miR-429对抽动障碍靶基因调控的生物信息学分析

doi:10.11852/zgetbjzz2022-0746

摘要/Abstract

摘要： 目的通过生物信息学分析,并将miR-429靶基因与抽动障碍(TD)相关基因(TRGs)关联,预测TD相关靶基因,以更好地理解miR-429在TD中的作用。方法通过miRbase数据库获取多物种成熟miR-429的序列,进行保守性分析。通过GeneCards和DisGeNET数据库获取TRGs,并将miRDB数据库及DIANA数据库的microT工具预测的miR-429的靶基因与TRGs取交集获得TD相关靶基因。运用RNAhybird数据库对杂交的位点序列和最小自由能(MFE)进行预测。通过DAVID数据库对TD相关靶基因进行功能富集分析。结果 miR-429的22个核苷酸中仅2个核苷酸在物种间存在差异,总共获得9个基因为TD相关靶基因。仅ASH1L、SLITRK 1 与miR-429杂交的序列中未包含物种间存在差异的核苷酸,最小的杂交MFE的基因为CHD2(-25.0 kcal/mol)。功能富集分析各分类的首个功能术语为生物学过程的成人行为,细胞组分的谷氨酸能突触,以及分子功能的染色质结合。未获得有统计学意义的通路富集。结论 miR-429可能通过相关基因调控谷氨酸能突触而影响TD行为,尤其是SLITRK1基因。

关键词: miR-429, 谷氨酸能, SLITRK1基因, 生物信息学分析, 抽动障碍

Abstract: Objective To predict tic disorders (TD) related target genes of microRNA (miRNA, miR)-429 by using bioinformatics analysis, and to take intersection between the target genes of miR-429 and TD related genes (TRGs), so as to further understand the impaction of miR-429 in TD. Method MiRbase was used to obtain the sequences of mature miR-429 in multiple species for conserved analysis.GeneCards database and DisGeNET database were used to acquire TRGs.MiRDB database and DIANA-microT were used to gain the target genes of miR-429.TD related target genes were obtained by intersection of the target genes gained by MiRDB database and DIANA-microT with TRGs.RNAhybird database was used to predict the sequences and minimum free energy (MFE) of hybridization.Functional enrichment analysis of TD related target genes was performed by DAVID database. Results Only 1 nucleotides among the 22 nucleotides of miR-429 was different among specie.A total of 9 genes were identified as TD related target genes.The sequences of hybridization of ASH1L and SLITRK1 with miR-429 did not include the nucleotide that differed among species, indicating that the two hybird pairs were more conserved.The first gene with the smallest MFE of hybridization were CHD2 (-25.0 kcal/mol).The first terms in each category of functional enrichment analysis were adult behavior of biological process, glutamatergic synapse of cell components and chromatin binding of molecular functions.No statistically significant pathway enrichment was obtained. Conclusion MiR-429 might impact behaviors in TD by regulating glutamatergic synapses via related genes, especially SLITRK1.

Key words: miR-429, glutamatergic, SLITRK1 gene, bioinformatics analysis, tic disorders

中图分类号:

R749.94

江极龙, 陈燕惠, 黄惠芳, 黄玉娴. miR-429对抽动障碍靶基因调控的生物信息学分析[J]. 中国儿童保健杂志, 2023, 31(3): 268-273.

JIANG Jilong, CHEN Yanhui, HUANG Huifang, HUANG Yuxian. Bioinformatics analysis of the regulation of miR-429 towards target genes in tic disorders[J]. Chinese Journal of Child Health Care, 2023, 31(3): 268-273.

参考文献

[1] Szejko N, Robinson S, Hartmann A, et al.European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0.Part I: assessment[J].Eur Child Adolesc Psychiatry, 2022, 31(31): 383-402.
[2] Liu ZS, Cui YH, Sun D, et al.Current status, diagnosis, and treatment recommendation for tic disorders in China[J].Front Psychiatry, 2020, 11: 774.
[3] American Psychiatric Association.Diagnostic and statistical manual of mental disorders, Fifth Edition[M].Washington DC: American Psychiatric Association, 2013.
[4] 杨春松, 张伶俐, 俞丹, 等.中国抽动障碍患者基因组学研究现状的循证评价[J].中国儿童保健杂志, 2018, 26(1): 55-58.
Yang CS, Zhang LL, Yu D, et al.Evidence based assessment of genomics in tic disorders in China[J].Chin J Child Health Care, 2018, 26(1): 55-58.
[5] Liu J, Yang T, Huang Z, et al.Transcriptional regulation of nuclear miRNAs in tumorigenesis (Review)[J].Int J Mol Med, 2022, 50(1): 92.
[6] Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr, et al.Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond[J].Stat Med, 2008, 27(2): 157-172.
[7] Rizzo R, Ragusa M, Barbagallo C, et al.Circulating miRNAs profiles in tourette syndrome: Molecular data and clinical implications[J].Mol Brain, 2015, 8: 44.
[8] 吴嘉美, 刘梦瑶, 许何丽, 等.hsa-miR-429的靶基因预测及功能分析[J].解剖科学进展,2019, 25(3): 312-315.
Wu JM, Liu MY, Xu HL, et al.Prediction of has-miR-429 target gene and bioinformatics analysis[J].Progress of Anatomical Sciences, 2019, 25(3): 312-315.
[9] Kozomara A, Birgaoanu M, Griffiths-Jones S.miRBase: From microRNA sequences to function[J].Nucleic Acids Res, 2019, 47(D1): 155-162.
[10] Stelzer G, Rosen N, Plaschkes I, et al.The genecards suite: From gene data mining to disease genome sequence analyses[J].Curr Protoc Bioinformatics, 2016, 54: 1.30.1-1.30.33.
[11] Piñero J, Bravo À, Queralt-Rosinach N, et al.DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants[J].Nucleic Acids Res, 2017, 45(D1): 833-839.
[12] Chen Y, Wang X.miRDB: An online database for prediction of functional microRNA targets[J].Nucleic Acids Res, 2020, 48(D1): 127-131.
[13] Paraskevopoulou MD, Georgakilas G, Kostoulas N, et al.DIANA-microT web server v5.0: Service integration into miRNA functional analysis workflows[J].Nucleic Acids Res, 2013, 41(Web Server issue): W169-W173.
[14] Chen H, Boutros PC.VennDiagram: A package for the generation of highly-customizable Venn and Euler diagrams in R[J].BMC Bioinformatics, 2011, 12: 35.
[15] Krüger J, Rehmsmeier M.RNAhybrid: MicroRNA target prediction easy, fast and flexible[J].Nucleic Acids Res, 2006, 34(Web Server issue): W451-W454.
[16] Ito K, Murphy D.Application of ggplot2 to Pharmacometric Graphics[J].CPT Pharmacometrics Syst Pharmacol, 2013, 2(10): e79.
[17] Huang DW, Sherman BT, Tan Q, et al.The DAVID gene functional classification tool: A novel biological module-centric algorithm to functionally analyze large gene lists[J].Genome Biol, 2007, 8(9): R183.
[18] Lewis BP, Burge CB, Bartel DP.Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets[J].Cell, 2005, 120(1): 15-20.
[19] Song M.miRNAs-dependent regulation of synapse formation and function[J].Genes Genomics, 2020, 42(8): 837-845.
[20] Trümbach D, Prakash N.The conserved miR-8/miR-200 microRNA family and their role in invertebrate and vertebrate neurogenesis[J].Cell and Tissue Res, 2015, 359(1): 161-177.
[21] Chen W, Zhang B, Guo W, et al.miR-429 inhibits glioma invasion through BMK1 suppression[J].J Neurooncol, 2015, 125(1): 43-54.
[22] Zhou X, Lu H, Li F, et al.MicroRNA-429 inhibits neuroblastoma cell proliferation, migration and invasion via the NF-κB pathway[J].Cell Mol Biol Lett, 2020, 25: 5.
[23] Qi R, Wang X.Inhibition of miR-429 improves neurological recovery of traumatic brain injury mice and attenuates microglial neuroinflammation[J].Int Immunopharmacol, 2020, 79: 106091.
[24] Fu S, Zhang J, Zhang S.Knockdown of miR-429 attenuates Aβ-Induced neuronal damage by targeting SOX2 and BCL2 in mouse cortical neurons[J].Neurochem Res, 2018, 43(12): 2240-2251.
[25] Murphy SJ, Lusardi TA, Phillips JI, et al.Sex differences in microRNA expression during development in rat cortex[J].Neurochem Int, 2014, 77: 24-32.
[26] Janik P, Kalbarczyk A, Gutowicz M, et al.The analysis of selected neurotransmitter concentrations in serum of patients with Tourette syndrome[J].Neurochem Int, 2010, 44(3): 251-259.
[27] 于文静, 白雪, 张雯, 等.健脾止动汤对多发性抽动症患儿神经递质的影响[J].中华中医药杂志, 2015, 30(5): 1757-1761.
Yu JW, Bai X, Zhang W, et al.Effects of Jianpi Zhidong Decoction on the neurotransmitters of Tourette syndrome chidren[J].China Journal of Traditional Chinese Medicine and Pharmacy, 2015, 30(5): 1757-1761.
[28] Mahone EM, Puts NA, Edden RAE, et al.GABA and glutamate in children with Tourette syndrome: A ¹H MR spectroscopy study at 7T[J].Psychiatry Res Neuroimaging, 2018, 273: 46-53.
[29] Naaijen J, Forde NJ, Lythgoe DJ, et al.Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder[J].Neuroimage Clin, 2017, 13: 16-23.
[30] Sun XR, Zhang X, Jiang KY, et al.Gastrodin attenuates tourette syndrome by regulating EAATs and NMDA receptors in the striatum of rats[J].Neuropsychiatr Dis Treat, 2021, 17: 2243-2255.
[31] Smith ID, Todd MJ, Beninger RJ.Glutamate receptor agonist injections into the dorsal striatum cause contralateral turning in the rat: Involvement of kainate and AMPA receptors[J].Eur J Pharmacol, 1996, 301(1-3): 7-17.
[32] Singh J, Raina A, Sangwan N, et al.Identification of homologous human miRNAs as antivirals towards COVID-19 genome[J].Adv Cell Gene Ther, 2021, 4(4): e114.
[33] Deng H, Le WD, Xie WJ, et al.Examination of the SLITRK1 gene in Caucasian patients with Tourette syndrome[J].Acta Neurol Scand, 2006, 114(6): 400-402.
[34] O'Roak BJ, Morgan TM, Fishman DO, et al.Additional support for the association of SLITRK1 var321 and Tourette syndrome[J].Mol Psychiatry, 2010, 15(5): 447-450.
[35] Beaubien F, Raja R, Kennedy TE, et al.Slitrk1 is localized to excitatory synapses and promotes their development[J].Sci Rep, 2016, 6: 27343.
[36] Stillman AA, Krsnik Z, Sun J, et al.Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome[J].J Comp Neurol, 2009, 513(1): 21-37.
[37] Uhl GR, Martinez MJ.PTPRD: Neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes[J].Ann NY Acad Sci, 2019, 1451(1): 112-129.
[38] Won SY, Lee P, Kim HM.Synaptic organizer: Slitrks and type IIa receptor protein tyrosine phosphatases[J].Curr Opion Struc Biol, 2019, 54: 95-103.
[39] Ali MZ, Farid A, Ahmad S, et al.In silico analysis identified putative pathogenic missense nsSNPs in human SLITRK1 gene[J].Genes, 2022, 13: 672.
[40] Schroeder A, Vanderlinden J, Vints K, et al.A modular organization of LRR protein-mediated synaptic adhesion defines synapse Identity[J].Neuron, 2018, 99(2): 329-344.
[41] Huang AY, Yu D, Davis LK, et al.Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome[J].Neuron, 2017, 94(6): 1101-1111.
[42] Etherton MR, Blaiss CA, Powell CM, et al.Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments[J].PNAS, 2009, 106(42): 17998-18003.
[43] Pak C, Danko T, Zhang Y, et al.Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1[J].Cell Stem Cell, 2015, 17(3): 316-328.
[44] Davatolhagh MF, Fuccillo MV.Neurexin1α differentially regulates synaptic efficacy within striatal circuits[J].Cell Rep, 2021, 34(8): 108773.
[45] Gunther J, Tian YF, Stamova B, et al.Catecholamine-related gene expression in blood correlates with tic severity in tourette syndrome[J].Psychiat Res, 2012, 200(2-3): 593-601.
[46] Huang Q, Lian C, Dong Y, et al.SNAP25 inhibits glioma progression by regulating synapse plasticity via GLS-mediated glutaminolysis[J].Front Oncol, 2021, 11: 698835.
[47] Liu P, Song C, Wang C, et al.Spinal SNAP-25 regulates membrane trafficking of GluA1-containing AMPA receptors in spinal injury-induced neuropathic pain in rats[J].Neurosci Lett, 2020, 715: 134616.
[48] Pozzi D, Corradini I, Matteoli M.The control of neuronal calcium homeostasis by SNAP-25 and its impact on neurotransmitter release[J].Neurosci, 2019, 420: 72-78.