lncRNAs including: lncRNAs with strong sequence conservation across the entire length of the gene, lncRNAs in which only a portion of the transcript (e.g. 5′ end, splice sites) is conserved, and lncRNAs that are transcribed from syntenic regions of the genome but have no recognizable sequence similarity.<ref>{{cite journal | vauthors = Chen J, Shishkin AA, Zhu X, Kadri S, Maza I, Guttman M, Hanna JH, Regev A, Garber M | title = Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs | journal = Genome Biology | volume = 17 | date = February 2016 | pmid = 26838501 | pmc = 4739325 | doi = 10.1186/s13059-016-0880-9 | article-number = 19 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ulitsky I | title = Evolution to the rescue: using comparative genomics to understand long non-coding RNAs | journal = Nature Reviews Genetics | volume = 17 | issue = 10 | pages = 601–614 | date = October 2016 | pmid = 27573374 | doi = 10.1038/nrg.2016.85 | s2cid = 13833164 }}</ref><ref>{{cite journal | vauthors = Hezroni H, Koppstein D, Schwartz MG, Avrutin A, Bartel DP, Ulitsky I | title = Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species | journal = Cell Reports | volume = 11 | issue = 7 | pages = 1110–1122 | date = May 2015 | pmid = 25959816 | pmc = 4576741 | doi = 10.1016/j.celrep.2015.04.023 | bibcode = 2015CellR..11.1110H }}</ref> Additionally, there have been attempts to identify conserved secondary structures in lncRNAs, though these studies have currently given way to conflicting results.<ref>{{cite journal | vauthors = Johnsson P, Lipovich L, Grandér D, Morris KV | title = Evolutionary conservation of long non-coding RNAs; sequence, structure, function | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1840 | issue = 3 | pages = 1063–1071 | date = March 2014 | pmid = 24184936 | pmc = 3909678 | doi = 10.1016/j.bbagen.2013.10.035 }}</ref><ref>{{cite journal | vauthors = Rivas E, Clements J, Eddy SR | title = A statistical test for conserved RNA structure shows lack of evidence for structure in lncRNAs | journal = Nature Methods | volume = 14 | issue = 1 | pages = 45–48 | date = January 2017 | pmid = 27819659 | pmc = 5554622 | doi = 10.1038/nmeth.4066 }}</ref> Several of the most well studied lncRNA have indicated conservation of structure within the functional domains of lncRNA, with lack of sequence similarity across species.<ref>{{Cite journal | vauthors = Owens MC, Clark SC, Yankey A, Somarowthu S | title = Identifying Structural Domains and Conserved Regions in the Long Non-Coding RNA lncTCF7 | journal = International Journal of Molecular Sciences | volume = 20 | issue = 19 | page = 4770 | date = 2019-09-26 | pmid = 31561429 | pmc = 6801803 | doi = 10.3390/ijms20194770 | language = en | doi-access = free | issn = 1422-0067 }}</ref>
== Functions == Some groups have claimed that the majority of long noncoding RNAs in mammals are likely to be functional,<ref name="Mercer_2009">{{cite journal | vauthors = Mercer TR, Dinger ME, Mattick JS | title = Long non-coding RNAs: insights into functions | journal = Nature Reviews Genetics | volume = 10 | issue = 3 | pages = 155–159 | date = March 2009 | pmid = 19188922 | doi = 10.1038/nrg2521 | s2cid = 18441501 }}</ref><ref name="Dinger_2009">{{cite journal | vauthors = Dinger ME, Amaral PP, Mercer TR, Mattick JS | title = Pervasive transcription of the eukaryotic genome: functional indices and conceptual implications | journal = Briefings in Functional Genomics & Proteomics | volume = 8 | issue = 6 | pages = 407–423 | date = November 2009 | pmid = 19770204 | doi = 10.1093/bfgp/elp038 | doi-access = free }}</ref> but other groups have claimed the opposite.<ref name="Palazzo_2015" /><ref name = Ponting&Haerty2022>{{cite journal | vauthors = Ponting CP, Haerty W | title = Genome-Wide Analysis of Human Long Noncoding RNAs: A Provocative Review | journal = Annual Review of Genomics and Human Genetics | volume = 23 | pages = 153–172 | date = Aug 2022 | pmid = 35395170 | doi = 10.1146/annurev-genom-112921-123710 | doi-access = free | hdl = 20.500.11820/ede40d70-b99c-42b0-a378-3b9b7b256a1b | hdl-access = free }}</ref> This is an active area of research.
Some lncRNAs have been functionally annotated in LncRNAdb (a database of literature described lncRNAs),<ref name="Amaral_2011">{{cite journal | vauthors = Amaral PP, Clark MB, Gascoigne DK, Dinger ME, Mattick JS | title = lncRNAdb: a reference database for long noncoding RNAs | journal = Nucleic Acids Research | volume = 39 | issue = Database issue | pages = D146–D151 | date = January 2011 | pmid = 21112873 | pmc = 3013714 | doi = 10.1093/nar/gkq1138 }}</ref><ref>{{cite journal | vauthors = Quek XC, Thomson DW, Maag JL, Bartonicek N, Signal B, Clark MB, Gloss BS, Dinger ME | title = lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs | journal = Nucleic Acids Research | volume = 43 | issue = Database issue | pages = D168–D173 | date = January 2015 | pmid = 25332394 | pmc = 4384040 | doi = 10.1093/nar/gku988 }}</ref> with the majority of these being described in humans. Over 2600 human lncRNAs with experimental evidences have been community-curated in LncRNAWiki (a wiki-based, publicly editable and open-content platform for community curation of human lncRNAs).<ref name="Liu_2022">{{Cite journal | vauthors = Liu L, Li Z, Liu C, Zou D, Li Q, Feng C, Jing W, Luo S, Zhang Z, Ma L | title = LncRNAWiki 2.0: a knowledgebase of human long non-coding RNAs with enhanced curation model and database system | journal = Nucleic Acids Research | volume = 50 | issue = D1 | pages = D190–D195 | date = 2022-01-07 | pmid = 34751395 | pmc = 8728265 | doi = 10.1093/nar/gkab998 | issn = 1362-4962 }}</ref> According to the curation of functional mechanisms of lncRNAs based on the literatures, lncRNAs are extensively reported to be involved in ceRNA regulation, transcriptional regulation, and epigenetic regulation.<ref name="Liu_2022" /> A further large-scale sequencing study provides evidence that many transcripts thought to be lncRNAs may, in fact, be translated into proteins.<ref>{{cite journal | vauthors = Smith JE, Alvarez-Dominguez JR, Kline N, Huynh NJ, Geisler S, Hu W, Coller J, Baker KE | title = Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae | journal = Cell Reports | volume = 7 | issue = 6 | pages = 1858–1866 | date = June 2014 | pmid = 24931603 | pmc = 4105149 | doi = 10.1016/j.celrep.2014.05.023 }}</ref>
===In the regulation of gene transcription=== ====In gene-specific transcription==== In eukaryotes, RNA transcription is a tightly regulated process. Noncoding RNAs act upon different aspects of this process, targeting transcriptional modulators, RNA polymerase (RNAP) II and even the DNA duplex to regulate gene expression.<ref name="Goodrich_2006">{{cite journal | vauthors = Goodrich JA, Kugel JF | title = Non-coding-RNA regulators of RNA polymerase II transcription | journal = Nature Reviews Molecular Cell Biology | volume = 7 | issue = 8 | pages = 612–616 | date = August 2006 | pmid = 16723972 | doi = 10.1038/nrm1946 | bibcode = 2006NRMCB...7..612G | s2cid = 22274894 }}</ref><ref name="Bernard_2022">{{cite journal | vauthors = Bernard L, Dubois A, Heurtier V, Fischer V, Gonzalez I, Chervova A, Tachtsidi A, Gil N, Owens N, Bates LE, Vandormael-Pournin S, Silva JC, Ulitsky I, Cohen-Tannoudji M, Navarro P | title = OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency | journal = Nucleic Acids Research | volume = 50 | issue = 13 | pages = 7367–7379 | date = July 2022 | pmid = 35762231 | pmc = 9303268 | doi = 10.1093/nar/gkac550 | hdl = 20.500.11820/19e92fef-5d5c-4b43-b73a-964bae704806 | hdl-access = free }}</ref>
NcRNAs modulate transcription by several mechanisms, including functioning themselves as co-regulators, modifying transcription factor activity, or regulating the association and activity of co-regulators. For example, the noncoding RNA Evf-2 functions as a co-activator for the homeobox transcription factor Dlx2, which plays important roles in forebrain development and neurogenesis.<ref name="Feng_2006">{{cite journal | vauthors = Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD | title = The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator | journal = Genes & Development | volume = 20 | issue = 11 | pages = 1470–1484 | date = June 2006 | pmid = 16705037 | pmc = 1475760 | doi = 10.1101/gad.1416106 }}</ref><ref>{{cite journal | vauthors = Panganiban G, Rubenstein JL | title = Developmental functions of the Distal-less/Dlx homeobox genes | journal = Development | volume = 129 | issue = 19 | pages = 4371–4386 | date = October 2002 | pmid = 12223397 | doi = 10.1242/dev.129.19.4371 | url = http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=12223397 | url-access = subscription }}</ref> Sonic hedgehog induces transcription of Evf-2 from an ultra-conserved element located between the Dlx5 and Dlx6 genes during forebrain development.<ref name="Feng_2006" /> Evf-2 then recruits the Dlx2 transcription factor to the same ultra-conserved element whereby Dlx2 subsequently induces expression of Dlx5. The existence of other similar ultra- or highly conserved elements within the mammalian genome that are both transcribed and fulfill enhancer functions suggest Evf-2 may be illustrative of a generalised mechanism that regulates developmental genes with complex expression patterns during vertebrate growth.<ref>{{cite journal | vauthors = Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM | title = In vivo enhancer analysis of human conserved non-coding sequences | journal = Nature | volume = 444 | issue = 7118 | pages = 499–502 | date = November 2006 | pmid = 17086198 | doi = 10.1038/nature05295 | bibcode = 2006Natur.444..499P | osti = 919760 | s2cid = 4307332 | url = https://digital.library.unt.edu/ark:/67531/metadc895300/ }}</ref><ref>{{cite journal | vauthors = Visel A, Prabhakar S, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Afzal V, Rubin EM, Pennacchio LA | title = Ultraconservation identifies a small subset of extremely constrained developmental enhancers | journal = Nature Genetics | volume = 40 | issue = 2 | pages = 158–160 | date = February 2008 | pmid = 18176564 | pmc = 2647775 | doi = 10.1038/ng.2007.55 }}</ref> Indeed, the transcription and expression of similar non-coding ultraconserved elements was shown to be abnormal in human leukaemia and to contribute to apoptosis in colon cancer cells, suggesting their involvement in tumorigenesis in like fashion to protein-coding RNA.<ref>{{cite journal | vauthors = Pibouin L, Villaudy J, Ferbus D, Muleris M, Prospéri MT, Remvikos Y, Goubin G | title = Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas | journal = Cancer Genetics and Cytogenetics | volume = 133 | issue = 1 | pages = 55–60 | date = February 2002 | pmid = 11890990 | doi = 10.1016/S0165-4608(01)00634-3 }}</ref><ref name="Calin_2007">{{cite journal | vauthors = Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M, Tili E, Rossi S, Taccioli C, Pichiorri F, Liu X, Zupo S, Herlea V, Gramantieri L, Lanza G, Alder H, Rassenti L, Volinia S, Schmittgen TD, Kipps TJ, Negrini M, Croce CM | title = Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas | journal = Cancer Cell | volume = 12 | issue = 3 | pages = 215–229 | date = September 2007 | pmid = 17785203 | doi = 10.1016/j.ccr.2007.07.027 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Zhang T, Yu H, Bai Y, Guo Y | title = Mutation density analyses on long noncoding RNA reveal comparable patterns to protein-coding RNA and prognostic value | journal = Computational and Structural Biotechnology Journal | volume = 21 | pages = 4887–4894 | date = 2023 | pmid = 37860228 | pmc = 10582829 | doi = 10.1016/j.csbj.2023.09.027 | issn = 2001-0370 }}</ref>
Local ncRNAs can also recruit transcriptional programmes to regulate adjacent protein-coding gene expression.
The RNA binding protein TLS binds and inhibits the CREB binding protein and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1. The recruitment of TLS to the promoter of cyclin D1 is directed by long ncRNAs expressed at low levels and tethered to 5' regulatory regions in response to DNA damage signals.<ref>{{cite journal | vauthors = Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, Tempst P, Rosenfeld MG, Glass CK, Kurokawa R | title = Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription | journal = Nature | volume = 454 | issue = 7200 | pages = 126–130 | date = July 2008 | pmid = 18509338 | pmc = 2823488 | doi = 10.1038/nature06992 | bibcode = 2008Natur.454..126W }}</ref> Moreover, these local ncRNAs act cooperatively as ligands to modulate the activities of TLS. In the broad sense, this mechanism allows the cell to harness RNA-binding proteins, which make up one of the largest classes within the mammalian proteome, and integrate their function in transcriptional programs. Nascent long ncRNAs have been shown to increase the activity of CREB binding protein, which in turn increases the transcription of that ncRNA.<ref>{{cite journal | vauthors = Adelman K, Egan E | title = Non-coding RNA: More uses for genomic junk | journal = Nature | volume = 543 | issue = 7644 | pages = 183–185 | date = March 2017 | pmid = 28277509 | doi = 10.1038/543183a | bibcode = 2017Natur.543..183A | doi-access = free }}</ref> A study found that a lncRNA in the antisense direction of the Apolipoprotein A1 (APOA1) regulates the transcription of APOA1 through epigenetic modifications.<ref>{{cite journal | vauthors = Halley P, Kadakkuzha BM, Faghihi MA, Magistri M, Zeier Z, Khorkova O, Coito C, Hsiao J, Lawrence M, Wahlestedt C | title = Regulation of the apolipoprotein gene cluster by a long noncoding RNA | journal = Cell Reports | volume = 6 | issue = 1 | pages = 222–230 | date = January 2014 | pmid = 24388749 | pmc = 3924898 | doi = 10.1016/j.celrep.2013.12.015 }}</ref>
Recent evidence has raised the possibility that transcription of genes that escape from X-inactivation might be mediated by expression of long non-coding RNA within the escaping chromosomal domains.<ref>{{cite journal | vauthors = Reinius B, Shi C, Hengshuo L, Sandhu KS, Radomska KJ, Rosen GD, Lu L, Kullander K, Williams RW, Jazin E | title = Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse | journal = BMC Genomics | volume = 11 | page = 614 | date = November 2010 | pmid = 21047393 | pmc = 3091755 | doi = 10.1186/1471-2164-11-614 | doi-access = free }}</ref>
====Regulating basal transcription machinery==== NcRNAs also target general transcription factors required for the RNAP II transcription of all genes.<ref name="Goodrich_2006" /> These general factors include components of the initiation complex that assemble on promoters or involved in transcription elongation. A ncRNA transcribed from an upstream minor promoter of the dihydrofolate reductase (DHFR) gene forms a stable RNA-DNA triplex within the major promoter of DHFR to prevent the binding of the transcriptional co-factor TFIIB.<ref>{{cite journal | vauthors = Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A | title = Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript | journal = Nature | volume = 445 | issue = 7128 | pages = 666–670 | date = February 2007 | pmid = 17237763 | doi = 10.1038/nature05519 | bibcode = 2007Natur.445..666M | s2cid = 3012142 | ref = ref17237763 }}</ref> This novel mechanism of regulating gene expression may represent a widespread method of controlling promoter usage, as thousands of RNA-DNA triplexes exist in eukaryotic chromosome.<ref>{{cite journal | vauthors = Lee JS, Burkholder GD, Latimer LJ, Haug BL, Braun RP | title = A monoclonal antibody to triplex DNA binds to eucaryotic chromosomes | journal = Nucleic Acids Research | volume = 15 | issue = 3 | pages = 1047–1061 | date = February 1987 | pmid = 2434928 | pmc = 340507 | doi = 10.1093/nar/15.3.1047 }}</ref> The U1 ncRNA can induce transcription by binding to and stimulating TFIIH to phosphorylate the C-terminal domain of RNAP II.<ref name="Kwek_2002">{{cite journal | vauthors = Kwek KY, Murphy S, Furger A, Thomas B, O'Gorman W, Kimura H, Proudfoot NJ, Akoulitchev A | title = U1 snRNA associates with TFIIH and regulates transcriptional initiation | journal = Nature Structural Biology | volume = 9 | issue = 11 | pages = 800–805 | date = November 2002 | pmid = 12389039 | doi = 10.1038/nsb862 | s2cid = 22982547 }}</ref> In contrast the ncRNA 7SK is able to repress transcription elongation by, in combination with HEXIM1/2, forming an inactive complex that prevents PTEFb from phosphorylating the C-terminal domain of RNAP II,<ref name="Kwek_2002" /><ref>{{cite journal | vauthors = Yang S, Tutton S, Pierce E, Yoon K | title = Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells | journal = Molecular and Cellular Biology | volume = 21 | issue = 22 | pages = 7807–7816 | date = November 2001 | pmid = 11604515 | pmc = 99950 | doi = 10.1128/MCB.21.22.7807-7816.2001 }}</ref><ref>{{cite journal | vauthors = Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q | title = Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA | journal = Molecular Cell | volume = 12 | issue = 4 | pages = 971–982 | date = October 2003 | pmid = 14580347 | doi = 10.1016/S1097-2765(03)00388-5 | doi-access = free }}</ref> repressing global elongation under stressful conditions. These examples, which bypass specific modes of regulation at individual promoters provide a means of quickly affecting global changes in gene expression.
The ability to quickly mediate global changes is also apparent in the rapid expression of non-coding repetitive sequences. The short interspersed nuclear (SINE) Alu elements in humans and analogous B1 and B2 elements in mice have succeeded in becoming the most abundant mobile elements within the genomes, comprising ~10% of the human and ~6% of the mouse genome, respectively.<ref name="Lander_2001" /><ref name="Waterston_2002" /> These elements are transcribed as ncRNAs by RNAP III in response to environmental stresses such as heat shock,<ref>{{cite journal | vauthors = Liu WM, Chu WM, Choudary PV, Schmid CW | title = Cell stress and translational inhibitors transiently increase the abundance of mammalian SINE transcripts | journal = Nucleic Acids Research | volume = 23 | issue = 10 | pages = 1758–1765 | date = May 1995 | pmid = 7784180 | pmc = 306933 | doi = 10.1093/nar/23.10.1758 }}</ref> where they then bind to RNAP II with high affinity and prevent the formation of active pre-initiation complexes.<ref name="Allen_2004">{{cite journal | vauthors = Allen E, Xie Z, Gustafson AM, Sung GH, Spatafora JW, Carrington JC | title = Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana | journal = Nature Genetics | volume = 36 | issue = 12 | pages = 1282–1290 | date = December 2004 | pmid = 15565108 | doi = 10.1038/ng1478 | s2cid = 11997028 }}</ref><ref name="Espinoza_2004">{{cite journal | vauthors = Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA | title = B2 RNA binds directly to RNA polymerase II to repress transcript synthesis | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 9 | pages = 822–829 | date = September 2004 | pmid = 15300239 | doi = 10.1038/nsmb812 | s2cid = 22199826 }}</ref><ref name="Espinoza_2007">{{cite journal | vauthors = Espinoza CA, Goodrich JA, Kugel JF | title = Characterization of the structure, function, and mechanism of B2 RNA, an ncRNA repressor of RNA polymerase II transcription | journal = RNA | volume = 13 | issue = 4 | pages = 583–596 | date = April 2007 | pmid = 17307818 | pmc = 1831867 | doi = 10.1261/rna.310307 }}</ref><ref name="Mariner_2008">{{cite journal | vauthors = Mariner PD, Walters RD, Espinoza CA, Drullinger LF, Wagner SD, Kugel JF, Goodrich JA | title = Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock | journal = Molecular Cell | volume = 29 | issue = 4 | pages = 499–509 | date = February 2008 | pmid = 18313387 | doi = 10.1016/j.molcel.2007.12.013 | doi-access = free }}</ref> This allows for the broad and rapid repression of gene expression in response to stress.<ref name="Allen_2004" /><ref name="Mariner_2008" />
A dissection of the functional sequences within Alu RNA transcripts has drafted a modular structure analogous to the organization of domains in protein transcription factors.<ref name="Shamovsky_2008">{{cite journal | vauthors = Shamovsky I, Nudler E | title = Modular RNA heats up | journal = Molecular Cell | volume = 29 | issue = 4 | pages = 415–417 | date = February 2008 | pmid = 18313380 | doi = 10.1016/j.molcel.2008.02.001 | doi-access = free }}</ref> The Alu RNA contains two 'arms', each of which may bind one RNAP II molecule, as well as two regulatory domains that are responsible for RNAP II transcriptional repression in vitro.<ref name="Mariner_2008" /> These two loosely structured domains may even be concatenated to other ncRNAs such as B1 elements to impart their repressive role.<ref name="Mariner_2008" /> The abundance and distribution of Alu elements and similar repetitive elements throughout the mammalian genome may be partly due to these functional domains being co-opted into other long ncRNAs during evolution, with the presence of functional repeat sequence domains being a common characteristic of several known long ncRNAs including Kcnq1ot1, Xlsirt and Xist.<ref>{{cite journal | vauthors = Mattick JS | title = Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms | journal = BioEssays | volume = 25 | issue = 10 | pages = 930–939 | date = October 2003 | pmid = 14505360 | doi = 10.1002/bies.10332 | citeseerx = 10.1.1.476.7561 }}</ref><ref>{{cite journal | vauthors = Mohammad F, Pandey RR, Nagano T, Chakalova L, Mondal T, Fraser P, Kanduri C | title = Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region | journal = Molecular and Cellular Biology | volume = 28 | issue = 11 | pages = 3713–3728 | date = June 2008 | pmid = 18299392 | pmc = 2423283 | doi = 10.1128/MCB.02263-07 }}</ref><ref>{{cite journal | vauthors = Wutz A, Rasmussen TP, Jaenisch R | title = Chromosomal silencing and localization are mediated by different domains of Xist RNA | journal = Nature Genetics | volume = 30 | issue = 2 | pages = 167–174 | date = February 2002 | pmid = 11780141 | doi = 10.1038/ng820 | s2cid = 28643222 }}</ref><ref>{{cite journal | vauthors = Zearfoss NR, Chan AP, Kloc M, Allen LH, Etkin LD | title = Identification of new Xlsirt family members in the Xenopus laevis oocyte | journal = Mechanisms of Development | volume = 120 | issue = 4 | pages = 503–509 | date = April 2003 | pmid = 12676327 | doi = 10.1016/S0925-4773(02)00459-8 | s2cid = 16781978 | doi-access = free }}</ref>
In addition to heat shock, the expression of SINE elements (including Alu, B1, and B2 RNAs) increases during cellular stress such as viral infection<ref>{{cite journal | vauthors = Singh K, Carey M, Saragosti S, Botchan M | title = Expression of enhanced levels of small RNA polymerase III transcripts encoded by the B2 repeats in simian virus 40-transformed mouse cells | journal = Nature | volume = 314 | issue = 6011 | pages = 553–556 | year = 1985 | pmid = 2581137 | doi = 10.1038/314553a0 | bibcode = 1985Natur.314..553S | s2cid = 4359937 }}</ref> in some cancer cells<ref>{{cite journal | vauthors = Tang RB, Wang HY, Lu HY, Xiong J, Li HH, Qiu XH, Liu HQ | title = Increased level of polymerase III transcribed Alu RNA in hepatocellular carcinoma tissue | journal = Molecular Carcinogenesis | volume = 42 | issue = 2 | pages = 93–96 | date = February 2005 | pmid = 15593371 | doi = 10.1002/mc.20057 | s2cid = 10513502 }}</ref> where they may similarly regulate global changes to gene expression. The ability of Alu and B2 RNA to bind directly to RNAP II provides a broad mechanism to repress transcription.<ref name="Espinoza_2004" /><ref name="Mariner_2008" /> Nevertheless, there are specific exceptions to this global response where Alu or B2 RNAs are not found at activated promoters of genes undergoing induction, such as the heat shock genes.<ref name="Mariner_2008" /> This additional hierarchy of regulation that exempts individual genes from the generalised repression also involves a long ncRNA, heat shock RNA-1 (HSR-1). It was argued that HSR-1 is present in mammalian cells in an inactive state, but upon stress is activated to induce the expression of heat shock genes.<ref name="Shamovsky_2006">{{cite journal | vauthors = Shamovsky I, Nudler E | title = Gene control by large noncoding RNAs | journal = Science's STKE | volume = 2006 | issue = 355 | article-number = pe40 | date = October 2006 | pmid = 17018852 | doi = 10.1126/stke.3552006pe40 | s2cid = 41151259 }}</ref> This activation involves a conformational alteration of HSR-1 in response to rising temperatures, permitting its interaction with the transcriptional activator HSF-1, which trimerizes and induces the expression of heat shock genes.<ref name="Shamovsky_2006" /> In the broad sense, these examples illustrate a regulatory circuit nested within ncRNAs whereby Alu or B2 RNAs repress general gene expression, while other ncRNAs activate the expression of specific genes.
====Transcribed by RNA polymerase III==== Many of the ncRNAs that interact with general transcription factors or RNAP II itself (including 7SK, Alu and B1 and B2 RNAs) are transcribed by RNAP III,<ref name="Dieci_2007">{{cite journal | vauthors = Dieci G, Fiorino G, Castelnuovo M, Teichmann M, Pagano A | title = The expanding RNA polymerase III transcriptome | journal = Trends in Genetics | volume = 23 | issue = 12 | pages = 614–622 | date = December 2007 | pmid = 17977614 | doi = 10.1016/j.tig.2007.09.001 | hdl = 11381/1706964 | hdl-access = free }}</ref> uncoupling their expression from RNAP II, which they regulate. RNAP III also transcribes other ncRNAs, such as BC2, BC200 and some microRNAs and snoRNAs, in addition to housekeeping ncRNA genes such as tRNAs, 5S rRNAs and snRNAs.<ref name="Dieci_2007" /> The existence of an RNAP III-dependent ncRNA transcriptome that regulates its RNAP II-dependent counterpart is supported by the finding of a set of ncRNAs transcribed by RNAP III with sequence homology to protein-coding genes. This prompted the authors to posit a 'cogene/gene' functional regulatory network,<ref>{{cite journal | vauthors = Pagano JM, Farley BM, McCoig LM, Ryder SP | title = Molecular basis of RNA recognition by the embryonic polarity determinant MEX-5 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 12 | pages = 8883–8894 | date = March 2007 | pmid = 17264081 | doi = 10.1074/jbc.M700079200 | doi-access = free }}</ref> showing that one of these ncRNAs, 21A, regulates the expression of its antisense partner gene, CENP-F in trans.
===In post-transcriptional regulation=== In addition to regulating transcription, ncRNAs also control various aspects of post-transcriptional mRNA processing. Similar to small regulatory RNAs such as microRNAs and snoRNAs, these functions often involve complementary base pairing with the target mRNA. The formation of RNA duplexes between complementary ncRNA and mRNA may mask key elements within the mRNA required to bind trans-acting factors, potentially affecting any step in post-transcriptional gene expression including pre-mRNA processing and splicing, transport, translation, and degradation.<ref>{{cite journal | vauthors = Yoon JH, Abdelmohsen K, Gorospe M | title = Posttranscriptional gene regulation by long noncoding RNA | journal = Journal of Molecular Biology | volume = 425 | issue = 19 | pages = 3723–3730 | date = October 2013 | pmid = 23178169 | pmc = 3594629 | doi = 10.1016/j.jmb.2012.11.024 | bibcode = 2013JMBio.425.3723Y }}</ref>
====In splicing==== The splicing of mRNA can induce its translation and functionally diversify the repertoire of proteins it encodes. The Zeb2 mRNA requires the retention of a 5'UTR intron that contains an internal ribosome entry site for efficient translation.<ref name="Beltran_2008">{{cite journal | vauthors = Beltran M, Puig I, Peña C, García JM, Alvarez AB, Peña R, Bonilla F, de Herreros AG | title = A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition | journal = Genes & Development | volume = 22 | issue = 6 | pages = 756–769 | date = March 2008 | pmid = 18347095 | pmc = 2275429 | doi = 10.1101/gad.455708 }}</ref> The retention of the intron depends on the expression of an antisense transcript that complements the intronic 5' splice site.<ref name="Beltran_2008" /> Therefore, the ectopic expression of the antisense transcript represses splicing and induces translation of the Zeb2 mRNA during mesenchymal development. Likewise, the expression of an overlapping antisense Rev-ErbAa2 transcript controls the alternative splicing of the thyroid hormone receptor ErbAa2 mRNA to form two antagonistic isoforms.<ref>{{cite journal | vauthors = Munroe SH, Lazar MA | title = Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA | journal = The Journal of Biological Chemistry | volume = 266 | issue = 33 | pages = 22083–22086 | date = November 1991 | pmid = 1657988 | doi = 10.1016/S0021-9258(18)54535-X | doi-access = free }}</ref> Another well-characterized lncRNA involved in splicing is MALAT1 (metastasis associated lung adenocarcinoma transcript 1). MALAT1 localizes predominantly to nuclear speckles and has been reported to regulate the distribution and activity of splicing factors, thereby influencing alternative splicing of a subset of pre-mRNAs. <ref>{{Cite journal |last1=Nakagawa |first1=Shinichi |last2=Ip |first2=Joanna Y. |last3=Shioi |first3=Go |last4=Tripathi |first4=Vidisha |last5=Zong |first5=Xinying |last6=Hirose |first6=Tetsuro |last7=Prasanth |first7=Kannanganattu V. |date=2012-08-01 |title=Malat1 is not an essential component of nuclear speckles in mice |url=http://rnajournal.cshlp.org/content/18/8/1487 |journal=RNA |language=en |volume=18 |issue=8 |pages=1487–1499 |doi=10.1261/rna.033217.112 |issn=1355-8382 |pmid=22718948 |pmc=3404370 }}</ref><ref>{{Cite journal |last1=Arun |first1=Gayatri |last2=Aggarwal |first2=Disha |last3=Spector |first3=David L. |date=2020-06-03 |title=MALAT1 Long Non-Coding RNA: Functional Implications |journal=Non-coding RNA |volume=6 |issue=2 |pages=22 |doi=10.3390/ncrna6020022 |doi-access=free |issn=2311-553X |pmc=7344863 |pmid=32503170}}</ref><ref>{{Cite journal |last1=Bitaraf |first1=Amirreza |last2=Zafarani |first2=Alireza |last3=Jahandideh |first3=Pardis |last4=Hakak-Zargar |first4=Benyamin |last5=Haghi |first5=Atousa |last6=Asgaritarghi |first6=Golareh |last7=Babashah |first7=Sadegh |date=2025-10-06 |title=MALAT1 as a molecular driver of tumor progression, immune evasion, and resistance to therapy |journal=Molecular Cancer |language=en |volume=24 |issue=1 |pages=245 |doi=10.1186/s12943-025-02415-6 |doi-access=free |issn=1476-4598 |pmc=12502584 |pmid=41053822}}</ref>
====In translation==== NcRNA may also apply additional regulatory pressures during translation, a property particularly exploited in neurons where the dendritic or axonal translation of mRNA in response to synaptic activity contributes to changes in synaptic plasticity and the remodelling of neuronal networks. The RNAP III transcribed BC1 and BC200 ncRNAs, that previously derived from tRNAs, are expressed in the mouse and human central nervous system, respectively.<ref>{{cite journal | vauthors = Tiedge H, Chen W, Brosius J | title = Primary structure, neural-specific expression, and dendritic location of human BC200 RNA | journal = The Journal of Neuroscience | volume = 13 | issue = 6 | pages = 2382–2390 | date = June 1993 | pmid = 7684772 | pmc = 6576500 | doi = 10.1523/JNEUROSCI.13-06-02382.1993 | author-link1 = Henri Tiedge }}</ref><ref>{{cite journal | vauthors = Tiedge H, Fremeau RT, Weinstock PH, Arancio O, Brosius J | title = Dendritic location of neural BC1 RNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 6 | pages = 2093–2097 | date = March 1991 | pmid = 1706516 | pmc = 51175 | doi = 10.1073/pnas.88.6.2093 | bibcode = 1991PNAS...88.2093T | doi-access = free }}</ref> BC1 expression is induced in response to synaptic activity and synaptogenesis and is specifically targeted to dendrites in neurons.<ref>{{cite journal | vauthors = Muslimov IA, Banker G, Brosius J, Tiedge H | title = Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture | journal = The Journal of Cell Biology | volume = 141 | issue = 7 | pages = 1601–1611 | date = June 1998 | pmid = 9647652 | pmc = 1828539 | doi = 10.1083/jcb.141.7.1601 }}</ref> Sequence complementarity between BC1 and regions of various neuron-specific mRNAs also suggest a role for BC1 in targeted translational repression.<ref>{{cite journal | vauthors = Wang H, Iacoangeli A, Lin D, Williams K, Denman RB, Hellen CU, Tiedge H | title = Dendritic BC1 RNA in translational control mechanisms | journal = The Journal of Cell Biology | volume = 171 | issue = 5 | pages = 811–821 | date = December 2005 | pmid = 16330711 | pmc = 1828541 | doi = 10.1083/jcb.200506006 }}</ref> Indeed, it was recently shown that BC1 is associated with translational repression in dendrites to control the efficiency of dopamine D2 receptor-mediated transmission in the striatum<ref>{{cite journal | vauthors = Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C | title = The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum | journal = The Journal of Neuroscience | volume = 27 | issue = 33 | pages = 8885–8892 | date = August 2007 | pmid = 17699670 | pmc = 6672174 | doi = 10.1523/JNEUROSCI.0548-07.2007 }}</ref> and BC1 RNA-deleted mice exhibit behavioural changes with reduced exploration and increased anxiety.<ref>{{cite journal | vauthors = Lewejohann L, Skryabin BV, Sachser N, Prehn C, Heiduschka P, Thanos S, Jordan U, Dell'Omo G, Vyssotski AL, Pleskacheva MG, Lipp HP, Tiedge H, Brosius J, Prior H | title = Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice | journal = Behavioural Brain Research | volume = 154 | issue = 1 | pages = 273–289 | date = September 2004 | pmid = 15302134 | doi = 10.1016/j.bbr.2004.02.015 | citeseerx = 10.1.1.572.8071 | s2cid = 18840384 }}</ref>
====In siRNA-directed gene regulation==== In addition to masking key elements within single-stranded RNA, the formation of double-stranded RNA duplexes can also provide a substrate for the generation of endogenous siRNAs (endo-siRNAs) in Drosophila and mouse oocytes.<ref>{{cite journal | vauthors = Golden DE, Gerbasi VR, Sontheimer EJ |author3-link=Erik J. Sontheimer | title = An inside job for siRNAs | journal = Molecular Cell | volume = 31 | issue = 3 | pages = 309–312 | date = August 2008 | pmid = 18691963 | pmc = 2675693 | doi = 10.1016/j.molcel.2008.07.008 }}</ref> The annealing of complementary sequences, such as antisense or repetitive regions between transcripts, forms an RNA duplex that may be processed by Dicer-2 into endo-siRNAs. Also, long ncRNAs that form extended intramolecular hairpins may be processed into siRNAs, compellingly illustrated by the esi-1 and esi-2 transcripts.<ref>{{cite journal | vauthors = Czech B, Malone CD, Zhou R, Stark A, Schlingeheyde C, Dus M, Perrimon N, Kellis M, Wohlschlegel JA, Sachidanandam R, Hannon GJ, Brennecke J | title = An endogenous small interfering RNA pathway in Drosophila | journal = Nature | volume = 453 | issue = 7196 | pages = 798–802 | date = June 2008 | pmid = 18463631 | pmc = 2895258 | doi = 10.1038/nature07007 | bibcode = 2008Natur.453..798C }}</ref> Endo-siRNAs generated from these transcripts seem particularly useful in suppressing the spread of mobile transposon elements within the genome in the germline. However, the generation of endo-siRNAs from antisense transcripts or pseudogenes may also silence the expression of their functional counterparts via RISC effector complexes, acting as an important node that integrates various modes of long and short RNA regulation, as exemplified by the Xist and Tsix (see above).<ref name="Ogawa_2008">{{cite journal | vauthors = Ogawa Y, Sun BK, Lee JT | title = Intersection of the RNA interference and X-inactivation pathways | journal = Science | volume = 320 | issue = 5881 | pages = 1336–1341 | date = June 2008 | pmid = 18535243 | pmc = 2584363 | doi = 10.1126/science.1157676 | bibcode = 2008Sci...320.1336O }}</ref>
===In epigenetic regulation=== Epigenetic modifications, including histone and DNA methylation, histone acetylation and sumoylation, affect many aspects of chromosomal biology, primarily including regulation of large numbers of genes by remodeling broad chromatin domains.<ref>{{cite journal | vauthors = Kiefer JC | title = Epigenetics in development | journal = Developmental Dynamics | volume = 236 | issue = 4 | pages = 1144–1156 | date = April 2007 | pmid = 17304537 | doi = 10.1002/dvdy.21094 | s2cid = 23292265 }}</ref><ref name="Mikkelsen_2007">{{cite journal | vauthors = Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O'Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE | title = Genome-wide maps of chromatin state in pluripotent and lineage-committed cells | journal = Nature | volume = 448 | issue = 7153 | pages = 553–560 | date = August 2007 | pmid = 17603471 | pmc = 2921165 | doi = 10.1038/nature06008 | bibcode = 2007Natur.448..553M }}</ref> While it has been known for some time that RNA is an integral component of chromatin,<ref>{{cite journal | vauthors = Nickerson JA, Krochmalnic G, Wan KM, Penman S | title = Chromatin architecture and nuclear RNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 1 | pages = 177–181 | date = January 1989 | pmid = 2911567 | pmc = 286427 | doi = 10.1073/pnas.86.1.177 | bibcode = 1989PNAS...86..177N | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rodríguez-Campos A, Azorín F | title = RNA is an integral component of chromatin that contributes to its structural organization | journal = PLOS ONE | volume = 2 | issue = 11 | article-number = e1182 | date = November 2007 | pmid = 18000552 | pmc = 2063516 | doi = 10.1371/journal.pone.0001182 | bibcode = 2007PLoSO...2.1182R | doi-access = free }}</ref> it is only recently that we are beginning to appreciate the means by which RNA is involved in pathways of chromatin modification.<ref>{{cite journal | vauthors = Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH | title = Integration of external signaling pathways with the core transcriptional network in embryonic stem cells | journal = Cell | volume = 133 | issue = 6 | pages = 1106–1117 | date = June 2008 | pmid = 18555785 | doi = 10.1016/j.cell.2008.04.043 | s2cid = 1768190 | doi-access = free }}</ref><ref name="Rinn_2007">{{cite journal | vauthors = Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY | title = Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs | journal = Cell | volume = 129 | issue = 7 | pages = 1311–1323 | date = June 2007 | pmid = 17604720 | pmc = 2084369 | doi = 10.1016/j.cell.2007.05.022 | author-link11 = Howard Y. Chang }}</ref><ref name="SanchezElsner_2006">{{cite journal | vauthors = Sanchez-Elsner T, Gou D, Kremmer E, Sauer F | title = Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax | journal = Science | volume = 311 | issue = 5764 | pages = 1118–1123 | date = February 2006 | pmid = 16497925 | doi = 10.1126/science.1117705 | bibcode = 2006Sci...311.1118S | s2cid = 16423723 }}{{Retracted|doi=10.1126/science.344.6187.981-a|pmid=24876484|http://retractionwatch.com/2014/05/29/science-retracts-two-papers-for-image-manipulation/ ''Retraction Watch''|http://retractionwatch.com/2017/06/29/evolving-inconsistent-tale-biochemist-barred-federal-grants-five-years/ ''Retraction Watch''|intentional=yes}}</ref> For example, Oplr16 epigenetically induces the activation of stem cell core factors by coordinating intrachromosomal looping and recruitment of DNA demethylase TET2.<ref>{{cite journal | vauthors = Jia L, Wang Y, Wang C, Du Z, Zhang S, Wen X, Zhang S | title = Oplr16 serves as a novel chromatin factor to control stem cell fate by modulating pluripotency-specific chromosomal looping and TET2-mediated DNA demethylation | journal = Nucleic Acids Research | volume = 48 | issue = 7 | pages = 3935–3948 | date = Apr 2020 | pmid = 32055844 | pmc = 7144914 | doi = 10.1093/nar/gkaa097 }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>
In ''Drosophila'', long ncRNAs induce the expression of the homeotic gene, Ubx, by recruiting and directing the chromatin modifying functions of the trithorax protein Ash1 to Hox regulatory elements.<ref name="SanchezElsner_2006" /> Similar models have been proposed in mammals, where strong epigenetic mechanisms are thought to underlie the embryonic expression profiles of the Hox genes that persist throughout human development.<ref>{{cite journal | vauthors = Mazo A, Hodgson JW, Petruk S, Sedkov Y, Brock HW | title = Transcriptional interference: an unexpected layer of complexity in gene regulation | journal = Journal of Cell Science | volume = 120 | issue = Pt 16 | pages = 2755–2761 | date = August 2007 | pmid = 17690303 | doi = 10.1242/jcs.007633 | s2cid = 16059065 }}</ref><ref name="Rinn_2007" /> Indeed, the human Hox genes are associated with hundreds of ncRNAs that are sequentially expressed along both the spatial and temporal axes of human development and define chromatin domains of differential histone methylation and RNA polymerase accessibility.<ref name="Rinn_2007" /> One ncRNA, termed HOTAIR, that originates from the HOXC locus represses transcription across 40 kb of the HOXD locus by altering chromatin trimethylation state. HOTAIR is thought to achieve this by directing the action of Polycomb chromatin remodeling complexes in trans to govern the cells' epigenetic state and subsequent gene expression. Components of the Polycomb complex, including Suz12, EZH2 and EED, contain RNA binding domains that may potentially bind HOTAIR and probably other similar ncRNAs.<ref name="Cerase_2020">{{cite journal | vauthors = Cerase A, Tartaglia GG | title = Long non-coding RNA-polycomb intimate rendezvous | journal = Open Biology | volume = 10 | issue = 9 | date = September 2020 | pmid = 32898472 | pmc = 7536065 | doi = 10.1098/rsob.200126 | doi-access = free| article-number = 200126 }}</ref><ref>{{cite journal | vauthors = Denisenko O, Shnyreva M, Suzuki H, Bomsztyk K | title = Point mutations in the WD40 domain of Eed block its interaction with Ezh2 | journal = Molecular and Cellular Biology | volume = 18 | issue = 10 | pages = 5634–5642 | date = October 1998 | pmid = 9742080 | pmc = 109149 | doi = 10.1128/MCB.18.10.5634 }}</ref><ref>{{cite journal | vauthors = Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H, Yap CC, Suzuki M, Kawai J, Suzuki H, Carninci P, Hayashizaki Y, Wells C, Frith M, Ravasi T, Pang KC, Hallinan J, Mattick J, Hume DA, Lipovich L, Batalov S, Engström PG, Mizuno Y, Faghihi MA, Sandelin A, Chalk AM, Mottagui-Tabar S, Liang Z, Lenhard B, Wahlestedt C | title = Antisense transcription in the mammalian transcriptome | journal = Science | volume = 309 | issue = 5740 | pages = 1564–1566 | date = September 2005 | pmid = 16141073 | doi = 10.1126/science.1112009 | bibcode = 2005Sci...309.1564R | s2cid = 34559885 }}</ref> This example nicely illustrates a broader theme whereby ncRNAs recruit the function of a generic suite of chromatin modifying proteins to specific genomic loci, underscoring the complexity of recently published genomic maps.<ref name="Mikkelsen_2007" /> Interestingly, long ncRNAs interact with chromatin modifying proteins such as the PRC2 complex to guide gene silencing in several malignancies. In MM, the long ncRNA PVT1 interacts with EZH2, the catalytic subunit of PRC2, to guide the silencing of genes with pro-apoptotic and tumor suppressor properties thus facilitating tumor growth and progression.<ref>{{cite journal |last1=Nylund |first1=Patrick |last2=Garrido-Zabala |first2=Berta |last3=Párraga |first3=Alba Atienza |last4=Vasquez |first4=Louella |last5=Pyl |first5=Paul Theodor |last6=Harinck |first6=George Mickhael |last7=Ma |first7=Anqi |last8=Jin |first8=Jian |last9=Öberg |first9=Fredrik |last10=Kalushkova |first10=Antonia |last11=Wiklund |first11=Helena Jernberg |title=PVT1 interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma |journal=Haematologica |date=27 July 2023 |volume=109 |issue=2 |pages=567–577 |doi=10.3324/haematol.2023.282965 |pmid=37496441 |pmc=10828784 }}</ref> Indeed, the prevalence of long ncRNAs associated with protein coding genes may contribute to localised patterns of chromatin modifications that regulate gene expression during development. For example, the majority of protein-coding genes have antisense partners, including many tumour suppressor genes that are frequently silenced by epigenetic mechanisms in cancer.<ref name="Yu_2008">{{cite journal | vauthors = Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H | title = Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA | journal = Nature | volume = 451 | issue = 7175 | pages = 202–206 | date = January 2008 | pmid = 18185590 | pmc = 2743558 | doi = 10.1038/nature06468 | bibcode = 2008Natur.451..202Y }}</ref> A recent study observed an inverse expression profile of the p15 gene and an antisense ncRNA in leukaemia.<ref name="Yu_2008" /> A detailed analysis showed the p15 antisense ncRNA (CDKN2BAS) was able to induce changes to heterochromatin and DNA methylation status of p15 by an unknown mechanism, thereby regulating p15 expression.<ref name="Yu_2008" /> Therefore, misexpression of the associated antisense ncRNAs may subsequently silence the tumour suppressor gene contributing towards cancer.
====Imprinting==== Many emergent themes of ncRNA-directed chromatin modification were first apparent within the phenomenon of imprinting, whereby only one allele of a gene is expressed from either the maternal or the paternal chromosome. In general, imprinted genes are clustered together on chromosomes, suggesting the imprinting mechanism acts upon local chromosome domains rather than individual genes. These clusters are also often associated with long ncRNAs whose expression is correlated with the repression of the linked protein-coding gene on the same allele.<ref>{{cite journal | vauthors = Pauler FM, Koerner MV, Barlow DP | title = Silencing by imprinted noncoding RNAs: is transcription the answer? | journal = Trends in Genetics | volume = 23 | issue = 6 | pages = 284–292 | date = June 2007 | pmid = 17445943 | pmc = 2847181 | doi = 10.1016/j.tig.2007.03.018 }}</ref> Indeed, detailed analysis has revealed a crucial role for the ncRNAs Kcnqot1 and Igf2r/Air in directing imprinting.<ref>{{cite journal | vauthors = Braidotti G, Baubec T, Pauler F, Seidl C, Smrzka O, Stricker S, Yotova I, Barlow DP | title = The Air noncoding RNA: an imprinted cis-silencing transcript | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 69 | pages = 55–66 | year = 2004 | pmid = 16117633 | pmc = 2847179 | doi = 10.1101/sqb.2004.69.55 | ref = ref16117633 }}</ref>
Almost all the genes at the Kcnq1 loci are maternally inherited, except the paternally expressed antisense ncRNA Kcnqot1.<ref>{{cite journal | vauthors = Mitsuya K, Meguro M, Lee MP, Katoh M, Schulz TC, Kugoh H, Yoshida MA, Niikawa N, Feinberg AP, Oshimura M | title = LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids | journal = Human Molecular Genetics | volume = 8 | issue = 7 | pages = 1209–1217 | date = July 1999 | pmid = 10369866 | doi = 10.1093/hmg/8.7.1209 }}</ref> Transgenic mice with truncated Kcnq1ot fail to silence the adjacent genes, suggesting that Kcnqot1 is crucial to the imprinting of genes on the paternal chromosome.<ref>{{cite journal | vauthors = Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM | title = Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes | journal = Genes & Development | volume = 20 | issue = 10 | pages = 1268–1282 | date = May 2006 | pmid = 16702402 | pmc = 1472902 | doi = 10.1101/gad.1416906 | ref = ref16702402 }}</ref> It appears that Kcnqot1 is able to direct the trimethylation of lysine 9 (H3K9me3) and 27 of histone 3 (H3K27me3) to an imprinting centre that overlaps the Kcnqot1 promoter and actually resides within a Kcnq1 sense exon.<ref name="Umlauf_2004">{{cite journal | vauthors = Umlauf D, Goto Y, Cao R, Cerqueira F, Wagschal A, Zhang Y, Feil R | title = Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes | journal = Nature Genetics | volume = 36 | issue = 12 | pages = 1296–1300 | date = December 2004 | pmid = 15516932 | doi = 10.1038/ng1467 | s2cid = 19084498 }}</ref> Similar to HOTAIR (see above), Eed-Ezh2 Polycomb complexes are recruited to the Kcnq1 loci paternal chromosome, possibly by Kcnqot1, where they may mediate gene silencing through repressive histone methylation.<ref name="Umlauf_2004" /> A differentially methylated imprinting centre also overlaps the promoter of a long antisense ncRNA Air that is responsible for the silencing of neighbouring genes at the Igf2r locus on the paternal chromosome.<ref>{{cite journal | vauthors = Sleutels F, Zwart R, Barlow DP | title = The non-coding Air RNA is required for silencing autosomal imprinted genes | journal = Nature | volume = 415 | issue = 6873 | pages = 810–813 | date = February 2002 | pmid = 11845212 | doi = 10.1038/415810a | bibcode = 2002Natur.415..810S | s2cid = 4420245 }}</ref><ref>{{cite journal | vauthors = Zwart R, Sleutels F, Wutz A, Schinkel AH, Barlow DP | title = Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes | journal = Genes & Development | volume = 15 | issue = 18 | pages = 2361–2366 | date = September 2001 | pmid = 11562346 | pmc = 312779 | doi = 10.1101/gad.206201 }}</ref> The presence of allele-specific histone methylation at the Igf2r locus suggests Air also mediates silencing via chromatin modification.<ref>{{cite journal | vauthors = Fournier C, Goto Y, Ballestar E, Delaval K, Hever AM, Esteller M, Feil R | title = Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes | journal = The EMBO Journal | volume = 21 | issue = 23 | pages = 6560–6570 | date = December 2002 | pmid = 12456662 | pmc = 136958 | doi = 10.1093/emboj/cdf655 }}</ref>
====Xist and X-chromosome inactivation==== The inactivation of a X-chromosome in female placental mammals is directed by one of the earliest and best characterized long ncRNAs, Xist.<ref name="Wutz_2007">{{cite journal | vauthors = Wutz A, Gribnau J | title = X inactivation Xplained | journal = Current Opinion in Genetics & Development | volume = 17 | issue = 5 | pages = 387–393 | date = October 2007 | pmid = 17869504 | doi = 10.1016/j.gde.2007.08.001 }}</ref> The expression of Xist from the future inactive X-chromosome, and its subsequent coating of the inactive X-chromosome, occurs during early embryonic stem cell differentiation. Xist expression is followed by irreversible layers of chromatin modifications that include the loss of the histone (H3K9) acetylation and H3K4 methylation that are associated with active chromatin, and the induction of repressive chromatin modifications including H4 hypoacetylation, H3K27 trimethylation,<ref name="Wutz_2007" /> H3K9 hypermethylation and H4K20 monomethylation as well as H2AK119 monoubiquitylation. These modifications coincide with the transcriptional silencing of the X-linked genes.<ref>{{cite journal | vauthors = Morey C, Navarro P, Debrand E, Avner P, Rougeulle C, Clerc P | title = The region 3′ to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene | journal = The EMBO Journal | volume = 23 | issue = 3 | pages = 594–604 | date = February 2004 | pmid = 14749728 | pmc = 1271805 | doi = 10.1038/sj.emboj.7600071 }}</ref> Xist RNA also localises the histone variant macroH2A to the inactive X–chromosome.<ref>{{cite journal | vauthors = Costanzi C, Pehrson JR | title = Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals | journal = Nature | volume = 393 | issue = 6685 | pages = 599–601 | date = June 1998 | pmid = 9634239 | doi = 10.1038/31275 | bibcode = 1998Natur.393..599C | s2cid = 205001095 }}</ref> There are additional ncRNAs that are also present at the Xist loci, including an antisense transcript Tsix, which is expressed from the future active chromosome and able to repress Xist expression by the generation of endogenous siRNA.<ref name="Ogawa_2008" /> Together these ncRNAs ensure that only one X-chromosome is active in female mammals.
====Telomeric non-coding RNAs==== Telomeres form the terminal region of mammalian chromosomes and are essential for stability and aging and play central roles in diseases such as cancer.<ref>{{cite journal | vauthors = Blasco MA | title = Telomere length, stem cells and aging | journal = Nature Chemical Biology | volume = 3 | issue = 10 | pages = 640–649 | date = October 2007 | pmid = 17876321 | doi = 10.1038/nchembio.2007.38 | bibcode = 2007NatCB...3..640B }}</ref> Telomeres have been long considered transcriptionally inert DNA-protein complexes until it was shown in the late 2000s that telomeric repeats may be transcribed as telomeric RNAs (TelRNAs)<ref name="Schoeftner_2008">{{cite journal | vauthors = Schoeftner S, Blasco MA | title = Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II | journal = Nature Cell Biology | volume = 10 | issue = 2 | pages = 228–236 | date = February 2008 | pmid = 18157120 | doi = 10.1038/ncb1685 | s2cid = 5890629 }}</ref> or telomeric repeat-containing RNAs.<ref name="Azzalin_2007">{{cite journal | vauthors = Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J | title = Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends | journal = Science | volume = 318 | issue = 5851 | pages = 798–801 | date = November 2007 | pmid = 17916692 | doi = 10.1126/science.1147182 | bibcode = 2007Sci...318..798A | s2cid = 20693275 | doi-access = free }}</ref> These ncRNAs are heterogeneous in length, transcribed from several sub-telomeric loci and physically localise to telomeres. Their association with chromatin, which suggests an involvement in regulating telomere specific heterochromatin modifications, is repressed by SMG proteins that protect chromosome ends from telomere loss.<ref name="Azzalin_2007" /> In addition, TelRNAs block telomerase activity in vitro and may therefore regulate telomerase activity.<ref name="Schoeftner_2008" /> Although early, these studies suggest an involvement for telomeric ncRNAs in various aspects of telomere biology.
=== In regulation of DNA replication timing and chromosome stability === Asynchronously replicating autosomal RNAs (ASARs) are very long (~200kb) non-coding RNAs that are non-spliced, non-polyadenylated, and are required for normal DNA replication timing and chromosome stability.<ref>{{cite journal | vauthors = Donley N, Stoffregen EP, Smith L, Montagna C, Thayer MJ | veditors = Bartolomei MS | title = Asynchronous replication, mono-allelic expression, and long range Cis-effects of ASAR6 | journal = PLOS Genetics | volume = 9 | issue = 4 | article-number = e1003423 | date = April 2013 | pmid = 23593023 | pmc = 3617217 | doi = 10.1371/journal.pgen.1003423 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Donley N, Smith L, Thayer MJ | veditors = Bartolomei MS | title = ASAR15, A cis-acting locus that controls chromosome-wide replication timing and stability of human chromosome 15 | journal = PLOS Genetics | volume = 11 | issue = 1 | article-number = e1004923 | date = January 2015 | pmid = 25569254 | pmc = 4287527 | doi = 10.1371/journal.pgen.1004923 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Heskett MB, Smith LG, Spellman P, Thayer MJ | title = Reciprocal monoallelic expression of ASAR lncRNA genes controls replication timing of human chromosome 6 | journal = RNA | volume = 26 | issue = 6 | pages = 724–738 | date = June 2020 | pmid = 32144193 | pmc = 7266157 | doi = 10.1261/rna.073114.119 | doi-access = free }}</ref> Deletion of any one of the genetic loci containing ASAR6, ASAR15, or ASAR6-141 results in the same phenotype of delayed replication timing and delayed mitotic condensation (DRT/DMC) of the entire chromosome. DRT/DMC results in chromosomal segregation errors that lead to increased frequency of secondary rearrangements and an unstable chromosome. Similar to Xist, ASARs show random monoallelic expression and exist in asynchronous DNA replication domains. Although the mechanism of ASAR function is still under investigation, it is hypothesized that they work via similar mechanisms as the Xist lncRNA, but on smaller autosomal domains resulting in allele specific changes in gene expression.
Incorrect reparation of DNA double-strand breaks (DSB) leading to chromosomal rearrangements is one of the oncogenesis's primary causes. A number of lncRNAs are crucial at the different stages of the main pathways of DSB repair in eukaryotic cells: nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Gene mutations or variation in expression levels of such RNAs can lead to local DNA repair defects, increasing the chromosome aberration frequency. Moreover, it was demonstrated that some RNAs could stimulate long-range chromosomal rearrangements.<ref>{{cite journal | vauthors = Murashko MM, Stasevich EM, Schwartz AM, Kuprash DV, Uvarova AN, Demin DE | veditors = Blanco FJ | title = The Role of RNA in DNA Breaks, Repair and Chromosomal Rearrangements | journal = Biomolecules | volume = 11 | issue = 4 | page = 550 | date = April 2021 | pmid = 33918762 | pmc = 8069526 | doi = 10.3390/biom11040550 | doi-access = free }}</ref>
== Structure == It took over two decades after the discovery of the first human long non-coding transcripts for the functional significance of lncRNA structures to be fully recognized. Early structural studies led to the proposal of several hypotheses for classifying lncRNA architectures. One hypothesis suggests that lncRNAs may feature a compact tertiary structure, similar to ribozymes like the ribosome or self-splicing introns. Another possibility is that lncRNAs could have structured protein-binding sites arranged in a decentralized scaffold, lacking a compact core. A third hypothesis posits that lncRNAs might exhibit a largely unstructured architecture, with loosely organized protein-binding domains interspersed with long regions of disordered single-stranded RNA.<ref>{{Cite journal | vauthors = Novikova IV, Hennelly SP, Sanbonmatsu KY | title = Sizing up long non-coding RNAs: Do lncRNAs have secondary and tertiary structure? | journal = BioArchitecture | volume = 2 | issue = 6 | pages = 189–199 | date = November 2012 | pmid = 23267412 | pmc = 3527312 | doi = 10.4161/bioa.22592 | osti = 1629346 | issn = 1949-0992 }}</ref>
Studying the tertiary structure of lncRNAs by conventional methods such as X- ray crystallography, cryo-EM and nuclear magnetic resonance (NMR) is unfortunately still hampered by their size and conformational dynamics, and by the fact that for now we still know too little about their mechanism to reconstruct stable and functionally-active lncRNA-ribonucleoprotein complexes. But some pioneering studies, showed that lncRNAs can already be studied by low-resolution single-particle and in-solution methods, such as atomic force microscopy (AFM) and small-angle X-ray scattering (SAXS), in some cases even in complexes with small molecule modulators.<ref>{{Cite journal | vauthors = Chillón I, Marcia M | title = The molecular structure of long non-coding RNAs: emerging patterns and functional implications | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 55 | issue = 6 | pages = 662–690 | date = 2020-10-12 | pmid = 33043695 | doi = 10.1080/10409238.2020.1828259 | issn = 1040-9238 }}</ref>
For instance, lncRNA MEG3 was shown to regulate transcription factor p53 thanks to its compact structured core.<ref>{{Cite journal | vauthors = Uroda T, Anastasakou E, Rossi A, Teulon JM, Pellequer JL, Annibale P, Pessey O, Inga A, Chillón I, Marcia M | title = Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway | journal = Molecular Cell | volume = 75 | issue = 5 | pages = 982–995.e9 | date = September 2019 | pmid = 31444106 | pmc = 6739425 | doi = 10.1016/j.molcel.2019.07.025 | issn = 1097-2765 }}</ref> Moreover, lncRNA Braveheart (Bvht) was shown to have a well-defined, albeit flexible 3D structure that is remodeled upon binding CNBP (Cellular Nucleic-acid Binding Protein) which recognizes distal domains in the RNA.<ref>{{Cite journal | vauthors = Kim DN, Thiel BC, Mrozowich T, Hennelly SP, Hofacker IL, Patel TR, Sanbonmatsu KY | title = Zinc-finger protein CNBP alters the 3-D structure of lncRNA Braveheart in solution | journal = Nature Communications | volume = 11 | issue = 1 | article-number = 148 | date = 2020-01-09 | pmid = 31919376 | pmc = 6952434 | doi = 10.1038/s41467-019-13942-4 | bibcode = 2020NatCo..11..148K | issn = 2041-1723 }}</ref> Finally, Xist a master regulator of X chromosome inactivation was shown to specifically bind a small molecule compound, which alters the conformation of Xist RepA motif and displaces two known interacting protein factors (PRC2 and SPEN) from the RNA. By such mechanism of action, the compound abrogates the initiation of X-chromosome inactivation.<ref>{{Cite journal | vauthors = Aguilar R, Spencer KB, Kesner B, Rizvi NF, Badmalia MD, Mrozowich T, Mortison JD, Rivera C, Smith GF, Burchard J, Dandliker PJ, Patel TR, Nickbarg EB, Lee JT | title = Targeting Xist with compounds that disrupt RNA structure and X inactivation | journal = Nature | volume = 604 | issue = 7904 | pages = 160–166 | date = 2022-03-30 | pmid = 35355011 | pmc = 11549687 | doi = 10.1038/s41586-022-04537-z | bibcode = 2022Natur.604..160A | issn = 0028-0836 }}</ref>
== See also == * List of long non-coding RNA databases * NONCODE * Pinc * Sphinx (gene) * VIS1 * ZNRD1-AS1 *Noncoding RNA Activated by DNA Damage
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{{DEFAULTSORT:Long Noncoding Rna}} Category:LncRNA Category:RNA Category:Non-coding RNA Category:Biotechnology