Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system. Studies have shown that lncRNAs are expressed in a highly lineage-specific manner and control the differentiation and function of innate and adaptive cell types. In this Review, we focus on mechanisms used by lncRNAs to regulate genes encoding products involved in the immune response, including direct interactions with chromatin, RNA and proteins. In addition, we address new areas of lncRNA biology, such as the functions of enhancer RNAs, circular RNAs and chemical modifications to RNA in cellular processes. We emphasize critical gaps in knowledge and future prospects for the roles of lncRNAs in the immune system and autoimmune disease.
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Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002).
Rinn, J.L. et al. The transcriptional activity of human chromosome 22. Genes Dev. 17, 529–540 (2003).
Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).
Iyer, M.K. et al. The landscape of long noncoding RNAs in the human transcriptome. Nat. Genet. 47, 199–208 (2015).
Mattick, J.S. & Rinn, J.L. Discovery and annotation of long noncoding RNAs. Nat. Struct. Mol. Biol. 22, 5–7 (2015).
Rinn, J.L. & Chang, H.Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).
Natoli, G. & Andrau, J.-C. Noncoding transcription at enhancers: general principles and functional models. Annu. Rev. Genet. 46, 1–19 (2012).
Hansen, T.B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).
Salzman, J., Gawad, C. & Wang, P.L Lacayo. N., Brown, P.O. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PloS One 7, e30733 (2012).
Jeck, W.R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 141–157 (2013).
Guo, J.U., Agarwal, V., Guo, H. & Bartel, D.P. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15, 409 (2014).
Brown, C.J. et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542 (1992).
Clemson, C.M., McNeil, J.A., Willard, H.F. & Lawrence, J.B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J. Cell Biol. 132, 259–275 (1996).
Zhao, J., Sun, B.K., Erwin, J.A., Song, J.-J. & Lee, J.T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756 (2008).
Leighton, P.A., Ingram, R.S., Eggenschwiler, J., Efstratiadis, A. & Tilghman, S.M. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375, 34–39 (1995).
Monnier, P. et al. H19 lncRNA controls gene expression of the imprinted gene network by recruiting MBD1. Proc. Natl. Acad. Sci. USA 110, 20693–20698 (2013).
Wang, Y. et al. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev. Cell 25, 69–80 (2013).
Loewer, S. et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat. Genet. 42, 1113–1117 (2010).
Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).
Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).
Flynn, R.A. & Chang, H.Y. Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell 14, 752–761 (2014).
Lee, J.T. & Bartolomei, M.S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).
Tsai, M.-C., Spitale, R.C. & Chang, H.Y. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 71, 3–7 (2011).
Wang, K.C. & Chang, H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914 (2011).
Cruz, J.A. & Westhof, E. The dynamic landscapes of RNA architecture. Cell 136, 604–609 (2009).
Guttman, M. & Rinn, J.L. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).
Latos, P.A. et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338, 1469–1472 (2012).
Petruk, S. et al. Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 127, 1209–1221 (2006).
Engreitz, J.M. et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539, 452–455 (2016).
Sigova, A.A. et al. Transcription factor trapping by RNA in gene regulatory elements. Science 350, 978–981 (2015).
Li, Y., Syed, J. & Sugiyama, H. RNA-DNA triplex formation by long noncoding RNAs. Cell Chem. Biol, 23, 1325–1333 (2016).
Martianov, I., Ramadass, A., Serra Barros, A., Chow, N. & Akoulitchev, A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007).
Schmitz, K.-M., Mayer, C., Postepska, A. & Grummt, I. Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev. 24, 2264–2269 (2010).
Lee, N., Moss, W.N., Yario, T.A. & Steitz, J.A. EBV noncoding RNA binds nascent RNA to drive host PAX5 to viral DNA. Cell 160, 607–618 (2015).
Tsai, M.-C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).
Peschansky, V.J. & Wahlestedt, C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics 9, 3–12 (2014).
Chu, C. et al. Systematic discovery of Xist RNA binding proteins. Cell 161, 404–416 (2015).
Wutz, A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat. Rev. Genet. 12, 542–553 (2011).
Wang, K.C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).
Dimitrova, N. et al. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol. Cell 54, 777–790 (2014).
Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).
Kino, T., Hurt, D.E., Ichijo, T., Nader, N. & Chrousos, G.P. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci. Signal. 3, ra8 (2010).
Rapicavoli, N.A. et al. A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. eLife 2, e00762 (2013).
Li, Z. et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22, 256–264 (2015).
Ashwal-Fluss, R. et al. circRNA biogenesis competes with pre-mRNA splicing. Mol. Cell 56, 55–66 (2014).
Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).
Guttman, M. et al. Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs. Nat. Biotechnol. 28, 503–510 (2010).
Washietl, S., Kellis, M. & Garber, M. Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals. Genome Res. 24, 616–628 (2014).
Li, L. et al. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep. 5, 3–12 (2013).
Kretz, M. et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493, 231–235 (2013).
Guttman, M. et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295–300 (2011).
Wang, P.L. et al. Circular RNA is expressed across the eukaryotic tree of life. PLoS One 9, e90859 (2014).
Guo, J.U., Agarwal, V., Guo, H. & Bartel, D.P. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15, 409 (2014).
Liang, D. & Wilusz, J.E. Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 28, 2233–2247 (2014).
Hu, G. et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat. Immunol. 14, 1190–1198 (2013).
Ranzani, V. et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat. Immunol. 16, 318–325 (2015).
Venkatraman, A. et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 500, 345–349 (2013).
Luo, M. et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell 16, 426–438 (2015).
Satpathy, A.T., Wu, X., Albring, J.C. & Murphy, K.M. Re(de)fining the dendritic cell lineage. Nat. Immunol. 13, 1145–1154 (2012).
Wang, P. et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science 344, 310–313 (2014).
Kotzin, J.J. et al. The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature 537, 239–243 (2016).
Dijkstra, J.M. & Ballingall, K.T. Non-human lnc-DC orthologs encode Wdnm1-like protein [version 2; referees: 3 approved]. F1000Research 3, 160 (2014).
Spurlock, C.F. III et al. Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat. Commun. 6, 6932–6943 (2015).
Huang, W. et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528, 517–522 (2015).
Mäkitie, O., Kaitila, I. & Savilahti, E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur. J. Pediatr. 157, 816–820 (1998).
Bonafé, L. et al. Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genet. 1, e47 (2005).
Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).
Carpenter, S. et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science 341, 789–792 (2013).
Geuens, T., Bouhy, D. & Timmerman, V. The hnRNP family: insights into their role in health and disease. Hum. Genet. 135, 851–867 (2016).
Li, Z. et al. The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL. Proc. Natl. Acad. Sci. USA 111, 1002–1007 (2014).
Krawczyk, M. & Emerson, B.M. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes. eLife 3, e01776 (2014).
Smith, W.L., DeWitt, D.L. & Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).
Sun, S. et al. Jpx RNA activates Xist by evicting CTCF. Cell 153, 1537–1551 (2013).
Chen, Y.G. et al. Sensing self and foreign circular RNAs by intron identity. Mol. Cell. 67, 1–11 (2017).
Ng, W.L. et al. Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway. RNA Biol. 13, 861–871 (2016).
Atianand, M.K. et al. A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell 165, 1672–1685 (2016).
Castellanos-Rubio, A. et al. A long noncoding RNA associated with susceptibility to celiac disease. Science 352, 91–95 (2016).
Liu, B. et al. A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27, 370–381 (2015).
Gomez, J.A. et al. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus. Cell 152, 743–754 (2013).
Brahic, M., Bureau, J.F. & Michiels, T. The genetics of the persistent infection and demyelinating disease caused by Theiler's virus. Annu. Rev. Microbiol. 59, 279–298 (2005).
Vigneau, S. et al. Homology between a 173-kb region from mouse chromosome 10, telomeric to the Ifng locus, and human chromosome 12q15. Genomics 78, 206–213 (2001).
Vigneau, S., Rohrlich, P.-S., Brahic, M. & Bureau, J.F. Tmevpg1, a candidate gene for the control of Theiler's virus persistence, could be implicated in the regulation of gamma interferon. J. Virol. 77, 5632–5638 (2003).
Bihl, F., Brahic, M. & Bureau, J.F. Two loci, Tmevp2 and Tmevp3, located on the telomeric region of chromosome 10, control the persistence of Theiler's virus in the central nervous system of mice. Genetics 152, 385–392 (1999).
Bureau, J.F. et al. Mapping loci influencing the persistence of Theiler's virus in the murine central nervous system. Nat. Genet. 5, 87–91 (1993).
Levillayer, F., Mas, M., Levi-Acobas, F., Brahic, M. & Bureau, J.F. Interleukin 22 is a candidate gene for Tmevp3, a locus controlling Theiler's virus-induced neurological diseases. Genetics 176, 1835–1844 (2007).
Collier, S.P., Collins, P.L., Williams, C.L., Boothby, M.R. & Aune, T.M. Influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J. immunol. 189, 2084–2088 (2012).
Collier, S.P., Henderson, M.A., Tossberg, J.T. & Aune, T.M. Regulation of the Th1 genomic locus from Ifng through Tmevpg1 by T-bet. J. Immunol. 193, 3959–3965 (2014).
Willingham, A.T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005).
Sharma, S. et al. Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc. Natl. Acad. Sci. USA 108, 11381–11386 (2011).
Liu, Z. et al. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat. Immunol. 12, 1063–1070 (2011).
Wang, Y. et al. Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection. Proc. Natl. Acad. Sci. USA 112, E3883–E3892 (2015).
Dunin-Horkawicz, S., Czerwoniec, A., Gajda, M.J., Feder, M., Grosjean, H. & Bujnicki, J.M. MODOMICS: a database of RNA modification pathways. Nucleic Acids Res. 34, D145–D149 (2006).
Meyer, K.D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).
Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).
Squires, J.E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).
Carlile, T.M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 advance online publication (2014).
Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014).
Gong, J. et al. LNCediting: a database for functional effects of RNA editing in lncRNAs. Nucleic Acids Res. 45, D79–D84 (2017).
Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).
Picardi, E. et al. Profiling RNA editing in human tissues: towards the inosinome Atlas. Sci. Rep. 5, 14941 (2015).
Marcu-Malina, V. et al. ADAR1 is vital for B cell lineage development in the mouse bone marrow. Oncotarget 7, 54370–54379 (2016).
Goldstein, B. et al. A-to-I RNA editing promotes developmental-stage-specific gene and lncRNA expression. Genome Res. 27, 462–470 (2016).
Limbach, P.A., Crain, P.F. & McCloskey, J.A. Summary: the modified nucleosides of RNA. Nucleic Acids Res. 22, 2183–2196 (1994).
Cao, G., Li, H.-B., Yin, Z. & Flavell, R.A. Recent advances in dynamic m6A RNA modification. Open Biol. 6, 160003 (2016).
Patil, D.P. et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).
Zhao, B.S. et al. m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 542, 475–478 (2017).
Picardi, E., D'Erchia, A.M., Gallo, A., Montalvo, A. & Pesole, G. Uncovering RNA editing sites in long non-coding RNAs. Front. Bioeng. Biotechnol. 2, 64 (2014).
Levanon, E.Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 1001–1005 (2004).
Bass, B.L. et al. A standardized nomenclature for adenosine deaminases that act on RNA. RNA 3, 947–949 (1997).
Liddicoat, B.J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).
Ramaswami, G. & Li, J.B. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 42, D109–D113 (2014).
Poulsen, H., Nilsson, J., Damgaard, C.K., Egebjerg, J. & Kjems, J. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol. Cell. Biol. 21, 7862–7871 (2001).
Eckmann, C.R., Neunteufl, A., Pfaffstetter, L. & Jantsch, M.F. The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein. Mol. Biol. Cell 12, 1911–1924 (2001).
Nie, Y., Zhao, Q., Su, Y. & Yang, J.-H. Subcellular distribution of ADAR1 isoforms is synergistically determined by three nuclear discrimination signals and a regulatory motif. J. Biol. Chem. 279, 13249–13255 (2004).
Desterro, J.M.P. et al. Dynamic association of RNA-editing enzymes with the nucleolus. J. Cell Sci. 116, 1805–1818 (2003).
Gallo, A. & Locatelli, F. ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. Biol. Rev. Camb. Philos. Soc. 87, 95–110 (2012).
Silberberg, G., Lundin, D., Navon, R. & Öhman, M. Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum. Mol. Genet. 21, 311–321 (2012).
Wang, Q., Khillan, J., Gadue, P. & Nishikura, K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 1765–1768 (2000).
Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78–81 (2000).
Han, L. et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28, 515–528 (2015).
Fumagalli, D. et al. Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep. 13, 277–289 (2015).
Paz-Yaacov, N. et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep. 13, 267–276 (2015).
Salameh, A. et al. PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proc. Natl. Acad. Sci. USA 112, 8403–8408 (2015).
Funabiki, M. et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity 40, 199–212 (2014).
Mannion, N.M. et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494 (2014).
Hung, T. et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350, 455–459 (2015).
Ivanov, A. et al. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10, 170–177 (2015).
Wilusz, J.E. Repetitive elements regulate circular RNA biogenesis. Mob. Genet. Elements 5, 1–7 (2015).
Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).
Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321–349 (2010).
Ramaswami, G. et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods 9, 579–581 (2012).
Dou, Y. et al. Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci. Rep. 6, 37982 (2016).
Motorin, Y. & Helm, M. RNA nucleotide methylation. Wiley Interdiscip. Rev. RNA 2, 611–631 (2011).
Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347, 1002–1006 (2015).
Blanco, S. & Frye, M. Role of RNA methyltransferases in tissue renewal and pathology. Curr. Opin. Cell Biol. 31, 1–7 (2014).
Batista, P.J. et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).
Klungland, A. & Dahl, J.A. Dynamic RNA modifications in disease. Curr. Opin. Genet. Dev. 26, 47–52 (2014).
Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).
Liu, N. et al. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).
Narayan, P. & Rottman, F.M. An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. Science 242, 1159–1162 (1988).
Bokar, J.A., Rath-Shambaugh, M.E., Ludwiczak, R., Narayan, P. & Rottman, F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J. Biol. Chem. 269, 17697–17704 (1994).
Bokar, J.A., Shambaugh, M.E., Polayes, D., Matera, A.G. & Rottman, F.M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3, 1233–1247 (1997).
Zhao, X. et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24, 1403–1419 (2014).
Meyer, K.D. et al. 5′ UTR m(6)A promotes cap-independent translation. Cell 163, 999–1010 (2015).
Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).
Spitale, R.C. et al. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 519, 486–490 (2015).
Roost, C. et al. Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. J. Am. Chem. Soc. 137, 2107–2115 (2015).
Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).
Diebold, S.S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143, 1–20 (2008).
Yang, Y. et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 27, 626–641 (2017).
Legnini, I. et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol. Cell 66, 22–37.e9 (2017).
Clark, M.B. et al. Genome-wide analysis of long noncoding RNA stability. Genome Res. 22, 885–898 (2012).
We thank members of the Chang laboratory for discussions, and J. Tumey for figure artwork. Supported by the US National Institutes of Health (P50HG007735), the Parker Institute for Cancer Immunotherapy, the Scleroderma Research Foundation (H.Y.C.) and the Cancer Research Institute (Irvington Fellowship to A.T.S.).
H.Y.C. is a founder of Epinomics and a member of its scientific advisory board.
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Chen, Y., Satpathy, A. & Chang, H. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18, 962–972 (2017). https://doi.org/10.1038/ni.3771
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