Henao-Mejia, Jorge

Kwon, Grace J

Williams, Adam

English

The Jackson Laboratory: The Mouseion at the JAXlibrary

The Jackson Laboratory The Mouseion at the JAXlibrary Faculty Research 2019 Faculty Research 10-9-2019 Editorial: Long Non-coding RNAs and Immunity. Grace J Kwon Jorge Henao-Mejia Adam Williams Follow this and additional works at: https://mouseion.jax.org/stfb2019  Part of the Life Sciences Commons, and the Medicine and Health Sciences Commons EDITORIALpublished: 09 October 2019doi: 10.3389/fimmu.2019.02378Frontiers in Immunology | www.frontiersin.org 1 October 2019 | Volume 10 | Article 2378Edited and reviewed by:Francesca Granucci,University of Milano Bicocca, Italy*Correspondence:Adam Williamsadam.williams@jax.orgSpecialty section:This article was submitted toMolecular Innate Immunity,a section of the journalFrontiers in ImmunologyReceived: 03 September 2019Accepted: 23 September 2019Published: 09 October 2019Citation:Kwon GJ, Henao-Mejia J andWilliams A (2019) Editorial: LongNon-coding RNAs and Immunity.Front. Immunol. 10:2378.doi: 10.3389/fimmu.2019.02378Editorial: Long Non-coding RNAs andImmunityGrace J. Kwon 1,2, Jorge Henao-Mejia 3,4,5 and Adam Williams 1,2*1Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, United States,2 The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States, 3Department of Pathology and LaboratoryMedicine, University of Pennsylvania, Philadelphia, PA, United States, 4 Institute for Immunology, Perelman School ofMedicine, University of Pennsylvania, Philadelphia, PA, United States, 5Division of Transplant Immunology, Department ofPathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA,United StatesKeywords: long non-coding RNA, immunity, circular RNA, X-chromosome inactivation, viral infection, rickettsialinfection, GWASEditorial on the Research TopicLong Non-coding RNAs and ImmunityNext-generation sequencing has shown that the majority of the human genome does notencode proteins, yet many such “non-coding” regions are actively transcribed into RNA. Inparticular, long non-coding RNAs (lncRNAs) have received considerable interest for theiressential roles in numerous biological processes. Defined as non-protein-coding transcripts longerthan 200 nucleotides, lncRNAs are frequently expressed in a tissue-specific or developmentalstage-specific manner (1, 2). Multiple studies have shown lncRNAs to be dysregulated in disease,and genome-wide association studies (GWAS) have also identified numerous single nucleotidepolymorphisms (SNPs) within lncRNAs (3–5). These features distinguish them as attractivecandidates for therapeutic targets or biomarkers. While still in its infancy, the dissection of lncRNAbiology has unveiled critical roles in immune cell development and function. However, as thefunctions of most lncRNAs are yet to be determined, the field must fill a considerable void tounderstand the breadth of their roles in immunity. This Research Topic focuses on how lncRNAscontribute to immune function in a variety of different contexts, and what key questions drive thisrapidly expanding field.DOSAGE COMPENSATION AND X-LINKED IMMUNE GENESFemales have a more responsive immune system than males (6, 7), potentially driving a higherpredisposition to autoimmune diseases such as systemic lupus erythematosus (SLE) (8). The Xchromosome carries a significant number of immune-related genes, but how this translates to sexdisparities in immune diseases remains to be determined. Xist is one of the best characterizedlncRNAs, and functions as an effector of dosage compensation in female cells. Xist maintainsinactivation of one X chromosome by binding along its length and recruiting repressive factors tosilence transcription. Immune cells, however, regulate X chromosome inactivation through diversemechanisms that are not limited to the use of Xist RNA, as recently revealed by Syrett et al. Forinstance, the inactivated X in female murine plasmacytoid dendritic cells (pDCs) lacks both XistRNA and the repressive chromatin modification H3K27me3. Interestingly, pDCs from femalemice that spontaneously develop SLE-like disease show increased biallelic expression of the X-linked gene Tlr7, as compared to healthy female mice. Further delineating the mechanisms ofX chromosome inactivation in immune cells will be necessary before we can develop a completeunderstanding of how sex and sex-linked genes contribute to autoimmune diseases.Kwon et al. Editorial: Long Non-coding RNAs and ImmunityLNCRNAS IN RICKETTSIAL INFECTIONThe Rickettsia genus of Gram-negative obligate intracellularbacteria is transmitted to humans via arthropod vectors,including ticks, fleas, and lice, and can infect the vascularendothelium to cause illnesses such as Rocky Mountain spottedfever. There are increasing concerns over the prevalenceof Rickettsia due to climate change and the spread ofvector populations. Understanding rickettsial infection anddeveloping novel therapeutics to mitigate its spread through thevascular endothelium will thus be crucial in the near future.Chowdhury et al. have begun to address the roles of lncRNAs inthe host response to Rickettsia species using a mouse model of R.conorii infection. The authors identified two enhancer lncRNAsaffecting expression of nearby genes, Id2 andApol10b, which havenot been previously studied in rickettsial infection. Furthermore,these two lncRNAs exhibit differential expression in infectedmacrophages compared to endothelial cells, emphasizing the celltype-specificity of lncRNAs. The resulting genome-wide analysisof lncRNA expression during rickettsial infection establishesa foundation to further study the host immune response toRickettsia species and reveals cell type-specific signaling pathwaysmediated by enhancer lncRNAs.VIRAL AND HOST LNCRNAS IN ANTIVIRALIMMUNITYSome of themost interesting advancements in our understandingof lncRNAs in immunity come from the study of their rolesin viral infection. While it would be intuitive to assume hostlncRNAs exist to suppress viral infections, it has been shownthat host lncRNAs can actually increase viral replication andpathogenesis during certain infections (9). This begets the needto further examine what purpose both host and viral lncRNAsserve, and how it may change in the context of non-infectedand infected states. Wang reviews in detail the known lncRNAsinvolved in multiple steps of the viral life cycle and infection.LNCING GWAS SNPS TO DISEASEPATHOGENESISGWAS have provided a more complete understanding ofcomplex diseases. Of the more than 70,000 variant-traitassociations cataloged from GWAS (10), a majority of thesemap to non-coding regions of the genome, including thosecontaining lncRNAs. Despite this, the impact of only a few SNPson lncRNA function has been described. A major limitation inthe field is that the function of most lncRNAs is unknown. Inaddition, while SNPs in lncRNAs likely affect their secondary andtertiary structure, we cannot currently predict how this will altertheir function. Castellanos-Rubio and Ghosh review the disease-associated lncRNA SNPs that have been described thus far.Further inquiry and development of tools to interpret lncRNAstructure and function will be necessary before the impact oflncRNA SNPs (and other genetic variants) on disease can befully realized.CIRCULAR RNAS AS A NEW CLASS OFIMMUNE REGULATORSWhile lncRNAs typically display features associated with linearmessenger RNA, such as 5′ capping, alternative splicing, andpolyadenylation, non-coding RNA loci can also be transcribedto form circular RNA (circRNAs). These circRNAs form closedloops without 5′ capping or polyadenylation and can containmultiple exons. Similar to lncRNAs, circRNAs are frequentlyexpressed in a tissue-specific manner, undergo chemicalmodifications, and function through varied mechanisms.Yang et al. review the mechanisms of circRNA biogenesis,summarize the current understanding of their function inimmunity, and present approaches and limitations to studyingcircRNA function.CONCLUSIONlncRNAs are now an established class of functional moleculeswith physiological relevance shown in nearly every humanorgan system. Their roles in immunity have been identifiedin immune cell differentiation, maintenance, and effectorfunction. Given that only a fraction of lncRNAs have beenfunctionally characterized a significant wealth of insightawaits discovery. Moreover, as personalized medicinebegins to drive the use of genetic tools in the clinic, wecan expect the identification of clinically-relevant lncRNAvariants and the development of therapeutics that targetlncRNA function.AUTHOR CONTRIBUTIONSAW and GK wrote and edited the manuscript. JH-M editedthe manuscript.FUNDINGGKwas supported by NIH F30-HL143986. AWwas supported byNIH R01AI141609, R21AI13522, and R21AI133440.REFERENCES1. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S,Tilgner H, et al. The GENCODE v7 catalog of human longnoncoding RNAs: analysis of their gene structure, evolution,and expression. Genome Res. (2012) 22:1775–89. doi: 10.1101/gr.132159.1112. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, et al.Integrative annotation of human large intergenic noncoding RNAs revealsglobal properties and specific subclasses. Genes Dev. (2011) 25:1915–27.doi: 10.1101/gad.174466113. Castellanos-Rubio A, Fernandez-Jimenez N, Kratchmarov R, Luo X, BhagatG, Green PH, et al. A long noncoding RNA associated with susceptibility toceliac disease. Science. (2016) 352:91–5. doi: 10.1126/science.aad0467Frontiers in Immunology | www.frontiersin.org 2 October 2019 | Volume 10 | Article 2378Kwon et al. Editorial: Long Non-coding RNAs and Immunity4. Kumar V, Westra HJ, Karjalainen J, Zhernakova DV, Esko T, HrdlickovaB, et al. Human disease-associated genetic variation impacts largeintergenic non-coding RNA expression. PLoS Genet. (2013) 9:e1003201.doi: 10.1371/journal.pgen.10032015. Mirza AH, Kaur S, Brorsson CA, Pociot F. Effects of GWAS-associated geneticvariants on lncRNAs within IBD and T1D candidate loci. PLoS ONE. (2014)9:e105723. doi: 10.1371/journal.pone.01057236. Ghosh S, Klein RS. Sex drives dimorphic immune responses to viral infections.J Immunol. (2017) 198:1782–90. doi: 10.4049/jimmunol.16011667. Spolarics Z. The X-files of inflammation: cellular mosaicism of X-linkedpolymorphic genes and the female advantage in the host response toinjury and infection. Shock. (2007) 27:597–604. doi: 10.1097/SHK.0b013e31802e40bd8. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions:when a chromosome makes a difference. Nat Rev Immunol. (2010) 10:594–604. doi: 10.1038/nri28159. Wang Z, Fan P, Zhao Y, Zhang S, Lu J, Xie W, et al. NEAT1modulates herpes simplex virus-1 replication by regulating viral genetranscription. Cell Mol Life Sci. (2017) 74:1117–31. doi: 10.1007/s00018-016-2398-410. Buniello A,MacArthuer JAL, CerezoM, Harris LW, Hayhurst J, Malangone C,et al. The NHGRI-EBI GWAS Catalog of published genome-wide associationstudies, targeted arrays and summary statistics 2019.Nucleic Acids Res. (2019)47:D1005–D1012. doi: 10.1093/nar/gky1120Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2019 Kwon, Henao-Mejia and Williams. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Immunology | www.frontiersin.org 3 October 2019 | Volume 10 | Article 2378

Editorial: Long Non-coding RNAs and Immunity.

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Editorial: Long Non-coding RNAs and Immunity.

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