The potential therapeutic applications of long non-coding RNAs

Abstract

The field of RNA-based therapeutics is rapidly evolving and targeting non-coding RNAs (ncRNAs) associated with disease is becoming increasingly feasible. MicroRNAs (miRNAs) are a class of small ncRNAs (sncRNAs) and the first anti-miRNA drugs, e.g., Miravirsen and Cobomarsen, have successfully completed phase II clinical trials. Long ncRNAs (lncRNAs) are another class of ncRNAs that are commonly dysregulated in disease. Thus, they hold potential as putative therapeutic targets or agents. LncRNAs can function through a variety of mechanisms, including as guide, scaffold or decoy molecules, and understanding of these actions is critical to devising effective targeting strategies. LncRNA expression can be modulated with small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), CRISPR-Cas9, or small molecule inhibitors. These approaches have been employed to target a number of lncRNAs and tested in animal models of disease, including targeting ANRIL for non-small cell lung cancer and H19 for pancreatitis. However, there are currently no clinical trials registered in the ClinicalTrials.gov database that target lncRNAs as a therapeutic intervention. In order to translate lncRNA targeting into clinical use, several limitations must be overcome, such as potential toxicity and off-target effects. Overall, while significant progress has been made in the field, further development is required before the clinical application of the first therapeutics targeting lncRNAs. In this review, we discuss recent advances in our understanding of the mechanisms of action of lncRNAs that present avenues for clinical therapeutic targeting and consider off-target effects as a limiting factor in their application.

Keywords

lncRNAs / mechanism of action / therapeutics / ASO / siRNA / CRISPR-Cas9

References

[1] MattickJS.Non-coding RNA.Hum Mol Genet2006;15:R17-29

[2] DerrienT,BussottiG.The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.Genome Res2012;22:1775-89 PMCID:PMC3431493

[3] KapranovP,DikeS.RNA maps reveal new RNA classes and a possible function for pervasive transcription.Science2007;316:1484-8

[4] YaoRW,ChenLL.Cellular functions of long noncoding RNAs.Nat Cell Biol2019;21:542-51

[5] ArnoldPR,LiXC.Diversity and emerging roles of enhancer RNA in regulation of gene expression and cell fate.Front Cell Dev Biol2019;7:377 PMCID:PMC6971116

[6] LasdaE.Circular RNAs: diversity of form and function.RNA2014;20:1829-42 PMCID:PMC4238349

[7] GENCODE. Release 46 (GRCh38.p14). 2024. Available from: https://www.gencodegenes.org/human/ [Last accessed on 13 Jun 2024]

[8] IyerMK,MalikR.The landscape of long noncoding RNAs in the human transcriptome.Nat Genet2015;47:199-208 PMCID:PMC4417758

[9] LiZ,FengC.LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations.Nucleic Acids Res2023;51:D186-91 PMCID:PMC9825513

[10] CabiliMN,McClanahanPD.Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution.Genome Biol2015;16:20 PMCID:PMC4369099

[11] BenoitBouvrette LP,BergaletJ.CeFra-seq reveals broad asymmetric mRNA and noncoding RNA distribution profiles in Drosophila and human cells.RNA2018;24:98-113 PMCID:PMC5733575

[12] Carlevaro-FitaJ,GuigóR,JohnsonR.Cytoplasmic long noncoding RNAs are frequently bound to and degraded at ribosomes in human cells.RNA2016;22:867-82 PMCID:PMC4878613

[13] BridgesMC,KourtidisA.LNCcation: lncRNA localization and function.J Cell Biol2021;220:e202009045 PMCID:PMC7816648

[14] ClarkMB,Inostroza-PontaM.Genome-wide analysis of long noncoding RNA stability.Genome Res2012;22:885-98 PMCID:PMC3337434

[15] MaL,ZhangZ.On the classification of long non-coding RNAs.RNA Biol2013;10:925-33 PMCID:PMC4111732

[16] ClinicalTrials.gov. 2024. Available from: https://clinicaltrials.gov/ [Last accessed on 13 Jun 2024]

[17] JanssenHL,LawitzEJ.Treatment of HCV infection by targeting microRNA.N Engl J Med2013;368:1685-94

[18] vander Ree MH,vanNuenen AC.Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma.Aliment Pharmacol Ther2016;43:102-13

[19] HongDS,BoradM.Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.Br J Cancer2020;122:1630-7 PMCID:PMC7251107

[20] Efficacy, safety, and tolerability of remlarsen (MRG-201) following intradermal injection in subjects with a history of keloids (NCT03601052). 2021. Available from: https://clinicaltrials.gov/study/NCT03601052 [Last accessed on 13 Jun 2024]

[21] WinkleM,FabbriM.Noncoding RNA therapeutics - challenges and potential solutions.Nat Rev Drug Discov2021;20:629-51 PMCID:PMC8212082

[22] ZhuY,WangX.RNA-based therapeutics: an overview and prospectus.Cell Death Dis2022;13:644 PMCID:PMC9308039

[23] BabarIA,BoothCJ.Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma.Proc Natl Acad Sci USA2012;109:E1695-704 PMCID:PMC3387084

[24] WoodrowKA,BoothCJ,WoodMJ.Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.Nat Mater2009;8:526-33 PMCID:PMC2693358

[25] AdamsBD,WalkerL,SlackFJ.Targeting noncoding RNAs in disease.J Clin Invest2017;127:761-71 PMCID:PMC5330746

[26] KamolaPJ,TakahashiT,Ui-TeiK.The siRNA non-seed region and its target sequences are auxiliary determinants of off-target effects.PLoS Comput Biol2015;11:e1004656 PMCID:PMC4676691

[27] GrimmD,JoplingCL.Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways.Nature2006;441:537-41

[28] ChodroffRA,SireyTM.Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes.Genome Biol2010;11:R72 PMCID:PMC2926783

[29] PangKC,MattickJS.Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function.Trends Genet2006;22:1-5

[30] NesterovaTB,ElisaphenkoEA.Characterization of the genomic xist locus in rodents reveals conservation of overall gene structure and tandem repeats but rapid evolution of unique sequence.Genome Res2001;11:833-49 PMCID:PMC311126

[31] KutterC,StefflovaK.Rapid turnover of long noncoding RNAs and the evolution of gene expression.PLoS Genet2012;8:e1002841 PMCID:PMC3406015

[32] GuoCJ,XingYH.Distinct processing of lncRNAs contributes to non-conserved functions in stem cells.Cell2020;181:621-36.e22

[33] UlitskyI,JanCH,BartelDP.Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution.Cell2012;151:684-6

[34] HezroniH,SchwartzMG,BartelDP.Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species.Cell Rep2015;11:1110-22 PMCID:PMC4576741

[35] deGoede OM,FerraroNM.Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.Cell2021;184:2633-48.e19

[36] SarropoulosI,Cardoso-MoreiraM.Developmental dynamics of lncRNAs across mammalian organs and species.Nature2019;571:510-4 PMCID:PMC6660317

[37] NguyenQ.Expression specificity of disease-associated lncRNAs: toward personalized medicine.Curr Top Microbiol Immunol2015;394:237-58

[38] HuarteM.The emerging role of lncRNAs in cancer.Nat Med2015;21:1253-61

[39] ZhouY,WangY.Activation of p53 by MEG3 non-coding RNA.J Biol Chem2007;282:24731-42

[40] BoonRA,HoldtL.Long noncoding RNAs: from clinical genetics to therapeutic targets?.J Am Coll Cardiol2016;67:1214-26

[41] LiuJY,LiXM.Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus.Cell Death Dis2014;5:e1506 PMCID:PMC4649539

[42] BhanA.Long noncoding RNAs: emerging stars in gene regulation, epigenetics and human disease.ChemMedChem2014;9:1932-56

[43] 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

[44] MishraA,MishraSN.Differential expression of non-coding RNAs in stem cell development and therapeutics of bone disorders. Cells 2023;12:1159. PMCID:PMC10137108

[45] LiX,ZhangGD,GuoPY.LncRNA ANRIL impacts the progress of osteoarthritis via regulating proliferation and apoptosis of osteoarthritis synoviocytes.Eur Rev Med Pharmacol Sci2019;23:9729-37

[46] GuptaRA,WangKC.Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.Nature2010;464:1071-6 PMCID:PMC3049919

[47] JiP,WangW.MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer.Oncogene2003;22:8031-41

[48] ChenPY,PengCY,YuCH.LncRNA MEG3 inhibits self-renewal and invasion abilities of oral cancer stem cells by sponging miR-421.J Formos Med Assoc2021;120:1137-42

[49] ChenC,HuangJ.LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment.Nat Commun2018;9:3826 PMCID:PMC6148066

[50] SunCC,LiSJ.FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway.Genome Med2020;12:77 PMCID:PMC7466809

[51] ChenY,ChenX.Long non-coding RNAs: from disease code to drug role.Acta Pharm Sin B2021;11:340-54 PMCID:PMC7893121

[52] LiangXH,NicholsJG.RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus.Mol Ther2017;25:2075-92 PMCID:PMC5589097

[53] BerezhnaSY,SupekF,DenizAA.siRNA in human cells selectively localizes to target RNA sites.Proc Natl Acad Sci USA2006;103:7682-7 PMCID:PMC1472505

[54] Public data from Article 57 database. 2023. Available from: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/data-medicines-iso-idmp-standards-post-authorisation/public-data-article-57-database [Last accessed on 13 Jun 2024]

[55] Drugs@FDA: FDA-approved drugs. 2024. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm [Last accessed on 13 Jun 2024]

[56] HuaY.Antisense-mediated exon inclusion. Methods Mol Biol 2012;867:307-23. PMCID:PMC3390937

[57] MatsuoM.Antisense oligonucleotide-mediated exon-skipping therapies: precision medicine spreading from duchenne muscular dystrophy.JMA J2021;4:232-40 PMCID:PMC8355726

[58] VickersTA,BurckinT,FreierSM.Fully modified 2′ MOE oligonucleotides redirect polyadenylation.Nucleic Acids Res2001;29:1293-9 PMCID:PMC29745

[59] CollottaD,ChiapelloE.Antisense oligonucleotides: a novel Frontier in pharmacological strategy.Front Pharmacol2023;14:1304342 PMCID:PMC10690781

[60] HawesJ,RenL,YangK. Toxicity of three antisense oligonucleotide drugs and eighteen of their impurities in primary human hepatocytes. 2023. Available from: https://www.fda.gov/science-research/fda-science-forum/toxicity-three-antisense-oligonucleotide-drugs-and-eighteen-their-impurities-primary-human [Last accessed on 13 Jun 2024]

[61] WuH,AlhamadaniF.Nephrotoxicity of marketed antisense oligonucleotide drugs.Curr Opin Toxicol2022;32:100373 PMCID:PMC10174585

[62] SwayzeEE,WancewiczEV.Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.Nucleic Acids Res2007;35:687-700 PMCID:PMC1802611

[63] GoyalA,GroßM,DuranArqué B.Challenges of CRISPR/Cas9 applications for long non-coding RNA genes.Nucleic Acids Res2017;45:e12 PMCID:PMC5388423

[64] MaederML,CascioVM,HoQH.CRISPR RNA-guided activation of endogenous human genes.Nat Methods2013;10:977-9 PMCID:PMC3794058

[65] BassettAR,BarlowDP.Science forum: considerations when investigating lncRNA function in vivo.Elife2014;3:e03058 PMCID:PMC4132285

[66] ZhaoR,ZhuL,LiuB.Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy.J Hematol Oncol2022;15:14 PMCID:PMC8817562

[67] RenY,ZhangJ.Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2.Clin Epigenetics2019;11:29 PMCID:PMC6376746

[68] DongP,YueJ.Long non-coding RNA NEAT1: a novel target for diagnosis and therapy in human tumors.Front Genet2018;9:471 PMCID:PMC6196292

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

[70] SpitaleRC,ChangHY.RNA templating the epigenome: long noncoding RNAs as molecular scaffolds.Epigenetics2011;6:539-43 PMCID:PMC3230545

[71] GuttmanM.Modular regulatory principles of large non-coding RNAs.Nature2012;482:339-46 PMCID:PMC4197003

[72] RinnJL,WangJK.Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.Cell2007;129:1311-23 PMCID:PMC2084369

[73] TsaiMC,WanY.Long noncoding RNA as modular scaffold of histone modification complexes.Science2010;329:689-93 PMCID:PMC2967777

[74] WangH,WangC,ZhaoX.Insight into HOTAIR structural features and functions as landing pads for transcription regulation proteins.Biochem Biophys Res Commun2017;485:679-85

[75] SørensenKP,TanQ.Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer.Breast Cancer Res Treat2013;142:529-36

[76] SomarowthuS,ChillónI,LiuF.HOTAIR forms an intricate and modular secondary structure.Mol Cell2015;58:353-61 PMCID:PMC4406478

[77] LiL,WapinskiOL.Targeted disruption of Hotair leads to homeotic transformation and gene derepression.Cell Rep2013;5:3-12 PMCID:PMC4038295

[78] MaQ,TolentinoK.Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis.Elife2022;11:e79126

[79] KotakeY,KitagawaK.Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.Oncogene2011;30:1956-62 PMCID:PMC3230933

[80] NieFQ,YangJS.Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression.Mol Cancer Ther2015;14:268-77

[81] 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

[82] EngreitzJM,McDonelP.The xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome.Science2013;341:1237973 PMCID:PMC3778663

[83] ChenCK,JacksonC.Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing.Science2016;354:468-72

[84] 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

[85] YounessA,GuéryJC.Escape from X chromosome inactivation and the female predominance in autoimmune diseases.Int J Mol Sci2021;22:1114 PMCID:PMC7865432

[86] BostC,BrooksWH,GueryJC.Long non-coding RNA xist contribution in systemic lupus erythematosus and rheumatoid arthritis.Clin Immunol2022;236:108937

[87] DuY,LiJ.Silencing of long noncoding RNA XIST attenuated Alzheimer's disease-related BACE1 alteration through miR-124.Cell Biol Int2020;44:630-6

[88] YanXW,HongYX,DuJ.lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer’s disease.J Neurogenet2022;36:11-20

[89] BattonKA,BrunoKA,ShapiroBP.Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease.Biol Sex Differ2018;9:15 PMCID:PMC5907450

[90] QinS,CarmanB.Up-regulation of the long noncoding RNA X-inactive-specific transcript and the sex bias in pulmonary arterial hypertension.Am J Pathol2021;191:1135-50 PMCID:PMC8176134

[91] LiJ,YangL,LiuG.Long noncoding RNA XIST: mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities.Genes Dis2022;9:1478-92 PMCID:PMC9485286

[92] ZhengR,GuanL.Long non-coding RNA XIST inhibited breast cancer cell growth, migration, and invasion via miR-155/CDX1 axis.Biochem Biophys Res Commun2018;498:1002-8

[93] XuR,ChenF.LncRNA XIST/miR-200c regulates the stemness properties and tumourigenicity of human bladder cancer stem cell-like cells.Cancer Cell Int2018;18:41 PMCID:PMC5859407

[94] SunN,LiuY.Long non-coding RNA XIST sponges miR-34a to promotes colon cancer progression via Wnt/β-catenin signaling pathway.Gene2018;665:141-8

[95] FangJ,GongC.Long noncoding RNA XIST acts as an oncogene in non-small cell lung cancer by epigenetically repressing KLF2 expression.Biochem Biophys Res Commun2016;478:811-7

[96] JiangJ,CostGJ.Translating dosage compensation to trisomy 21.Nature2013;500:296-300 PMCID:PMC3848249

[97] ChiangJC,NewburgerPE.Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro.Nat Commun2018;9:5180 PMCID:PMC6281598

[98] MondalT,VaidR.MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures.Nat Commun2015;6:7743 PMCID:PMC4525211

[99] ZhangW,JiangJ,LuH.LncRNA MEG3 inhibits cell epithelial-mesenchymal transition by sponging miR-421 targeting E-cadherin in breast cancer.Biomed Pharmacother2017;91:312-9

[100] XiaY,LiuB,ChenY.Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway.Mol Med Rep2015;12:4530-7

[101] ZhangJ,GaoY.Downregulation of long noncoding RNA MEG3 is associated with poor prognosis and promoter hypermethylation in cervical cancer.J Exp Clin Cancer Res2017;36:5 PMCID:PMC5216566

[102] ChunharojrithP,JiangX.Tumor suppression by MEG3 lncRNA in a human pituitary tumor derived cell line.Mol Cell Endocrinol2015;416:27-35 PMCID:PMC4605874

[103] KaragkouniD,ParaskevopoulouMD.Characterizing miRNA-lncRNA interplay. Methods Mol Biol 2021;2372:243-62.

[104] FilipowiczW,SonenbergN.Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?.Nat Rev Genet2008;9:102-14

[105] MonnierP,PontisJ,Ait-Si-AliS.H19 lncRNA controls gene expression of the imprinted gene network by recruiting MBD1.Proc Natl Acad Sci USA2013;110:20693-8 PMCID:PMC3870736

[106] JiangX.The mechanism of lncRNA H19 in fibrosis and its potential as novel therapeutic target.Mech Ageing Dev2020;188:111243

[107] SongG,SongR.Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p.Stem Cell Res Ther2020;11:420 PMCID:PMC7519546

[108] WangN,ZhanY.LncRNA PTCSC3 inhibits triple-negative breast cancer cell proliferation by downregulating lncRNA H19.J Cell Biochem2019;120:15083-8

[109] GaoL,GuoS.LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy.J Cell Physiol2019;234:4944-58

[110] KarbasforooshanH.The role of SIRT1 in diabetic cardiomyopathy.Biomed Pharmacother2017;90:386-92

[111] JungHH,KimJY,ParkYH.Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.Sci Rep2016;6:33035 PMCID:PMC5015082

[112] SaigusaS,TanakaK.Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer.Med Oncol2013;30:620

[113] QuX,WangL.Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer.Drug Resist Updat2023;68:100936

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

[115] WuG,HanY.LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity.Circulation2014;130:1452-65

[116] DhamijaS.From junk to master regulators of invasion: lncRNA functions in migration, EMT and metastasis.Int J Cancer2016;139:269-80

[117] BiswasS,ChenS.MALAT1: an epigenetic regulator of inflammation in diabetic retinopathy.Sci Rep2018;8:6526 PMCID:PMC5916949

[118] AshjariD,RajabinejadM.The axis of long non-coding RNA MALAT1/miR-1-3p/CXCR4 is dysregulated in patients with diabetic neuropathy.Heliyon2022;8:e09178 PMCID:PMC8969120

[119] ZhouLJ,OuLN,WuBL.Circulating expression level of LncRNA malat1 in diabetic kidney disease patients and its clinical significance.J Diabetes Res2020;2020:4729019 PMCID:PMC7421584

[120] ZhangY,WangF,ZhuH.Long non-coding RNA MALAT1 expression in patients with gestational diabetes mellitus.Int J Gynaecol Obstet2018;140:164-9

[121] MichalikKM,ManavskiY.Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.Circ Res2014;114:1389-97

[122] ArunG,AkermanM.Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.Genes Dev2016;30:34-51 PMCID:PMC4701977

[123] ClemsonCM,SaraSA.An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles.Mol Cell2009;33:717-26 PMCID:PMC2696186

[124] JiangX.The mechanisms and therapeutic potential of long noncoding RNA NEAT1 in fibrosis.Clin Exp Med2023;23:3339-47

[125] YuF,ChenB,ZhengJ.NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6.J Mol Med2017;95:1191-202

[126] ChenY,DuanZB,XuCY.LncRNA NEAT1 accelerates renal fibrosis progression via targeting miR-31 and modulating RhoA/ROCK signal pathway.Am J Physiol Cell Physiol2023;324:C292-306

[127] GeZ,LiY.Long noncoding RNA NEAT1 promotes cardiac fibrosis in heart failure through increased recruitment of EZH2 to the Smad7 promoter region.J Transl Med2022;20:7 PMCID:PMC8722118

[128] FukushimaK,SugiharaF.Dysregulated expression of the nuclear exosome targeting complex component Rbm7 in nonhematopoietic cells licenses the development of fibrosis.Immunity2020;52:542-56.e13

[129] JinSS,ZhengJZ,GuanHQ.lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3.Eur Cytokine Netw2019;30:98-106

[130] WashietlS,GarberM.Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals.Genome Res2014;24:616-28 PMCID:PMC3975061

[131] PontingCP.Genome-wide analysis of human long noncoding RNAs: a provocative review.Annu Rev Genomics Hum Genet2022;23:153-72

[132] MaiJ,GaoQ,XiaoJ.Transcriptome-wide association studies: recent advances in methods, applications and available databases.Commun Biol2023;6:899 PMCID:PMC10474133