Overlapping mechanisms of lncRNA and expanded microsatellite RNA

Focus Article

Thomas A. Cooper, Sara J. Johnson

Published Online: Nov 16 2020

DOI: 10.1002/wrna.1634

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Abstract RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3–10 nt) repeats located within coding genes. Expanded repeat‐containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro‐RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease

LncRNAs and expanded microsatellite RNA display extensive functional overlap. Shared mechanisms include protein sequestration, peptide translation, miRNA processing, and miRNA sequestration. Understanding parallel mechanisms shared between the two RNA species can reveal biological impact relevant to both lncRNAs and pathogenic microsatellite RNAs. (Created withBioRender.com)

[ Normal View | Magnified View ]

Certain lncRNAs have been shown to exhibit phase separation capacity. A commonality between these lncRNA is the presence of repeat tracts. The lncRNA NEAT1 contains evolutionarily conserved UG repeat tracts which recruit proteins including FUS and NONO leading to paraspeckle formation. The lncRNA HSRω inD. melanogasterencodes a 280 bp repeat tract. Upon heat shock, the lncRNA localizes to its locus of origin and recruits hnRNP proteins leading to omega speckle formation at the gene locus. The lncRNA Xist, containing six conserved repeat tracts (the sequence of the repeats varies), has also been hypothesized to exhibit phase separation during X‐chromosome inactivation by recruiting hnRNPs and paraspeckle proteins. Evidence suggests that expanded repeat RNA, specifically CUG and CCUG (the repeat expansions exhibited in DM1 and DM2, respectively), phase separates to form the pathogenic RNA foci. Whether proteins are required for this process is yet to be fully understood as there is evidence for both instances. (Created withBioRender.com)

[ Normal View | Magnified View ]

References

Aly,, M. K., Ninomiya,, K., Adachi,, S., Natsume,, T., & Hirose,, T. (2019). Two distinct nuclear stress bodies containing different sets of RNA‐binding proteins are formed with HSATIII architectural noncoding RNAs upon thermal stress exposure. Biochemical and Biophysical Research Communications, 516(2), 419–423. https://doi.org/10.1016/j.bbrc.2019.06.061
Anderson,, D. M., Anderson,, K. M., Chang,, C.‐L., Makarewich,, C. A., Nelson,, B. R., McAnally,, J. R., … Olson,, E. N. (2015). A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell, 160(4), 595–606. https://doi.org/10.1016/j.cell.2015.01.009
Ash,, P. E. A., Bieniek,, K. F., Gendron,, T. F., Caulfield,, T., Lin,, W.‐L., DeJesus‐Hernandez,, M., … Petrucelli,, L. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron, 77(4), 639–646. https://doi.org/10.1016/j.neuron.2013.02.004
Balendra,, R., & Isaacs,, A. M. (2018). C9orf72‐mediated ALS and FTD: Multiple pathways to disease. Nature Reviews Neurology, 14(9), 544–558. https://doi.org/10.1038/s41582-018-0047-2
Batra,, R., Charizanis,, K., Manchanda,, M., Mohan,, A., Li,, M., Finn,, D. J., … Swanson,, M. S. (2014). Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA‐mediated disease. Molecular Cell, 56(2), 311–322. https://doi.org/10.1016/j.molcel.2014.08.027
Beermann,, J., Piccoli,, M.‐T., Viereck,, J., & Thum,, T. (2016). Non‐coding RNAs in development and disease: Background, mechanisms, and therapeutic approaches. Physiological Reviews, 96(4), 1297–1325. https://doi.org/10.1152/physrev.00041.2015
Bierhoff,, H., Dammert,, M. A., Brocks,, D., Dambacher,, S., Schotta,, G., & Grummt,, I. (2014). Quiescence‐induced LncRNAs trigger H4K20 Trimethylation and transcriptional silencing. Molecular Cell, 54(4), 675–682. https://doi.org/10.1016/j.molcel.2014.03.032
Blice‐Baum,, A. C., & Mihailescu,, M.‐R. (2014). Biophysical characterization of G‐quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms. RNA, 20(1), 103–114. https://doi.org/10.1261/rna.041442.113
Blythe,, A. J., Fox,, A. H., & Bond,, C. S. (2016). The ins and outs of lncRNA structure: How, why and what comes next? Biochimica et Biophysica Acta (BBA) ‐ Gene Regulatory Mechanisms, 1859(1), 46–58. https://doi.org/10.1016/j.bbagrm.2015.08.009
Brook,, J. D., McCurrach,, M. E., Harley,, H. G., Buckler,, A. J., Church,, D., Aburatani,, H., … Hudson,, T. (1992). Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell, 68(4), 799–808. https://doi.org/10.1016/0092-8674(92)90154-5
Burberry,, A., Wells,, M. F., Limone,, F., Couto,, A., Smith,, K. S., Keaney,, J., … Eggan,, K. (2020). C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature, 582(7810), 89–94. https://doi.org/10.1038/s41586-020-2288-7
Cai,, X., & Cullen,, B. R. (2007). The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA, 13(3), 313–316. https://doi.org/10.1261/rna.351707
Cao,, X., & Slavoff,, S. A. (2020). Non‐AUG start codons: Expanding and regulating the small and alternative ORFeome. Experimental Cell Research, 391(1), 111973. https://doi.org/10.1016/j.yexcr.2020.111973
Carrieri,, C., Cimatti,, L., Biagioli,, M., Beugnet,, A., Zucchelli,, S., Fedele,, S., … Gustincich,, S. (2012). Long non‐coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature, 491(7424), 454–457. https://doi.org/10.1038/nature11508
Cerase,, A., Armaos,, A., Neumayer,, C., Avner,, P., Guttman,, M., & Tartaglia,, G. G. (2019). Phase separation drives X‐chromosome inactivation: A hypothesis. Nature Structural %26 Molecular Biology, 26(5), 331–334. https://doi.org/10.1038/s41594-019-0223-0
Chen,, J., Brunner,, A.‐D., Cogan,, J. Z., Nuñez,, J. K., Fields,, A. P., Adamson,, B., … Weissman,, J. S. (2020). Pervasive functional translation of noncanonical human open reading frames. Science, 367(6482), 1140–1146. https://doi.org/10.1126/science.aay0262
Childs‐Disney,, J. L., Yildirim,, I., Park,, H., Lohman,, J. R., Guan,, L., Tran,, T., … Disney,, M. D. (2013). Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chemical Biology, 9(2), 538–550. https://doi.org/10.1021/cb4007387
Cid‐Samper,, F., Gelabert‐Baldrich,, M., Lang,, B., Lorenzo‐Gotor,, N., Ponti,, R. D., Severijnen,, L.‐A. W. F. M., … Tartaglia,, G. G. (2018). An integrative study of protein‐RNA condensates identifies scaffolding RNAs and reveals players in fragile X‐associated tremor/Ataxia syndrome. Cell Reports, 25(12), 3422–3434.e7. https://doi.org/10.1016/j.celrep.2018.11.076
Cooper‐Knock,, J., Walsh,, M. J., Higginbottom,, A., Highley,, J. R., Dickman,, M. J., Edbauer,, D., … Shaw,, P. J. (2014). Sequestration of multiple RNA recognition motif‐containing proteins by C9orf72 repeat expansions. Brain, 137(7), 2040–2051. https://doi.org/10.1093/brain/awu120
Dai,, B., Qiao,, L., Zhang,, M., Cheng,, L., Zhang,, L., Geng,, L., … Yang,, J. (2019). lncRNA AK054386 functions as a ceRNA to sequester miR‐199 and induce sustained endoplasmic reticulum stress in hepatic reperfusion injury. Oxidative Medicine and Cellular Longevity, 2019, 1–15. https://doi.org/10.1155/2019/8189079
DeJesus‐Hernandez,, M., Mackenzie,, I. R., Boeve,, B. F., Boxer,, A. L., Baker,, M., Rutherford,, N. J., … Rademakers,, R. (2011). Expanded GGGGCC Hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p‐linked FTD and ALS. Neuron, 72(2), 245–256. https://doi.org/10.1016/j.neuron.2011.09.011
Dere,, R., Napierala,, M., Ranum,, L. P. W., & Wells,, R. D. (2004). Hairpin structure‐forming propensity of the (CCTG·CAGG) Tetranucleotide repeats contributes to the genetic instability associated with myotonic dystrophy type 2. Journal of Biological Chemistry, 279(40), 41715–41726. https://doi.org/10.1074/jbc.m406415200
Diederichs,, S. (2014). The four dimensions of noncoding RNA conservation. Trends in Genetics, 30(4), 121–123. https://doi.org/10.1016/j.tig.2014.01.004
Dunham,, I., Kundaje,, A., Aldred,, S. F., Collins,, P. J., Davis,, C. A., Doyle,, F., … Birney,, E. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489(7414), 57–74. https://doi.org/10.1038/nature11247
Emmrich,, S., Streltsov,, A., Schmidt,, F., Thangapandi,, V., Reinhardt,, D., & Klusmann,, J.‐H. (2014). LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia. Molecular Cancer, 13(1), 171. https://doi.org/10.1186/1476-4598-13-171
Erdel,, F., & Rippe,, K. (2018). Formation of chromatin subcompartments by phase separation. Biophysical Journal, 114(10), 2262–2270. https://doi.org/10.1016/j.bpj.2018.03.011
Fay,, M. M., Anderson,, P. J., & Ivanov,, P. (2017). ALS/FTD‐associated C9ORF72 repeat RNA promotes phase transitions in vitro and in cells. Cell Reports, 21(12), 3573–3584. https://doi.org/10.1016/j.celrep.2017.11.093
Fickett,, J. W. (1982). Recognition of protein coding regions in DNA sequences. Nucleic Acids Research, 10(17), 5303–5318. https://doi.org/10.1093/nar/10.17.5303
Fratta,, P., Mizielinska,, S., Nicoll,, A. J., Zloh,, M., Fisher,, E. M. C., Parkinson,, G., & Isaacs,, A. M. (2012). C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G‐quadruplexes. Scientific Reports, 2(1), 1016. https://doi.org/10.1038/srep01016
Gloss,, B. S., & Dinger,, M. E. (2016). The specificity of long noncoding RNA expression. Biochimica et Biophysica Acta (BBA) ‐ Gene Regulatory Mechanisms, 1859(1), 16–22. https://doi.org/10.1016/j.bbagrm.2015.08.005
Green,, K. M., Glineburg,, M. R., Kearse,, M. G., Flores,, B. N., Linsalata,, A. E., Fedak,, S. J., … Todd,, P. K. (2017). RAN translation at C9orf72‐associated repeat expansions is selectively enhanced by the integrated stress response. Nature Communications, 8(1), 2005. https://doi.org/10.1038/s41467-017-02200-0
Green,, K. M., Linsalata,, A. E., & Todd,, P. K. (2016). RAN translation—What makes it run? Brain Research, 1647, 30–42. https://doi.org/10.1016/j.brainres.2016.04.003
Guo,, G., Kang,, Q., Zhu,, X., Chen,, Q., Wang,, X., Chen,, Y., … Chen,, J.‐L. (2015). A long noncoding RNA critically regulates Bcr‐Abl‐mediated cellular transformation by acting as a competitive endogenous RNA. Oncogene, 34(14), 1768–1779. https://doi.org/10.1038/onc.2014.131
HafezQorani,, S., Houdjedj,, A., Arici,, M., Said,, A., & Kazan,, H. (2019). RBPSponge: Genome‐wide identification of lncRNAs that sponge RBPs. Bioinformatics, 35(22), 4760–4763. https://doi.org/10.1093/bioinformatics/btz448
Handa,, V., Saha,, T., & Usdin,, K. (2003). The fragile X syndrome repeats form RNA hairpins that do not activate the interferon‐inducible protein kinase, PKR, but are cut by Dicer. Nucleic Acids Research, 31(21), 6243–6248. https://doi.org/10.1093/nar/gkg818
Hautbergue,, G. M., Castelli,, L. M., Ferraiuolo,, L., Sanchez‐Martinez,, A., Cooper‐Knock,, J., Higginbottom,, A., … Shaw,, P. J. (2017). SRSF1‐dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications, 8(1), 16063. https://doi.org/10.1038/ncomms16063
HGNC Database, 2020. HUGO Gene Nomenclature Committee (HGNC), European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL‐EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom. www.genenames.org. Retrieval from https://www.genenames.org/data/genegroup/#!/group/1688
Ho,, T. H., Bundman,, D., Armstrong,, D. L., & Cooper,, T. A. (2005). Transgenic mice expressing CUG‐BP1 reproduce splicing mis‐regulation observed in myotonic dystrophy. Human Molecular Genetics, 14(11), 1539–1547. https://doi.org/10.1093/hmg/ddi162
Holt,, I., Mittal,, S., Furling,, D., Butler‐Browne,, G. S., Brook,, J. D., & Morris,, G. E. (2007). Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles. Genes to Cells, 12(9), 1035–1048. https://doi.org/10.1111/j.1365-2443.2007.01112.x
Huang,, Y.‐S., Chang,, C.‐C., Lee,, S.‐S., Jou,, Y.‐S., & Shih,, H.‐M. (2016). Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3‐mediated repression of PHLPP1 expression. Oncotarget, 7(28), 43256–43266. https://doi.org/10.18632/oncotarget.9673
Ingolia,, N. T., Lareau,, L. F., & Weissman,, J. S. (2011). Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell, 147(4), 789–802. https://doi.org/10.1016/j.cell.2011.10.002
Jackson,, R., Kroehling,, L., Khitun,, A., Bailis,, W., Jarret,, A., York,, A. G., … Flavell,, R. A. (2018). The translation of non‐canonical open reading frames controls mucosal immunity. Nature, 564(7736), 434–438. https://doi.org/10.1038/s41586-018-0794-7
Jain,, A., & Vale,, R. D. (2017). RNA phase transitions in repeat expansion disorders. Nature, 546(7657), 243–247. https://doi.org/10.1038/nature22386
Ji,, Z., Song,, R., Regev,, A., & Struhl,, K. (2015). Many lncRNAs, 5′UTRs, and pseudogenes are translated and some are likely to express functional proteins. eLife, 4, e08890. https://doi.org/10.7554/elife.08890
Jiang,, H., Mankodi,, A., Swanson,, M. S., Moxley,, R. T., & Thornton,, C. A. (2004). Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Human Molecular Genetics, 13(24), 3079–3088. https://doi.org/10.1093/hmg/ddh327
Jones,, K., Wei,, C., Iakova,, P., Bugiardini,, E., Schneider‐Gold,, C., Meola,, G., … Timchenko,, L. T. (2012). GSK3β mediates muscle pathology in myotonic dystrophy. Journal of Clinical Investigation, 122(12), 4461–4472. https://doi.org/10.1172/jci64081
Jones,, K., Wei,, C., Schoser,, B., Meola,, G., Timchenko,, N., & Timchenko,, L. (2015). Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5. Proceedings of the National Academy of Sciences, 112(26), 8041–8045. https://doi.org/10.1073/pnas.1422273112
Karreth,, F. A., Tay,, Y., Perna,, D., Ala,, U., Tan,, S. M., Rust,, A. G., … Pandolfi,, P. P. (2011). In vivo identification of tumor‐ suppressive PTEN ceRNAs in an oncogenic BRAF‐induced mouse model of melanoma. Cell, 147(2), 382–395. https://doi.org/10.1016/j.cell.2011.09.032
Kearse,, M. G., Green,, K. M., Krans,, A., Rodriguez,, C. M., Linsalata,, A. E., Goldstrohm,, A. C., & Todd,, P. K. (2016). CGG repeat‐associated non‐AUG translation utilizes a cap‐dependent scanning mechanism of initiation to produce toxic proteins. Molecular Cell, 62(2), 314–322. https://doi.org/10.1016/j.molcel.2016.02.034
Kim,, D.‐H., Langlois,, M.‐A., Lee,, K.‐B., Riggs,, A. D., Puymirat,, J., & Rossi,, J. J. (2005). HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Research, 33(12), 3866–3874. https://doi.org/10.1093/nar/gki698
Kim,, D. H., Marinov,, G. K., Pepke,, S., Singer,, Z. S., He,, P., Williams,, B., … Wold,, B. J. (2015). Single‐cell transcriptome analysis reveals dynamic changes in lncRNA expression during reprogramming. Cell Stem Cell, 16(1), 88–101. https://doi.org/10.1016/j.stem.2014.11.005
Kim,, Y.‐K., Kim,, B., & Kim,, V. N. (2016). Re‐evaluation of the roles of DROSHA, Exportin 5, and DICER in microRNA biogenesis. Proceedings of the National Academy of Sciences, 113(13), E1881–E1889. https://doi.org/10.1073/pnas.1602532113
Kong,, X., Duan,, Y., Sang,, Y., Li,, Y., Zhang,, H., Liang,, Y., … Yang,, Q. (2019). LncRNA–CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA‐215. Journal of Cellular Physiology, 234(6), 9105–9117. https://doi.org/10.1002/jcp.27587
Koscianska,, E., Witkos,, T. M., Kozlowska,, E., Wojciechowska,, M., & Krzyzosiak,, W. J. (2015). Cooperation meets competition in microRNA‐mediated DMPK transcript regulation. Nucleic Acids Research, 43(19), 9500–9518. https://doi.org/10.1093/nar/gkv849
Kraan,, C. M., Godler,, D. E., & Amor,, D. J. (2019). Epigenetics of fragile X syndrome and fragile X‐related disorders. Developmental Medicine %26 Child Neurology, 61(2), 121–127. https://doi.org/10.1111/dmcn.13985
Krause,, H. M. (2018). New and prospective roles for lncRNAs in organelle formation and function. Trends in Genetics, 34(10), 736–745. https://doi.org/10.1016/j.tig.2018.06.005
Kremer,, E., Pritchard,, M., Lynch,, M., Yu,, S., Holman,, K., Baker,, E., … Richards,, R. (1991). Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science, 252(5013), 1711–1714. https://doi.org/10.1126/science.1675488
Krol,, J., Fiszer,, A., Mykowska,, A., Sobczak,, K., de Mezer,, M., & Krzyzosiak,, W. J. (2007). Ribonuclease Dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Molecular Cell, 25(4), 575–586. https://doi.org/10.1016/j.molcel.2007.01.031
Kumar,, A., Park,, H., Fang,, P., Parkesh,, R., Guo,, M., Nettles,, K. W., & Disney,, M. D. (2011). Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations. Biochemistry, 50(45), 9928–9935. https://doi.org/10.1021/bi2013068
Kuyumcu‐Martinez,, N. M., Wang,, G.‐S., & Cooper,, T. A. (2007). Increased steady‐state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC‐mediated hyperphosphorylation. Molecular Cell, 28(1), 68–78. https://doi.org/10.1016/j.molcel.2007.07.027
Laurent,, F.‐X., Sureau,, A., Klein,, A. F., Trouslard,, F., Gasnier,, E., Furling,, D., & Marie,, J. (2012). New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Research, 40(7), 3159–3171. https://doi.org/10.1093/nar/gkr1228
Lee,, Y.‐B., Chen,, H.‐J., Peres,, J. N., Gomez‐Deza,, J., Attig,, J., Štalekar,, M., … Shaw,, C. E. (2013). Hexanucleotide repeats in ALS/FTD form length‐dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Reports, 5(5), 1178–1186. https://doi.org/10.1016/j.celrep.2013.10.049
Li,, Q., Dong,, C., Cui,, J., Wang,, Y., & Hong,, X. (2018). Over‐expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up‐regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme. Journal of Experimental %26 Clinical Cancer Research, 37(1), 265. https://doi.org/10.1186/s13046-018-0941-x
Lin,, X., Miller,, J. W., Mankodi,, A., Kanadia,, R. N., Yuan,, Y., Moxley,, R. T., … Thornton,, C. A. (2006). Failure of MBNL1‐dependent post‐natal splicing transitions in myotonic dystrophy. Human Molecular Genetics, 15(13), 2087–2097. https://doi.org/10.1093/hmg/ddl132
Liquori,, C. L., Ricker,, K., Moseley,, M. L., Jacobsen,, J. F., Kress,, W., Naylor,, S. L., … Ranum,, L. P. W. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293(5531), 864–867. https://doi.org/10.1126/science.1062125
Liu,, C., Peng,, Z., Li,, P., Fu,, H., Feng,, J., Zhang,, Y., … Wu,, M. (2020). LncRNA RMST suppressed GBM cells mitophagy through enhancing FUS SUMOylation. Molecular Therapy ‐ Nucleic Acids, 19, 1198–1208. https://doi.org/10.1016/j.omtn.2020.01.008
Liu,, S. J., Nowakowski,, T. J., Pollen,, A. A., Lui,, J. H., Horlbeck,, M. A., Attenello,, F. J., … Lim,, D. A. (2016). Single‐cell analysis of long non‐coding RNAs in the developing human neocortex. Genome Biology, 17(1), 67. https://doi.org/10.1186/s13059-016-0932-1
Liu,, X., Xiao,, Z.‐D., Han,, L., Zhang,, J., Lee,, S.‐W., Wang,, W., … Gan,, B. (2016). LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nature Cell Biology, 18(4), 431–442. https://doi.org/10.1038/ncb3328
Liu,, X., Zhu,, Q., Guo,, Y., Xiao,, Z., Hu,, L., & Xu,, Q. (2019). LncRNA LINC00689 promotes the growth, metastasis and glycolysis of glioma cells by targeting miR‐338‐3p/PKM2 axis. Biomedicine %26 Pharmacotherapy, 117, 109069. https://doi.org/10.1016/j.biopha.2019.109069
Lu,, S., Zhang,, J., Lian,, X., Sun,, L., Meng,, K., Chen,, Y., … He,, Q.‐Y. (2019). A hidden human proteome encoded by ‘non‐coding’ genes. Nucleic Acids Research, 47(15), 8111–8125. https://doi.org/10.1093/nar/gkz646
Lu,, Z., Zhang,, Q. C., Lee,, B., Flynn,, R. A., Smith,, M. A., Robinson,, J. T., … Chang,, H. Y. (2016). RNA duplex map in living cells reveals higher‐order transcriptome structure. Cell, 165(5), 1267–1279. https://doi.org/10.1016/j.cell.2016.04.028
Luo,, S., Lu,, J. Y., Liu,, L., Yin,, Y., Chen,, C., Han,, X., … Shen,, X. (2016). Divergent lncRNAs regulate gene expression and lineage differentiation in pluripotent cells. Cell Stem Cell, 18(5), 637–652. https://doi.org/10.1016/j.stem.2016.01.024
Ma,, L., Sun,, X., Kuai,, W., Hu,, J., Yuan,, Y., Feng,, W., & Lu,, X. (2019). LncRNA SOX2 overlapping transcript acts as a miRNA sponge to promote the proliferation and invasion of Ewing`s sarcoma. American Journal of Translational Research, 11(6), 3841–3849 Retrieved from https://pubmed.ncbi.nlm.nih.gov/31312393
Ma,, L., Cao,, J., Liu,, L., Du,, Q., Li,, Z., Zou,, D., … Zhang,, Z. (2018). LncBook: A curated knowledgebase of human long non‐coding RNAs. Nucleic Acids Research, 47(D1), gky960. https://doi.org/10.1093/nar/gky960
Maida,, Y., Yasukawa,, M., Furuuchi,, M., Lassmann,, T., Possemato,, R., Okamoto,, N., … Masutomi,, K. (2009). An RNA‐dependent RNA polymerase formed by TERT and the RMRP RNA. Nature, 461(7261), 230–235. https://doi.org/10.1038/nature08283
Mao,, C., Wang,, X., Liu,, Y., Wang,, M., Yan,, B., Jiang,, Y., … Tao,, Y. (2018). A G3BP1‐interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Research, 78(13), 3484–3496. https://doi.org/10.1158/0008-5472.can-17-3454.
McCauley,, M. E., O`Rourke,, J. G., Yáñez,, A., Markman,, J. L., Ho,, R., Wang,, X., … Baloh,, R. H. (2020). C9orf72 in myeloid cells suppresses STING‐induced inflammation. Nature, 585(7823), 96–101. https://doi.org/10.1038/s41586-020-2625-x
Miller,, J. W., Urbinati,, C. R., Teng‐umnuay,, P., Stenberg,, M. G., Byrne,, B. J., Thornton,, C. A., & Swanson,, M. S. (2000). Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. The EMBO Journal, 19(17), 4439–4448. https://doi.org/10.1093/emboj/19.17.4439
Min,, K.‐W., Davila,, S., Zealy,, R. W., Lloyd,, L. T., Lee,, I. Y., Lee,, R., … Yoon,, J.‐H. (2017). eIF4E phosphorylation by MST1 reduces translation of a subset of mRNAs, but increases lncRNA translation. Biochimica et Biophysica Acta (BBA) ‐ Gene Regulatory Mechanisms, 1860(7), 761–772. https://doi.org/10.1016/j.bbagrm.2017.05.002
Mitrea,, D. M., & Kriwacki,, R. W. (2016). Phase separation in biology; functional organization of a higher order. Cell Communication and Signaling, 14(1), 1. https://doi.org/10.1186/s12964-015-0125-7
Mooers,, B. H., Logue,, J. S., & Berglund,, J. A. (2005). The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proceedings of the National Academy of Sciences of the United States of America, 102(46), 16626–16631. https://doi.org/10.1073/pnas.0505873102
Morriss,, G. R., & Cooper,, T. A. (2017). Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions. Human Genetics, 136(9), 1247–1263. https://doi.org/10.1007/s00439-017-1807-6
Niu,, L., Lou,, F., Sun,, Y., Sun,, L., Cai,, X., Liu,, Z., … Wang,, H. (2020). A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation. Science Advances, 6(21), eaaz2059. https://doi.org/10.1126/sciadv.aaz2059
Palazzo,, A. F., & Lee,, E. S. (2015). Non‐coding RNA: What is functional and what is junk? Frontiers in Genetics, 6, 2. https://doi.org/10.3389/fgene.2015.00002
Paul,, S., Dansithong,, W., Kim,, D., Rossi,, J., Webster,, N. J., Comai,, L., & Reddy,, S. (2006). Interaction of musleblind, CUG‐BP1 and hnRNP H proteins in DM1‐associated aberrant IR splicing. The EMBO Journal, 25(18), 4271–4283. https://doi.org/10.1038/sj.emboj.7601296
Pearson,, C. E. (2011). Repeat associated non‐ATG translation initiation: One DNA, two transcripts, seven Reading frames, potentially nine toxic entities! PLoS Genetics, 7(3), e1002018. https://doi.org/10.1371/journal.pgen.1002018
Peng,, W.‐X., Koirala,, P., & Mo,, Y.‐Y. (2017). LncRNA‐mediated regulation of cell signaling in cancer. Oncogene, 36(41), 5661–5667. https://doi.org/10.1038/onc.2017.184
Ponting,, C. P., Oliver,, P. L., & Reik,, W. (2009). Evolution and functions of long noncoding RNAs. Cell, 136(4), 629–641. https://doi.org/10.1016/j.cell.2009.02.006
Prasanth,, K. V., Rajendra,, T. K., Lal,, A. K., & Lakhotia,, S. C. (2000). Omega speckles ‐ a novel class of nuclear speckles containing hnRNPs associated with noncoding hsr‐omega RNA in Drosophila. Journal of Cell Science, 113(19), 3485. Retrieved from. http://jcs.biologists.org/content/113/19/3485.abstract
Qu,, L., Ding,, J., Chen,, C., Wu,, Z.‐J., Liu,, B., Gao,, Y., … Wang,, L.‐H. (2016). Exosome‐transmitted lncARSR promotes Sunitinib resistance in renal Cancer by acting as a competing endogenous RNA. Cancer Cell, 29(5), 653–668. https://doi.org/10.1016/j.ccell.2016.03.004
Ren,, J., Fu,, J., Ma,, T., Yan,, B., Gao,, R., An,, Z., & Wang,, D. (2018). LncRNA H19‐elevated LIN28B promotes lung cancer progression through sequestering miR‐196b. Cell Cycle, 17(11), 1372–1380. https://doi.org/10.1080/15384101.2018.1482137
Rivas,, E., Clements,, J., & Eddy,, S. R. (2017). A statistical test for conserved RNA structure shows lack of evidence for structure in lncRNAs. Nature Methods, 14(1), 45–48. https://doi.org/10.1038/nmeth.4066
Rogler,, L. E., Kosmyna,, B., Moskowitz,, D., Bebawee,, R., Rahimzadeh,, J., Kutchko,, K., … Rogler,, C. E. (2014). Small RNAs derived from lncRNA RNase MRP have gene‐silencing activity relevant to human cartilage–Hair hypoplasia. Human Molecular Genetics, 23(2), 368–382. https://doi.org/10.1093/hmg/ddt427
Ruan,, X., Li,, P., Chen,, Y., Shi,, Y., Pirooznia,, M., Seifuddin,, F., … Cao,, H. (2020). In vivo functional analysis of non‐conserved human lncRNAs associated with cardiometabolic traits. Nature Communications, 11(1), 45. https://doi.org/10.1038/s41467-019-13688-z
Rybak‐Wolf,, A., Jens,, M., Murakawa,, Y., Herzog,, M., Landthaler,, M., & Rajewsky,, N. (2014). A variety of Dicer substrates in human and C. elegans. Cell, 159(5), 1153–1167. https://doi.org/10.1016/j.cell.2014.10.040
Salmena,, L., Poliseno,, L., Tay,, Y., Kats,, L., & Pandolfi,, P. P. (2011). A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell, 146(3), 353–358. https://doi.org/10.1016/j.cell.2011.07.014
Santoro,, M., Fontana,, L., Masciullo,, M., Bianchi,, M. L. E., Rossi,, S., Leoncini,, E., … Silvestri,, G. (2015). Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1). Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1852(12), 2645–2652. https://doi.org/10.1016/j.bbadis.2015.09.007
Sellier,, C., Rau,, F., Liu,, Y., Tassone,, F., Hukema,, R. K., Gattoni,, R., … Charlet‐Berguerand,, N. (2010). Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. The EMBO Journal, 29(7), 1248–1261. https://doi.org/10.1038/emboj.2010.21
Smola,, M. J., Christy,, T. W., Inoue,, K., Nicholson,, C. O., Friedersdorf,, M., Keene,, J. D., … Weeks,, K. M. (2016). SHAPE reveals transcript‐wide interactions, complex structural domains, and protein interactions across the Xist lncRNA in living cells. Proceedings of the National Academy of Sciences, 113(37), 10322–10327. https://doi.org/10.1073/pnas.1600008113
Spencer,, H. L., Sanders,, R., Boulberdaa,, M., Meloni,, M., Cochrane,, A., Spiroski,, A.‐M., … Baker,, A. H. (2020). The LINC00961 transcript and its encoded micropeptide SPAAR regulate endothelial cell function. Cardiovascular Research, 116, 1981–1994. https://doi.org/10.1093/cvr/cvaa008
Starck,, S. R., Tsai,, J. C., Chen,, K., Shodiya,, M., Wang,, L., Yahiro,, K., … Walter,, P. (2016). Translation from the 5′ untranslated region shapes the integrated stress response. Science, 351(6272), aad3867. https://doi.org/10.1126/science.aad3867
Su,, Z., Zhang,, Y., Gendron,, T. F., Bauer,, P. O., Chew,, J., Yang,, W. Y., … Disney,, M. D. (2014). Discovery of a biomarker and lead small molecules to target r(GGGGCC)‐associated defects in c9FTD/ALS. Neuron, 83(5), 1043–1050. https://doi.org/10.1016/j.neuron.2014.07.041
Tang,, J., Zhong,, G., Zhang,, H., Yu,, B., Wei,, F., Luo,, L., … Bi,, A. (2018). LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA. Cell Death %26 Disease, 9(12), 1167. https://doi.org/10.1038/s41419-018-1220-7
Tavares,, R. C. A., Pyle,, A. M., & Somarowthu,, S. (2019). Phylogenetic analysis with improved parameters reveals conservation in lncRNA structures. Journal of Molecular Biology, 431(8), 1592–1603. https://doi.org/10.1016/j.jmb.2019.03.012
Thomson,, D. W., & Dinger,, M. E. (2016). Endogenous microRNA sponges: Evidence and controversy. Nature Reviews Genetics, 17(5), 272–283. https://doi.org/10.1038/nrg.2016.20
Tian,, B., White,, R. J., Xia,, T., Welle,, S., Turner,, D. H., Mathews,, M. B., & Thornton,, C. A. (2000). Expanded CUG repeat RNAs form hairpins that activate the double‐stranded RNA‐dependent protein kinase PKR. RNA, 6(1), 79–87. https://doi.org/10.1017/s1355838200991544
Todd,, P. K., Oh,, S. Y., Krans,, A., He,, F., Sellier,, C., Frazer,, M., … Paulson,, H. L. (2013). CGG repeat‐associated translation mediates neurodegeneration in fragile X tremor Ataxia syndrome. Neuron, 78(3), 440–455. https://doi.org/10.1016/j.neuron.2013.03.026
Ulitsky,, I., & Bartel,, D. P. (2013). lincRNAs: Genomics, evolution, and mechanisms. Cell, 154(1), 26–46. https://doi.org/10.1016/j.cell.2013.06.020
Uroda,, T., Anastasakou,, E., Rossi,, A., Teulon,, J.‐M., Pellequer,, J.‐L., Annibale,, P., … Marcia,, M. (2019). Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway. Molecular Cell, 75(5), 982–995. https://doi.org/10.1016/j.molcel.2019.07.025
van Cruchten,, R. T. P., Wieringa,, B., & Wansink,, D. G. (2019). Expanded CUG repeats in DMPK transcripts adopt diverse hairpin conformations without influencing the structure of the flanking sequences. RNA, 25(4), 481–495. https://doi.org/10.1261/rna.068940.118
Venter,, J. C., Adams,, M. D., Myers,, E. W., Li,, P. W., Mural,, R. J., Sutton,, G. G., … Zhu,, X. (2001). The sequence of the human genome. Science, 291(5507), 1304–1351. https://doi.org/10.1126/science.1058040
Wan,, G., Hu,, X., Liu,, Y., Han,, C., Sood,, A. K., Calin,, G. A., … Lu,, X. (2013). A novel non‐coding RNA lncRNA‐JADE connects DNA damage signalling to histone H4 acetylation. The EMBO Journal, 32(21), 2833–2847. https://doi.org/10.1038/emboj.2013.221
Wang,, C., Ge,, L., Wu,, J., Wang,, X., & Yuan,, L. (2018). MiR‐219 represses expression of dFMR1 in Drosophila melanogaster. Life Sciences, 218, 31–37. https://doi.org/10.1016/j.lfs.2018.12.008
Wang,, E. T., Ward,, A. J., Cherone,, J. M., Giudice,, J., Wang,, T. T., Treacy,, D. J., … Burge,, C. B. (2015). Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins. Genome Research, 25(6), 858–871. https://doi.org/10.1101/gr.184390.114
Witkos,, T. M., Krzyzosiak,, W. J., Fiszer,, A., & Koscianska,, E. (2018). A potential role of extended simple sequence repeats in competing endogenous RNA crosstalk. RNA Biology, 15(11), 1399–1409. https://doi.org/10.1080/15476286.2018.1536593
Wu,, H., Yin,, Q.‐F., Luo,, Z., Yao,, R.‐W., Zheng,, C.‐C., Zhang,, J., … Chen,, L.‐L. (2016). Unusual processing generates SPA LncRNAs that sequester multiple RNA binding proteins. Molecular Cell, 64(3), 534–548. https://doi.org/10.1016/j.molcel.2016.10.007
Xing,, W., Xu,, W.‐Y., Chang,, L., Zhang,, K., & Wang,, S.‐R. (2020). SP1‐induced lncRNA LINC00689 overexpression contributes to osteosarcoma progression via the miR‐655/SOX18 axis. European Review for Medical and Pharmacological Sciences, 24(5), 2205–2217. https://doi.org/10.26355/eurrev_202003_20486
Xue,, Z., Hennelly,, S., Doyle,, B., Gulati,, A. A., Novikova,, I. V., Sanbonmatsu,, K. Y., & Boyer,, L. A. (2016). A G‐rich motif in the lncRNA Braveheart interacts with a zinc‐finger transcription factor to specify the cardiovascular lineage. Molecular Cell, 64(1), 37–50. https://doi.org/10.1016/j.molcel.2016.08.010
Yadava,, R. S., Foff,, E. P., Yu,, Q., Gladman,, J. T., Kim,, Y. K., Bhatt,, K. S., … Mahadevan,, M. S. (2015). TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human Molecular Genetics, 24(7), 2035–2048. https://doi.org/10.1093/hmg/ddu617
Yamazaki,, T., Nakagawa,, S., & Hirose,, T. (2020). Architectural RNAs for Membraneless nuclear body formation. Cold Spring Harbor Symposia on Quantitative Biology, 039404, 227–237. https://doi.org/10.1101/sqb.2019.84.039404
Yang,, F., Deng,, X., Ma,, W., Berletch,, J. B., Rabaia,, N., Wei,, G., … Disteche,, C. M. (2015). The lncRNA firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biology, 16(1), 52. https://doi.org/10.1186/s13059-015-0618-0
Yeasmin,, F., Yada,, T., & Akimitsu,, N. (2018). Micropeptides encoded in transcripts previously identified as long noncoding RNAs: A new chapter in transcriptomics and proteomics. Frontiers in Genetics, 9, 144. https://doi.org/10.3389/fgene.2018.00144
Yoon,, J.‐H., Abdelmohsen,, K., Kim,, J., Yang,, X., Martindale,, J. L., Tominaga‐Yamanaka,, K., … Gorospe,, M. (2013). Scaffold function of long non‐coding RNA HOTAIR in protein ubiquitination. Nature Communications, 4(1), 2939. https://doi.org/10.1038/ncomms3939
Yu,, Z., Teng,, X., & Bonini,, N. M. (2011). Triplet repeat–derived siRNAs enhance RNA–mediated toxicity in a Drosophila model for myotonic dystrophy. PLoS Genetics, 7(3), e1001340. https://doi.org/10.1371/journal.pgen.1001340
Yuan,, G., Liu,, B., Han,, W., & Zhao,, D. (2019). LncRNA‐MIR17HG mediated upregulation of miR‐17 and miR‐18a promotes colon cancer progression via activating Wnt/β‐catenin signaling. Translational Cancer Research, 8(4), 1097–1108. https://doi.org/10.21037/tcr.2019.06.20
Zhang,, K., Donnelly,, C. J., Haeusler,, A. R., Grima,, J. C., Machamer,, J. B., Steinwald,, P., … Rothstein,, J. D. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature, 525(7567), 56–61. https://doi.org/10.1038/nature14973
Zhang,, Y.‐J., Gendron,, T. F., Grima,, J. C., Sasaguri,, H., Jansen‐West,, K., Xu,, Y.‐F., … Petrucelli,, L. (2016). C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nature Neuroscience, 19(5), 668–677. https://doi.org/10.1038/nn.4272
Zhao,, Z., Sentürk,, N., Song,, C., & Grummt,, I. (2018). lncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures. Genes %26 Development, 32(11–12), 836–848. https://doi.org/10.1101/gad.311688.118
Zhou,, W., Ye,, X., Xu,, J., Cao,, M.‐G., Fang,, Z.‐Y., Li,, L.‐Y., … Xie,, D. (2017). The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR‐200b/c and let‐7b. Science Signaling, 10(483), eaak9557. https://doi.org/10.1126/scisignal.aak9557
Zongaro,, S., Hukema,, R., D`Antoni,, S., Davidovic,, L., Barbry,, P., Catania,, M. V., … Bardoni,, B. (2013). The 3′ UTR of FMR1 mRNA is a target of miR‐101, miR‐129‐5p and miR‐221: Implications for the molecular pathology of FXTAS at the synapse. Human Molecular Genetics, 22(10), 1971–1982. https://doi.org/10.1093/hmg/ddt044
Zu,, T., Cleary,, J. D., Liu,, Y., Bañez‐Coronel,, M., Bubenik,, J. L., Ayhan,, F., … Ranum,, L. P. W. (2017). RAN translation regulated by Muscleblind proteins in myotonic dystrophy type 2. Neuron, 95(6), 1292–1305. https://doi.org/10.1016/j.neuron.2017.08.039
Zu,, T., Gibbens,, B., Doty,, N. S., Gomes‐Pereira,, M., Huguet,, A., Stone,, M. D., … Ranum,, L. P. W. (2011). Non‐ATG–initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences, 108(1), 260–265. https://doi.org/10.1073/pnas.1013343108
Zumwalt,, M., Ludwig,, A., Hagerman,, P. J., & Dieckmann,, T. (2007). Secondary structure and dynamics of the r(CGG) repeat in the mRNA of the fragile X mental retardation 1(FMR1) gene. RNA Biology, 4(2), 93–100. https://doi.org/10.4161/rna.4.2.5039

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Overlapping mechanisms of lncRNA and expanded microsatellite RNA

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox