lncRNA involvement in immune-related diseases - from SNP association to implication in pathogenesis and therapeutic potential

Abstract

Development of new high throughput array-based techniques and, more recently, next-generation sequencing (NGS) technologies have revolutionized our capability to accurately characterize single nucleotide polymorphisms (SNPs) throughout the genome. These advances have facilitated large-scale genome-wide association studies (GWAS), which have served as fundamental elements in establishing links between SNPs and the susceptibility to several complex diseases, including those related to the immune system. Nevertheless, the molecular mechanisms underlying the development of most of these disorders are still poorly defined. Decoding the functionality of SNPs becomes increasingly challenging due to the predominant presence of these risk variants in non-coding regions of the genome. Among them, long non-coding RNAs (lncRNAs) are enriched in disease-associated SNPs. lncRNAs are involved in governing the control of gene expression both during transcription and at the post-transcriptional level. The existence of SNPs within the sequences of lncRNAs has the potential to alter their expression, structure, or function. This, in turn, can influence their regulatory roles and consequently contribute to the onset or progression of various diseases. In this review, we describe the implication of SNPs located in lncRNAs in the development of different immune-related diseases and highlight the potential of these molecules in the development of emerging RNA-based therapies.

Keywords

lncRNA / SNP / immune-related diseases / RNA-based therapies

References

[1] van Dijk EL, Auger H, Jaszczyszyn Y, Thermes C. Ten years of next-generation sequencing technology.Trends Genet2014;30:418-26

[2] ArunimaA,SamuelJE.The emerging roles of long non-coding RNA in host immune response and intracellular bacterial infections.Front Cell Infect Microbiol2023;13:1160198 PMCID:PMC10160451

[3] ParkesM,vanHeel DA.Genetic insights into common pathways and complex relationships among immune-mediated diseases.Nat Rev Genet2013;14:661-73

[4] Ricaño-PonceI.Mapping of immune-mediated disease genes.Annu Rev Genomics Hum Genet2013;14:325-53

[5] AltshulerD,LanderES.Genetic mapping in human disease.Science2008;322:881-8 PMCID:PMC2694957

[6] TakYG.Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome.Epigenetics Chromatin2015;8:57 PMCID:PMC4696349

[7] FarhKK,ZhuJ.Genetic and epigenetic fine mapping of causal autoimmune disease variants.Nature2015;518:337-43 PMCID:PMC4336207

[8] HangauerMJ,McManusMT.Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs.PLoS Genet2013;9:e1003569 PMCID:PMC3688513

[9] RinnJL.Genome regulation by long noncoding RNAs.Annu Rev Biochem2012;81:145-66 PMCID:PMC3858397

[10] ChoiSW,NamJW.The small peptide world in long noncoding RNAs.Brief Bioinform2019;20:1853-64 PMCID:PMC6917221

[11] BatistaPJ.Long noncoding RNAs: cellular address codes in development and disease.Cell2013;152:1298-307 PMCID:PMC3651923

[12] HrdlickovaB,KanduriK.Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity.Genome Med2014;6:88 PMCID:PMC4240855

[13] Castellanos-RubioA.Disease-associated SNPs in inflammation-related lncRNAs.Front Immunol2019;10:420 PMCID:PMC6418042

[14] AznaourovaM,SchmeckB.Disease-causing mutations and rearrangements in long non-coding RNA gene loci.Front Genet2020;11:527484 PMCID:PMC7735109

[15] StatelloL,ChenLL.Gene regulation by long non-coding RNAs and its biological functions.Nat Rev Mol Cell Biol2021;22:96-118 PMCID:PMC7754182

[16] ArunkumarG.LncRNAs: the good, the bad, and the unknown. Biochem Cell Biol 2023. Online ahead of print

[17] KungJTY,LeeJT.Long noncoding RNAs: past, present, and future.Genetics2013;193:651-69 PMCID:PMC3583990

[18] BirneyE,DuttaA.Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.Nature2007;447:799-816 PMCID:PMC2212820

[19] MattickJS,CarninciP.Long non-coding RNAs: definitions, functions, challenges and recommendations.Nat Rev Mol Cell Biol2023;24:430-47 PMCID:PMC10213152

[20] AglianoF,MedvedevAE,VellaAT.Long noncoding RNAs in host-pathogen interactions.Trends Immunol2019;40:492-510 PMCID:PMC6556373

[21] WangKC.Molecular mechanisms of long noncoding RNAs.Mol Cell2011;43:904-14 PMCID:PMC3199020

[22] NaganoT.No-nonsense functions for long noncoding RNAs.Cell2011;145:178-81

[23] ChaumeilJ,WutzA.A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced.Genes Dev2006;20:2223-37 PMCID:PMC1553206

[24] PandeyRR,MohammadF.Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation.Mol Cell2008;32:232-46

[25] AhmadP,MekkiI,KotsyfakisM.Long non-coding RNAs and their potential roles in the vector-host-pathogen triad.Life2021;11:56 PMCID:PMC7830631

[26] HuarteM,FeldserD.A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.Cell2010;142:409-19 PMCID:PMC2956184

[27] KhalilAM,HuarteM.Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.Proc Natl Acad Sci USA2009;106:11667-72 PMCID:PMC2704857

[28] ØromUA,BeringerM.Long noncoding RNAs with enhancer-like function in human cells.Cell2010;143:46-58 PMCID:PMC4108080

[29] TripathiV,ShenZ.The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.Mol Cell2010;39:925-38 PMCID:PMC4158944

[30] YamazakiT,ChujoT.Functional domains of NEAT1 architectural lncRNA induce paraspeckle assembly through phase separation.Mol Cell2018;70:1038-53.e7

[31] MaoYS,ZhangB.Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs.Nat Cell Biol2011;13:95-101 PMCID:PMC3007124

[32] ChenKW.Functional roles of long non-coding RNAs in motor neuron development and disease.J Biomed Sci2020;27:38 PMCID:PMC7041250

[33] FaghihiMA,KhalilAM.Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.Nat Med2008;14:723-30 PMCID:PMC2826895

[34] KallenAN,XuJ.The imprinted H19 lncRNA antagonizes let-7 microRNAs.Mol Cell2013;52:101-12 PMCID:PMC3843377

[35] YoonJH,SrikantanS.LincRNA-p21 suppresses target mRNA translation.Mol Cell2012;47:648-55 PMCID:PMC3509343

[36] CarrieriC,BiagioliM.Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat.Nature2012;491:454-7

[37] MatsumotoA,MatsumotoM.mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide.Nature2017;541:228-32

[38] SlavoffSA,SchwaidAG.Peptidomic discovery of short open reading frame-encoded peptides in human cells.Nat Chem Biol2013;9:59-64 PMCID:PMC3625679

[39] ZhaoY,WangRR,CuiJ.The effects of mitochondria-associated long noncoding RNAs in cancer mitochondria: New players in an old arena.Crit Rev Oncol Hematol2018;131:76-82

[40] DingJ,OuyangY.A long noncoding RNA regulates photoperiod-sensitive male sterility, an essential component of hybrid rice.Proc Natl Acad Sci USA2012;109:2654-9 PMCID:PMC3289353

[41] GongJ,ZhangJ,GuoAY.lncRNASNP: a database of SNPs in lncRNAs and their potential functions in human and mouse.Nucleic Acids Res2015;43:D181-6 PMCID:PMC4383871

[42] LiX,FuX.lncRNAs: insights into their function and mechanics in underlying disorders.Mutat Res Rev Mutat Res2014;762:1-21

[43] StadelmannC.Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications.Curr Opin Neurol2011;24:224-9

[44] NourbakhshB.Multiple sclerosis risk factors and pathogenesis.Continuum2019;25:596-610

[45] YangX,ZhangB.Noncoding RNAs in multiple sclerosis.Clin Epigenetics2018;10:149 PMCID:PMC6267072

[46] HaywoodMEK,HorswellS.Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes.Genes Immun2006;7:250-63

[47] Eftekharian M, Noroozi R, Komaki A, Mazdeh M, Taheri M, Ghafouri-Fard S. GAS5 genomic variants and risk of multiple sclerosis.Neurosci Lett2019;701:54-7

[48] Mourtada-MaarabouniM,KirkhamL,WilliamsGT.Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5).J Cell Sci2008;121:939-46

[49] SunD,FangX.LncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination.EMBO Rep2017;18:1801-16 PMCID:PMC5623836

[50] WilliamsGT,FarzanehF.A critical role for non-coding RNA GAS5 in growth arrest and rapamycin inhibition in human T-lymphocytes.Biochem Soc Trans2011;39:482-6

[51] SunG,MuraiK.miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.Nat Commun2011;2:529 PMCID:PMC3298567

[52] ChenF,WangE,LiX.LncRNA GAS5 regulates ischemic stroke as a competing endogenous RNA for miR-137 to regulate the Notch1 signaling pathway.Biochem Biophys Res Commun2018;496:184-90

[53] GuoZ,ZhaoY.Genetic polymorphisms of long non-coding RNA GAS5 predict platinum-based concurrent chemoradiotherapy response in nasopharyngeal carcinoma patients.Oncotarget2017;8:62286-97 PMCID:PMC5617505

[54] SenousyMA,SayedNH,KortamMA.LncRNA GAS5 and miR-137 polymorphisms and expression are associated with multiple sclerosis risk: mechanistic insights and potential clinical impact.ACS Chem Neurosci2020;11:1651-60

[55] HusbyS,Korponay-SzabóIR.European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease.J Pediatr Gastroenterol Nutr2012;54:136-60

[56] Gutierrez-AchuryJ,PulitSL.Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease.Nat Genet2015;47:577-8 PMCID:PMC4449296

[57] DuboisPCA,FrankeL.Multiple common variants for celiac disease influencing immune gene expression.Nat Genet2010;42:295-302

[58] Plaza-IzurietaL,IrastorzaI.Expression analysis in intestinal mucosa reveals complex relations among genes under the association peaks in celiac disease.Eur J Hum Genet2015;23:1100-5 PMCID:PMC4795102

[59] SantinI,VelayosT.Celiac diasease-associated lncRNA named HCG14 regulates NOD1 expression in intestinal cells.J Pediatr Gastroenterol Nutr2018;67:225-31

[60] Jauregi-MiguelA,Garcia-EtxebarriaK.MAGI2 gene region and celiac disease.Front Nutr2019;6:187 PMCID:PMC6930898

[61] Castellanos-RubioA,KratchmarovR.A long noncoding RNA associated with susceptibility to celiac disease.Science2016;352:91-5 PMCID:PMC4994711

[62] ZhernakovaA,FrankeL.Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.Am J Hum Genet2008;82:1202-10 PMCID:PMC2427314

[63] CoenenMJH,HeskampS.Common and different genetic background for rheumatoid arthritis and coeliac disease.Hum Mol Genet2009;18:4195-203

[64] SmythDJ,WalkerNM.Shared and distinct genetic variants in type 1 diabetes and celiac disease.N Engl J Med2008;359:2767-77 PMCID:PMC2840835

[65] EizirikDL,OrtisF.The role of inflammation in insulitis and beta-cell loss in type 1 diabetes.Nat Rev Endocrinol2009;5:219-26

[66] SantinI.Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis.Diabetes Obes Metab2013;15 Suppl 3:71-81

[67] CarpenterS,AtianandMK.A long noncoding RNA mediates both activation and repression of immune response genes.Science2013;341:789-92 PMCID:PMC4376668

[68] ZhangQ,PatilVS.The long noncoding RNA ROCKI regulates inflammatory gene expression.EMBO J2019;38:e100041 PMCID:PMC6463213

[69] Gonzalez-MoroI,ColliML.The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA.Proc Natl Acad Sci USA2020;117:9022-31 PMCID:PMC7183221

[70] KrogvoldL,BuanesT.Detection of a low-grade enteroviral infection in the islets of langerhans of living patients newly diagnosed with type 1 diabetes.Diabetes2015;64:1682-7

[71] González-MoroI,MendozaLM.LncRNA ARGI contributes to virus-induced pancreatic β cell inflammation through transcriptional activation of IFN-stimulated genes.Adv Sci2023;10:e2300063 PMCID:PMC10477904

[72] Ayala-FontánezN,McCormickTS.Current knowledge on psoriasis and autoimmune diseases.Psoriasis2016;6:7-32 PMCID:PMC5683130

[73] BarreaL,DiSomma C.Environmental risk factors in psoriasis: the point of view of the nutritionist.Int J Environ Res Public Health2016;13:743 PMCID:PMC4962284

[74] GuptaR,LaiK.Landscape of long noncoding RNAs in psoriatic and healthy skin.J Invest Dermatol2016;136:603-9 PMCID:PMC5546103

[75] RakhshanA,MoradiA.A single nucleotide polymorphism within HOX transcript antisense RNA (HOTAIR) is associated with risk of psoriasis.Int J Immunogenet2020;47:430-4

[76] YaoX,XueT,ZhangY.Association of HOTAIR polymorphisms with susceptibility to psoriasis in a Chinese Han population.Biomed Res Int2021;2021:5522075 PMCID:PMC8357505

[77] ObaidM,DebP,ZakiMH.LncRNA HOTAIR regulates lipopolysaccharide-induced cytokine expression and inflammatory response in macrophages.Sci Rep2018;8:15670 PMCID:PMC6199307

[78] LizzulPF,MalaviyaR.Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept.J Invest Dermatol2005;124:1275-83

[79] GuoW,BaiY.Associations between polymorphisms of HOTAIR and risk of gastric cardia adenocarcinoma in a population of north China.Tumour Biol2015;36:2845-54

[80] ZhangDD,XiongJ.Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes.Sci Rep2017;7:46204 PMCID:PMC5385552

[81] GaoW,WangH.Association of polymorphisms in long non-coding RNA H19 with coronary artery disease risk in a Chinese population.Mutat Res2015;772:15-22

[82] HanDKM,PollockRA,LiauG.H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.J Clin Invest1996;97:1276-85 PMCID:PMC507181

[83] BaoMH,ZhangYW,ChengYU.Let-7 in cardiovascular diseases, heart development and cardiovascular differentiation from stem cells.Int J Mol Sci2013;14:23086-102 PMCID:PMC3856107

[84] KongY,AlonsoLC.ANRIL: a lncRNA at the CDKN2A/B locus with roles in cancer and metabolic disease.Front Endocrinol2018;9:405 PMCID:PMC6066557

[85] ChiJS,JiaJJ,LiuXM.Long non-coding RNA ANRIL in gene regulation and its duality in atherosclerosis.J Huazhong Univ Sci Technolog Med Sci2017;37:816-22

[86] ZhaoW,MaoG.The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region.BMC Med Genomics2015;8:21 PMCID:PMC4432789

[87] RankinCR,ElliottJ.The IBD-associated long noncoding RNA IFNG-AS1 regulates the balance between inflammatory and anti-inflammatory cytokine production after T-cell stimulation.Am J Physiol Gastrointest Liver Physiol2020;318:34-40 PMCID:PMC6985849

[88] PaduaD,KaXI.A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation.Am J Physiol Gastrointest Liver Physiol2016;311:446-57 PMCID:PMC5076004

[89] VigneauS,BrahicM.Tmevpg1, a candidate gene for the control of Theiler's virus persistence, could be implicated in the regulation of gamma interferon.J Virol2003;77:5632-8 PMCID:PMC154023

[90] PetermannF,JohnsonCA.The magnitude of IFN-γ responses is fine-tuned by DNA architecture and the non-coding transcript of ifng-as1.Mol Cell2019;75:1229-42.e5 PMCID:PMC6754279

[91] GomezJA,YangYW.The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus.Cell2013;152:743-54 PMCID:PMC3577098

[92] McInnesIB.Pathogenetic insights from the treatment of rheumatoid arthritis.Lancet2017;389:2328-37

[93] TeraoC,GregersenPK.Recent advances in defining the genetic basis of rheumatoid arthritis.Annu Rev Genomics Hum Genet2016;17:273-301 PMCID:PMC6727201

[94] YangJ,WangL.The role of non-coding RNAs (miRNA and lncRNA) in the clinical management of rheumatoid arthritis.Pharmacol Res2022;186:106549

[95] ZhangZ,WenQW.Associations of genetic polymorphisms within MALAT1, UCA1, FAM211A-AS1 and AC000111.6 with genetic susceptibility to rheumatoid arthritis.Autoimmunity2020;53:408-14

[96] PanF,LvH.Quercetin promotes the apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by upregulating lncRNA MALAT1.Int J Mol Med2016;38:1507-14

[97] YanZF,LiuW.UCA1 impacts progress of rheumatoid arthritis by inducing the apoptosis of fibroblast-like synoviocyte.Eur Rev Med Pharmacol Sci2018;22:914-20

[98] YuanM,YuL.Long noncoding RNA profiling revealed differentially expressed lncRNAs associated with disease activity in PBMCs from patients with rheumatoid arthritis.PLoS One2017;12:e0186795 PMCID:PMC5687725

[99] ZhangY,SunN.Long noncoding RNA expression profile in fibroblast-like synoviocytes from patients with rheumatoid arthritis.Arthritis Res Ther2016;18:227 PMCID:PMC5053204

[100] ReidS,FrodlundM.High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus.Ann Rheum Dis2020;79:363-9 PMCID:PMC7034364

[101] ZhaoCN,LiuLN,WangDG.Emerging role of lncRNAs in systemic lupus erythematosus.Biomed Pharmacother2018;106:584-92

[102] HaoH,OhkuboN.Involvement of lncRNA IL21-AS1 in interleukin-2 and T follicular regulatory cell activation in systemic lupus erythematosus.Arthritis Res Ther2021;23:302 PMCID:PMC8665514

[103] HaoH,YamagataK.Conversion of T follicular helper cells to T follicular regulatory cells by interleukin-2 through transcriptional regulation in systemic lupus erythematosus.Arthritis Rheumatol2021;73:132-42

[104] GregersenPK.Recent advances in the genetics of autoimmune disease.Annu Rev Immunol2009;27:363-91 PMCID:PMC2992886

[105] MercerTR,MattickJS.The potential of long noncoding RNA therapies.Trends Pharmacol Sci2022;43:269-80

[106] LeeJS.Antisense-mediated transcript knockdown triggers premature transcription termination.Mol Cell2020;77:1044-54.e3 PMCID:PMC7093083

[107] ArunG,SpectorDL.Therapeutic targeting of long non-coding RNAs in cancer.Trends Mol Med2018;24:257-77 PMCID:PMC5840027

[108] ShiY,PatelR.Stabilization of lncRNA GAS5 by a small molecule and its implications in diabetic adipocytes.Cell Chem Biol2019;26:319-30.e6 PMCID:PMC10498384

[109] AbulwerdiFA,AgeeliAA.Selective small-molecule targeting of a triple helix encoded by the long noncoding RNA, MALAT1.ACS Chem Biol2019;14:223-35 PMCID:PMC6709583

[110] AguiloF,WalshMJ.Long non-coding RNA ANRIL and polycomb in human cancers and cardiovascular disease.Curr Top Microbiol Immunol2016;394:29-39 PMCID:PMC4732918