ABSTRACT
Autism spectrum disorder is a neurodevelopmental disorder characterized by delays or deviations in social interaction and communication, lack of interest in the social environment, repetitive-restrictive-anomalous behaviors and interests, and insistence on sameness. In recent years, studies on etiopathogenesis of autism have focused on epigenetic changes. Among epigenetic mechanisms non-coding RNAs (ncRNA) which do not code proteins and lead to transcripts which do not translate into proteins have become the recent focus of research. Interest in short ncRNAs (sncRNA) is increasing especially in the etiology of neurodevelopmental disorders. In this review, our aim was to review the sncRNA, their relationship with autism and values as a target molecule in etiology and treatment.
References
1
Volkmar FR, Reichow B. Autism in DSM-5: progress and challenges. Mol Autism. 2013;4:13.
2
Knopf A. Autism prevalence increases from 1 in 60 to 1 in 54: CDC, The Brown University Child and Adolescent Behavior Letter. 2020;36:4. https://onlinelibrary.wiley.com/doi/abs/10.1002/cbl.30470
3
Le Couteur A, Szatmari P. Autism spectrum disorder. Rutter’s child and adolescent psychiatry. 2015;6:665-683.
4
Frye RE, Vassall S, Kaur G, Lewis C, Karim M, Rossignol D. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019;7:792.
5
Ziats MN, Rennert OM. The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder. Front Genet. 2016;7:65.
6
Tick B, Bolton P, Happé F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatry. 2016;57:585-595.
7
Saxena R, Babadi M, Namvarhaghighi H, Roullet FI. Role of environmental factors and epigenetics in autism spectrum disorders. Prog Mol Biol Transl Sci. 2020;173:35-60.
8
Loke YJ, Hannan AJ, Craig JM. The Role of Epigenetic Change in Autism Spectrum Disorders. Front Neurol. 2015;6:107.
9
Yoon SH, Choi J, Lee WJ, Do JT. Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder. J Clin Med. 2020;9:966.
10
Felsenfeld G. A brief history of epigenetics. Cold Spring Harb Perspect Biol. 2014;6:a018200.
11
Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571:489-499.
12
Constantin L. The Role of MicroRNAs in Cerebellar Development and Autism Spectrum Disorder During Embryogenesis. Mol Neurobiol. 2017;54:6944-6959.
13
Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR. Landscape of transcription in human cells. Nature. 2012;489:101-108.
14
Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157:77-94.
15
Hung T, Chang HY. Long noncoding RNA in genome regulation: prospects and mechanisms. RNA Biol. 2010;7:582-585.
16
Wang P, Mokhtari R, Pedrosa E, Kirschenbaum M, Bayrak C, Zheng D, Lachman HM. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol Autism. 2017;8:11.
17
Wang Y, Zhao X, Ju W, Flory M, Zhong J, Jiang S, Wang P, Dong X, Tao X, Chen Q, Shen C, Zhong M, Yu Y, Brown WT, Zhong N. Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder. Transl Psychiatry. 2015;5:e660.
18
Ziats MN, Rennert OM. Aberrant expression of long noncoding RNAs in autistic brain. J Mol Neurosci. 2013;49:589-593.
19
Kerin T, Ramanathan A, Rivas K, Grepo N, Coetzee GA, Campbell DB. A noncoding RNA antisense to moesin at 5p14.1 in autism. Sci Transl Med. 2012;4:128ra40.
20
Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459:528-533.
21
Sarachana T, Zhou R, Chen G, Manji HK, Hu VW. Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med. 2010;2:23.
22
Ghahramani Seno MM, Hu P, Gwadry FG, Pinto D, Marshall CR, Casallo G, Scherer SW. Gene and miRNA expression profiles in autism spectrum disorders. Brain Res. 2011;1380:85-97.
23
Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM. Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders. Mol Autism. 2015;6:37.
24
Mor M, Nardone S, Sams DS, Elliott E. Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Mol Autism. 2015;6:46.
25
Hicks SD, Carpenter RL, Wagner KE, Pauley R, Barros M, Tierney-Aves C, Barns S, Greene CD, Middleton FA. Saliva MicroRNA Differentiates Children With Autism From Peers With Typical and Atypical Development. J Am Acad Child Adolesc Psychiatry. 2020;59:296-308.
26
Hicks SD, Middleton FA. A Comparative Review of microRNA Expression Patterns in Autism Spectrum Disorder. Front Psychiatry. 2016;7:176.
27
Narayanan R, Schratt G. miRNA regulation of social and anxiety-related behaviour. Cell Mol Life Sci. 2020;77:4347-4364.
28
Lyu JW, Yuan B, Cheng TL, Qiu ZL, Zhou WH. Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs. Sci Rep. 2016;6:20392.
29
Lee K, Kim JH, Kwon OB, An K, Ryu J, Cho K, Suh YH, Kim HS. An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. J Neurosci. 2012;32:5678-5687.
30
Kichukova TM, Popov NT, Ivanov IS, Vachev TI. Profiling of Circulating Serum MicroRNAs in Children with Autism Spectrum Disorder using Stem-loop qRT-PCR Assay. Folia Med (Plovdiv). 2017;59:43-52.
31
Mundalil Vasu M, Anitha A, Thanseem I, Suzuki K, Yamada K, Takahashi T, Wakuda T, Iwata K, Tsujii M, Sugiyama T, Mori N. Serum microRNA profiles in children with autism. Mol Autism. 2014;5:40.
32
Talebizadeh Z, Butler MG, Theodoro MF. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res. 2008;1:240-250.
33
Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K, Kosik KS. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008;9:153-161.
34
Salloum-Asfar S, Elsayed AK, Elhag SF, Abdulla SA. Circulating Non-Coding RNAs as a Signature of Autism Spectrum Disorder Symptomatology. Int J Mol Sci. 2021;22:6549.
35
Mohn F, Handler D, Brennecke J. Noncoding RNA. piRNA-guided slicing specifies transcripts for Zucchini-dependent, phased piRNA biogenesis. Science. 2015;348:812-817.
36
Vychytilova-Faltejskova P, Stitkovcova K, Radova L, Sachlova M, Kosarova Z, Slaba K, Kala Z, Svoboda M, Kiss I, Vyzula R, Cho WC, Slaby O. Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer. Cancer Epidemiol Biomarkers Prev. 2018;27:1019-1028.
37
Chiappori F, Cupaioli FA, Consiglio A, Di Nanni N, Mosca E, Licciulli VF, Mezzelani A. Analysis of Faecal Microbiota and Small ncRNAs in Autism: Detection of miRNAs and piRNAs with Possible Implications in Host-Gut Microbiota Cross-Talk. Nutrients. 2022;14:1340.
38
Xu Y, Wang Y, Xu J, Song Y, Liu B, Xiong Z. Leveraging Existing 16SrRNA Microbial Data to Define a Composite Biomarker for Autism Spectrum Disorder. Microbiol Spectr. 2022;10:e0033122.
39
Kowalski MP, Krude T. Functional roles of non-coding Y RNAs. Int J Biochem Cell Biol. 2015;66:20-29.
40
Kühnlein A, Lanzmich SA, Braun D. tRNA sequences can assemble into a replicator. Elife. 2021;10:e63431.
41
Anderson P, Ivanov P. tRNA fragments in human health and disease. FEBS Lett. 2014;588:4297-4304.
42
Kumar P, Kuscu C, Dutta A. Biogenesis and Function of Transfer RNA-Related Fragments (tRFs). Trends Biochem Sci. 2016;41:679-689.
43
Rechavi O. Guest list or black list: heritable small RNAs as immunogenic memories. Trends Cell Biol. 2014;24:212-220.
44
Chan JC, Nugent BM, Bale TL. Parental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment. Biol Psychiatry. 2018;83:886-894.
45
Sheng J, Xu Z. Three decades of research on angiogenin: a review and perspective. Acta Biochim Biophys Sin (Shanghai). 2016;48:399-410.
46
Thompson DM, Parker R. Stressing out over tRNA cleavage. Cell. 2009;138:215-219.
47
Nawrot B, Sochacka E, Düchler M. tRNA structural and functional changes induced by oxidative stress. Cell Mol Life Sci. 2011;68:4023-4032.
48
Huang HY, Hopper AK. Multiple Layers of Stress-Induced Regulation in tRNA Biology. Life (Basel). 2016;6:16.
49
Jehn J, Treml J, Wulsch S, Ottum B, Erb V, Hewel C, Kooijmans RN, Wester L, Fast I, Rosenkranz D. 5’ tRNA halves are highly expressed in the primate hippocampus and might sequence-specifically regulate gene expression. RNA. 2020;26:694-707.
50
Xie Y, Yao L, Yu X, Ruan Y, Li Z, Guo J. Action mechanisms and research methods of tRNA-derived small RNAs. Signal Transduct Target Ther. 2020;5:109.
51
Su Z, Wilson B, Kumar P, Dutta A. Noncanonical Roles of tRNAs: tRNA Fragments and Beyond. Annu Rev Genet. 2020;54:47-69.
52
Hogg MC, Raoof R, El Naggar H, Monsefi N, Delanty N, O’Brien DF, Bauer S, Rosenow F, Henshall DC, Prehn JH. Elevation in plasma tRNA fragments precede seizures in human epilepsy. J Clin Invest. 2019;129:2946-2951.
53
Speer J, Gehrke CW, Kuo KC, Waalkes TP, Borek E. tRNA breakdown products as markers for cancer. Cancer. 1979;44:2120-2123.
54
Borek E, Baliga BS, Gehrke CW, Kuo CW, Belman S, Troll W, Waalkes TP. High turnover rate of transfer RNA in tumor tissue. Cancer Res. 1977;37:3362-3366.
55
Park J, Ahn SH, Shin MG, Kim HK, Chang S. tRNA-Derived Small RNAs: Novel Epigenetic Regulators. Cancers (Basel). 2020;12:2773.
56
Chiou NT, Kageyama R, Ansel KM. Selective Export into Extracellular Vesicles and Function of tRNA Fragments during T Cell Activation. Cell Rep. 2018;25:3356-3370.e4.
57
Sun C, Fu Z, Wang S, Li J, Li Y, Zhang Y, Yang F, Chu J, Wu H, Huang X, Li W, Yin Y. Roles of tRNA-derived fragments in human cancers. Cancer Lett. 2018;414:16-25.
58
Balatti V, Pekarsky Y, Croce CM. Role of the tRNA-Derived Small RNAs in Cancer: New Potential Biomarkers and Target for Therapy. Adv Cancer Res. 2017;135:173-187.
59
Kim HK, Fuchs G, Wang S, Wei W, Zhang Y, Park H, Roy-Chaudhuri B, Li P, Xu J, Chu K, Zhang F, Chua MS, So S, Zhang QC, Sarnow P, Kay MA. A transfer-RNA-derived small RNA regulates ribosome biogenesis. Nature. 2017;552:57-62.
60
Keam SP, Hutvagner G. tRNA-Derived Fragments (tRFs): Emerging New Roles for an Ancient RNA in the Regulation of Gene Expression. Life (Basel). 2015;5:1638-1651.
61
Kumar P, Anaya J, Mudunuri SB, Dutta A. Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol. 2014;12:78.
62
Winek K, Lobentanzer S, Nadorp B, Dubnov S, Dames C, Jagdmann S, Moshitzky G, Hotter B, Meisel C, Greenberg DS, Shifman S, Klein J, Shenhar-Tsarfaty S, Meisel A, Soreq H. Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade. Proc Natl Acad Sci U S A. 2020;117:32606-32616.
63
Li Q, Hu B, Hu GW, Chen CY, Niu X, Liu J, Zhou SM, Zhang CQ, Wang Y, Deng ZF. tRNA-Derived Small Non-Coding RNAs in Response to Ischemia Inhibit Angiogenesis. Sci Rep. 2016;6:20850.
64
Abbasi-Moheb L, Mertel S, Gonsior M, Nouri-Vahid L, Kahrizi K, Cirak S, Wieczorek D, Motazacker MM, Esmaeeli-Nieh S, Cremer K, Weißmann R, Tzschach A, Garshasbi M, Abedini SS, Najmabadi H, Ropers HH, Sigrist SJ, Kuss AW. Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet. 2012;90:847-855.
65
Bednářová A, Hanna M, Durham I, VanCleave T, England A, Chaudhuri A, Krishnan N. Lost in Translation: Defects in Transfer RNA Modifications and Neurological Disorders. Front Mol Neurosci. 2017;10:135.