Prevalence of inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gut, has been on the rise in recent years-not only in the adult population but also especially in pediatric patients. Despite the absence of curative treatments, current therapeutic options are able to achieve long-term remission in a significant proportion of cases. To this end, however, there is a need for biomarkers enabling accurate diagnosis, prognosis, and prediction of response to therapies to facilitate a more individualized approach to pediatric IBD patients. In recent years, evidence has continued to evolve concerning noncoding RNAs (ncRNAs) and their roles as integral factors in key immune-related cellular pathways. Specific deregulation patterns of ncRNAs have been linked to pathogenesis of various diseases, including pediatric IBD. In this article, we provide an overview of current knowledge on ncRNAs, their altered expression profiles in pediatric IBD patients, and how these are emerging as potentially valuable clinical biomarkers as we enter an era of personalized medicine.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Gastroenterology and Internal Medicine University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of Hope Comprehensive Cancer Center Duarte California USA

Department of Pediatrics University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Surgery University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

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Benchimol EI, Fortinsky KJ, Gozdyra P, et al. . Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis. 2011;17:423–439. PubMed

Ghione S, Sarter H, Fumery M, et al. ; Epimad Group Dramatic increase in incidence of ulcerative colitis and Crohn’s disease (1988-2011): a population-based study of French adolescents. Am J Gastroenterol. 2018;113:265–272. PubMed

Van Limbergen J, Russell RK, Drummond HE, et al. . Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008;135:1114–1122. PubMed

Kelsen J, Baldassano RN. Inflammatory bowel disease: the difference between children and adults. Inflamm Bowel Dis. 2008;14(Suppl 2):S9–11. PubMed

Molodecky NA, Soon IS, Rabi DM, et al. . Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.e42; quiz e30. PubMed

Ng SC, Shi HY, Hamidi N, et al. . Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–2778. PubMed

Sýkora J, Pomahačová R, Kreslová M, et al. . Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol. 2018;24:2741–2763. PubMed PMC

IBD Working Group of the European Society for Paediatric Gastroenterology HpaN. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis--the Porto criteria. J Pediatr Gastroenterol Nutr. 2005;41:1–7. PubMed

Levine A, Koletzko S, Turner D, et al. ; European Society of Pediatric Gastroenterology, Hepatology, and Nutrition ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr. 2014;58:795–806. PubMed

De Iudicibus S, Stocco G, Martelossi S, et al. . Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases. J Clin Gastroenterol. 2011;45:e1–e7. PubMed

Pastore S, Naviglio S, Canuto A, et al. . Serious adverse events associated with anti-tumor necrosis factor alpha agents in pediatric-onset inflammatory bowel disease and juvenile idiopathic arthritis in a real-life setting. Paediatr Drugs. 2018;20:165–171. PubMed

Consortium IHGS. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–945. PubMed

Wise JA, Weiner AM. Dictyostelium small nuclear RNA D2 is homologous to rat nucleolar RNA U3 and is encoded by a dispersed multigene family. Cell. 1980;22:109–118. PubMed

Calvet JP, Pederson T. Base-pairing interactions between small nuclear RNAs and nuclear RNA precursors as revealed by psoralen cross-linking in vivo. Cell. 1981;26:363–370. PubMed

Calvet JP, Meyer LM, Pederson T. Small nuclear RNA U2 is base-paired to heterogeneous nuclear RNA. Science. 1982;217:456–458. PubMed

Lacoste-Royal G, Simard R. Localization of small nuclear RNA by EM autoradiography in Chinese hamster ovary (CHO) cells. Exp Cell Res. 1983;149:311–323. PubMed

Elkin M, Shevelev A, Schulze E, et al. . The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma. FEBS Lett. 1995;374:57–61. PubMed

Smith CM, Steitz JA. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5’-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998;18:6897–6909. PubMed PMC

Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. . DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59:5975–5979. PubMed

Fire A, Albertson D, Harrison SW, et al. . Production of antisense RNA leads to effective and specific inhibition of gene expression in C. elegans muscle. Development. 1991;113:503–514. PubMed

Fire A, Xu S, Montgomery MK, et al. . Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811. PubMed

Frith MC, Pheasant M, Mattick JS. The amazing complexity of the human transcriptome. Eur J Hum Genet. 2005;13:894–897. PubMed

Martens-Uzunova ES, Olvedy M, Jenster G. Beyond microRNA–novel RNAs derived from small non-coding RNA and their implication in cancer. Cancer Lett. 2013;340:201–211. PubMed

Chooniedass-Kothari S, Emberley E, Hamedani MK, et al. . The steroid receptor RNA activator is the first functional RNA encoding a protein. FEBS Lett. 2004;566:43–47. PubMed

Kondo T, Plaza S, Zanet J, et al. . Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science. 2010;329:336–339. PubMed

Bánfai B, Jia H, Khatun J, et al. . Long noncoding RNAs are rarely translated in two human cell lines. Genome Res. 2012;22:1646–1657. PubMed PMC

Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–854. PubMed

Reinhart BJ, Slack FJ, Basson M, et al. . The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403:901–906. PubMed

Slack FJ, Basson M, Liu Z, et al. . The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol Cell. 2000;5:659–669. PubMed

Pasquinelli AE, Reinhart BJ, Slack F, et al. . Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408:86–89. PubMed

Friedman RC, Farh KK, Burge CB, et al. . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105. PubMed PMC

Alles J, Fehlmann T, Fischer U, et al. . An estimate of the total number of true human miRNAs. Nucleic Acids Res. 2019;47:3353–3364. PubMed PMC

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233. PubMed PMC

Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11:537–561. PubMed PMC

Olena AF, Patton JG. Genomic organization of microRNAs. J Cell Physiol. 2010;222:540–545. PubMed PMC

Lee Y, Kim M, Han J, et al. . MicroRNA genes are transcribed by RNA polymerase II. Embo J. 2004;23:4051–4060. PubMed PMC

Aukerman MJ, Sakai H. Regulation of flowering time and floral organ identity by a MicroRNA and its APETALA2-like target genes. Plant Cell. 2003;15:2730–2741. PubMed PMC

Tam W. Identification and characterization of human BIC, a gene on chromosome 21 that encodes a noncoding RNA. Gene. 2001;274:157–167. PubMed

Lee Y, Ahn C, Han J, et al. . The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–419. PubMed

Han J, Lee Y, Yeom KH, et al. . The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004;18:3016–3027. PubMed PMC

Landthaler M, Yalcin A, Tuschl T. The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol. 2004;14:2162–2167. PubMed

Yi R, Qin Y, Macara IG, et al. . Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17:3011–3016. PubMed PMC

Lee YS, Nakahara K, Pham JW, et al. . Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell. 2004;117:69–81. PubMed

Chendrimada TP, Gregory RI, Kumaraswamy E, et al. . TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436:740–744. PubMed PMC

Okamura K, Liu N, Lai EC. Distinct mechanisms for microRNA strand selection by Drosophila Argonautes. Mol Cell. 2009;36:431–444. PubMed PMC

Kim YK, Kim B, Kim VN. Re-evaluation of the roles of DROSHA, Export in 5, and DICER in microRNA biogenesis. Proc Natl Acad Sci U S A. 2016;113:E1881–E1889. PubMed PMC

Herrera-Carrillo E, Berkhout B. Dicer-independent processing of small RNA duplexes: mechanistic insights and applications. Nucleic Acids Res. 2017;45:10369–10379. PubMed PMC

Babiarz JE, Ruby JG, Wang Y, et al. . Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev. 2008;22:2773–2785. PubMed PMC

Okamura K, Hagen JW, Duan H, et al. . The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell. 2007;130:89–100. PubMed PMC

Wang J, Zhang J, Zheng H, et al. . Mouse transcriptome: neutral evolution of ‘non-coding’ complementary DNAs. Nature. 2004;431:1 p following 757; discussion following 757. PubMed

Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155–159. PubMed

Derrien T, Johnson R, Bussotti G, et al. . The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22:1775–1789. PubMed PMC

Guttman M, Amit I, Garber M, et al. . Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458:223–227. PubMed PMC

Pang KC, Frith MC, Mattick JS. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet. 2006;22:1–5. PubMed

Carninci P, Kasukawa T, Katayama S, et al. ; FANTOM Consortium; RIKEN Genome Exploration Research Group and Genome Science Group (Genome Network Project Core Group) The transcriptional landscape of the mammalian genome. Science. 2005;309:1559–1563. PubMed

Ponjavic J, Ponting CP, Lunter G. Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res. 2007;17:556–565. PubMed PMC

Iyer MK, Niknafs YS, Malik R, et al. . The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47:199–208. PubMed PMC

Fang S, Zhang L, Guo J, et al. . NONCODEV5: a comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res. 2018;46:D308–D314. PubMed PMC

An G, Sun J, Ren C, et al. . LIVE: a manually curated encyclopedia of experimentally validated interactions of lncRNAs. Database (Oxford). 2019;2019:bazz011. PubMed PMC

Cabili MN, Trapnell C, Goff L, et al. . Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011;25:1915–1927. PubMed PMC

Ravasi T, Suzuki H, Pang KC, et al. . Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 2006;16:11–19. PubMed PMC

Mercer TR, Dinger ME, Sunkin SM, et al. . Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A. 2008;105:716–721. PubMed PMC

Djebali S, Davis CA, Merkel A, et al. . Landscape of transcription in human cells. Nature. 2012;489:101–108. PubMed PMC

Khalil AM, Guttman M, Huarte M, et al. . Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106:11667–11672. PubMed PMC

Wang KC, Yang YW, Liu B, et al. . A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120–124. PubMed PMC

Feng J, Bi C, Clark BS, et al. . The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 2006;20:1470–1484. PubMed PMC

Shamovsky I, Ivannikov M, Kandel ES, et al. . RNA-mediated response to heat shock in mammalian cells. Nature. 2006;440:556–560. PubMed

Lai F, Orom UA, Cesaroni M, et al. . Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature. 2013;494:497–501. PubMed PMC

Yang L, Lin C, Jin C, et al. . lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 2013;500:598–602. PubMed PMC

Wang X, Arai S, Song X, et al. . Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature. 2008;454:126–130. PubMed PMC

Ramos AD, Andersen RE, Liu SJ, et al. . The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell. 2015;16:439–447. PubMed PMC

Gonzalez I, Munita R, Agirre E, et al. . A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature. Nat Struct Mol Biol. 2015;22:370–376. PubMed PMC

Yoon JH, Abdelmohsen K, Kim J, et al. . Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nat Commun. 2013;4:2939. PubMed PMC

Hu G, Lou Z, Gupta M. The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. Plos One. 2014;9:e107016. PubMed PMC

Carrieri C, Cimatti L, Biagioli M, et al. . Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491:454–457. PubMed

Willingham AT, Orth AP, Batalov S, et al. . A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science. 2005;309:1570–1573. PubMed

Noh JH, Kim KM, Abdelmohsen K, et al. . HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev. 2016;30:1224–1239. PubMed PMC

Salmena L, Poliseno L, Tay Y, et al. . A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146:353–358. PubMed PMC

Kino T, Hurt DE, Ichijo T, et al. . Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010;3:ra8. PubMed PMC

Melé M, Mattioli K, Mallard W, et al. . Chromatin environment, transcriptional regulation, and splicing distinguish lincRNAs and mRNAs. Genome Res. 2017;27:27–37. PubMed PMC

Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17:47–62. PubMed

Kunej T, Obsteter J, Pogacar Z, et al. . The decalog of long non-coding RNA involvement in cancer diagnosis and monitoring. Crit Rev Clin Lab Sci. 2014;51:344–357. PubMed

Ulitsky I. Interactions between short and long noncoding RNAs. FEBS Lett. 2018;592:2874–2883. PubMed

Zheng GX, Do BT, Webster DE, et al. . Dicer-microRNA-Myc circuit promotes transcription of hundreds of long noncoding RNAs. Nat Struct Mol Biol. 2014;21:585–590. PubMed PMC

Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18:5–18. PubMed PMC

Salviano-Silva A, Lobo-Alves SC, Almeida RC, et al. . Besides pathology: long non-coding RNA in cell and tissue homeostasis. Noncoding RNA. 2018;4:3. PubMed PMC

Jia H, Osak M, Bogu GK, et al. . Genome-wide computational identification and manual annotation of human long noncoding RNA genes. Rna. 2010;16:1478–1487. PubMed PMC

Lagos-Quintana M, Rauhut R, Meyer J, et al. . New microRNAs from mouse and human. Rna. 2003;9:175–179. PubMed PMC

Béres NJ, Kiss Z, Sztupinszki Z, et al. . Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. Dig Liver Dis. 2017;49:378–387. PubMed

Fasseu M, Tréton X, Guichard C, et al. . Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PLoS One. 2010;5:e13160. PubMed PMC

Mirza AH, Kaur S, Brorsson CA, Pociot F. Effects of GWAS-associated genetic variants on lncRNAs within IBD and T1D candidate loci. Plos One. 2014;9:e105723. PubMed PMC

Mirza AH, Berthelsen CH, Seemann SE, et al. . Transcriptomic landscape of lncRNAs in inflammatory bowel disease. Genome Med. 2015;7:39. PubMed PMC

Dalal SR, Kwon JH. The role of MicroRNA in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2010;6:714–722. PubMed PMC

Koukos G, Polytarchou C, Kaplan JL, et al. . MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology. 2013;145:842–52.e2. PubMed PMC

Kwon JH, Keates AC, Anton PM, et al. . Topical antisense oligonucleotide therapy against LIX, an enterocyte-expressed CXC chemokine, reduces murine colitis. Am J Physiol Gastrointest Liver Physiol. 2005;289:G1075–G1083. PubMed

Koukos G, Polytarchou C, Kaplan JL, et al. . A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium. Inflamm Bowel Dis. 2015;21:996–1005. PubMed PMC

Zahm AM, Hand NJ, Tsoucas DM, et al. . Rectal microRNAs are perturbed in pediatric inflammatory bowel disease of the colon. J Crohns Colitis. 2014;8:1108–1117. PubMed PMC

Béres NJ, Szabó D, Kocsis D, et al. . Role of altered expression of miR-146a, miR-155, and miR-122 in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22:327–335. PubMed

Szűcs D, Béres NJ, Rokonay R, et al. . Increased duodenal expression of miR-146a and -155 in pediatric Crohn’s disease. World J Gastroenterol. 2016;22:6027–6035. PubMed PMC

Sheedy FJ. Turning 21: induction of miR-21 as a key switch in the inflammatory response. Front Immunol. 2015;6:19. PubMed PMC

Neudecker V, Haneklaus M, Jensen O, et al. . Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med. 2017;214:1737–1752. PubMed PMC

Tang WJ, Peng KY, Tang ZF, et al. . MicroRNA-15a - cell division cycle 42 signaling pathway in pathogenesis of pediatric inflammatory bowel disease. World J Gastroenterol. 2018;24:5234–5245. PubMed PMC

Zahm AM, Thayu M, Hand NJ, et al. . Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2011;53:26–33. PubMed PMC

Heier CR, Fiorillo AA, Chaisson E, et al. . Identification of pathway-specific serum biomarkers of response to glucocorticoid and infliximab treatment in children with inflammatory bowel disease. Clin Transl Gastroenterol. 2016;7:e192. PubMed PMC

De Iudicibus S, Lucafò M, Vitulo N, et al. . High-throughput sequencing of microRNAs in glucocorticoid sensitive paediatric inflammatory bowel disease patients. Int J Mol Sci. 2018;19:1399. PubMed PMC

Lucafò M, Di Silvestre A, Romano M, et al. . Role of the long non-coding RNA growth arrest-specific 5 in glucocorticoid response in children with inflammatory bowel disease. Basic Clin Pharmacol Toxicol. 2018;122:87–93. PubMed

Park JH, Peyrin-Biroulet L, Eisenhut M, et al. . IBD immunopathogenesis: a comprehensive review of inflammatory molecules. Autoimmun Rev. 2017;16:416–426. PubMed

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