基于全转录组技术研究慢性应激抑郁模型中微小RNA、长链非编码RNA及环状RNA的表达谱及调控网络

孟盼; 张熙; 刘彤彤; 赵洪庆; 杨蕙; 刘检; 方锐; 王宇红; 葛金文; 王枭冶

doi:10.16098/j.issn.0529-1356.2023.04.005

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解剖学报 ›› 2023, Vol. 54 ›› Issue (4) : 405-413. DOI: 10.16098/j.issn.0529-1356.2023.04.005

基于全转录组技术研究慢性应激抑郁模型中微小RNA、长链非编码RNA及环状RNA的表达谱及调控网络

孟盼¹ 张熙² 杨蕙³ 刘检³ 方锐⁴ 王枭冶^2* 葛金文^1,4* 刘彤彤⁵ 赵洪庆⁵ 王宇红⁵

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Expression profiles and regulatory network of microRNA, long non-coding RNA and circular RNA in rat chronic stress depression model based on whole transcriptome technology

MENG Pan¹ ZHANG Xi ² YANG Hui³ LIU Jian³ FANG Rui⁴ WANG Xiao-ye^2* GE Jin-wen^1,4* LIU Tong-tong⁵ ZHAO Hong-qing⁵ WANG Yu-hong⁵#br#

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摘要

目的筛选慢性应激抑郁模型大鼠海马组织中微小RNA（miRNA）、长链非编码RNA（lncRNA）、环状RNA（circRNA）的表达谱及其竞争性内源RNA（ceRNA）调控网络，探讨抑郁症潜在的病理生理机制。方法 12只SD 大鼠分为空白组和模型组，采用慢性温和不可预测性应激（CUMS）构建抑郁症大鼠模型，取大鼠海马组织进行全转录组分析，并用生物信息学方法找出可能存在的 lncRNA-miRNA-mRNA、circRNA-miRNA-mRNA调控网络。结果根据|差异倍数（fold change）|≥1.5和P≤0.05共鉴定出29个差异miRNAs（上调21个，下调8个），686个差异lncRNAs（上调163个，下调523个），8个差异circRNAs（上调3个，下调5个）。基因本体论（GO）和京都基因和基因组百科全书（KEGG）通路分析显示，miRNAs的靶基因主要富集于细胞膜内的高尔基体和钙离子结合过程；LncRNAs靶基因的功能涉及核酸结合的调节、细胞因子和蛋白质泛素化等；CircRNAs的宿主基因主要集中在细胞刺激反应、代谢进程、催化活性等过程中。LncRNAs和circRNAs相互竞争的ceRNA网络显示，非编码RNA（ncRNA）与突触可塑性相关的mRNA之间存在复杂相互作用，如与轴突导向相关的Wnt-ta蛋白（WNT5a）和Ⅷ型胶原α1（COL8α1），以及神经发育相关的层黏连蛋白A2（LAMA2）。结论 LncRNA和circRNA的ceRNA网络显示，ncRNA和mRNA之间的复杂相互作用与抑郁症的神经可塑性受损有关。

Abstract

Objective To explore the potential pathophysiological mechanism of depression by screening the expression profiles and competing endogenous RNA (ceRNA) regulatory network microRNA(miRNA), long non\|coding RNA(lncRNA) and circular RNA(circRNA) in the hippocampus of chronic stress depression rat model. Methods Twelve SD rats were divided into blank group and model group. Chronic mild unpredictability stress (CUMS) was used to construct the rat model of depression. The whole transcriptome analysis was performed on the hippocampus of the rats, and the possible regulatory networks among lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA were explored by bioinformatics method. Results According to the |fold change|≥1.5 and P≤0.05, 29 differentially expressed miRNAs (21 up-regulated and 8 down-regulated), 686 differentially expressed lncRNAs (163 up-regulated and 523 down-regulated) and 8 differentially expressed circRNAs (3 up-regulated and 5 down-regulated) were identified. Gene Ontology(GO) and Kytot Encyclopedia of Genes and Genomes(KEGG) pathway analysis showed that the target genes of miRNAs were mainly enriched in the Golgi apparatus and calcium ion binding process in the cell membrane, the functions of lncRNAs target genes involved nucleic acid binding regulation, cytokine and protein ubiquitination, etc, and the functions of host genes of circRNAs were associated with cellular stimulation response, metabolic process, catalytic activity and other processes. The ceRNA network of lncRNAs and circRNAs showed complex interactions between non-coding RNA (ncRNA) and mRNA related to synaptic plasticity, such as protein Wnt-sa(WNT5a) and collagentype Ⅲ alpha1(COL8a1) related to axon orientation and laminin A2(LAMA2) related to neurodevelopment. Conclusion The ceRNA network of lncRNA and circRNA shows that the complex interaction betweens ncRNA and mRNA is highly associated with the neuroplasticity, which support the neuroplasticity hypothesis of depression.

导出引用

孟盼张熙杨蕙刘检方锐王枭冶葛金文刘彤彤赵洪庆王宇红. 基于全转录组技术研究慢性应激抑郁模型中微小RNA、长链非编码RNA及环状RNA的表达谱及调控网络[J]. 解剖学报. 2023, 54(4): 405-413 https://doi.org/10.16098/j.issn.0529-1356.2023.04.005

MENG Pan ZHANG Xi YANG Hui LIU Jian FANG Rui WANG Xiao-ye GE Jin-wen LIU Tong-tong ZHAO Hong-qing WANG Yu-hong.

Expression profiles and regulatory network of microRNA, long non-coding RNA and circular RNA in rat chronic stress depression model based on whole transcriptome technology

[J]. Acta Anatomica Sinica. 2023, 54(4): 405-413 https://doi.org/10.16098/j.issn.0529-1356.2023.04.005

中图分类号： R-332 R749.99

参考文献

［1］Khan AR,Geiger L,Wiborg O, et al.Stress-induced morphological, cellular and molecular changes in the brain-lessons learned from the chronic mild stress model of depression［J］.Cells,2020,9(4):1026-1054.

［2］Cui X,Niu W,Kong L, et al.Long noncoding RNA expression in peripheral blood mononuclear cells and suicide risk in Chinese patients with major depressive disorder［J］.Brain Behav,2017,7(6):e00711.

［3］Godoy LD,Rossignoli MT,Delfino-Pereira P, et al.A comprehensive overview on stress neurobiology: basic concepts and clinical implications［J］.Front Behav Neurosci,2018,12:127-150.

［4］Yoshino Y,Dwivedi Y.Non-coding RNAs in psychiatric disorders and suicidal behavior［J］.Front Psychiatry,2020,11:543893-543913.

［5］Dadi AF,Miller ER,Bisetegn TA, et al.Global burden of antenatal depression and its association with adverse birth outcomes: an umbrella review［J］.BMC Public Health,2020,20(1):173-189.

［6］Willner P.The chronic mild stress (CMS) model of depression: History, evaluation and usage［J］.Neurobiol Stress,2017,6:78-93.

［7］Zhou M,Wang M,Wang X, et al.Abnormal expression of micrornas induced by chronic unpredictable mild stress in rat hippocampal tissues［J］.Mol Neurobiol,2018,55(2):917-935.

［8］Impey S,Davare M,Lesiak A, et al.An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling［J］.Mol Cell Neurosci,2010,43(1):146-156.

［9］Sai YCKT, Zhao J, Luo T, et al. Differential expression and bioinformatics analysis of miRNA in hippocampus of chronic stress depression rats［J］.Chinese Journal of Behavioral Medicine and Brain Science, 2020, 29(12):1073-1079.(in Chinese)

赛音朝克图,赵俊,罗彤,等.慢性应激抑郁大鼠海马miRNA的差异表达及生物信息学分析［J］.中华行为医学与脑科学杂志,2020,29(12):1073-1079.

［10］Zhang Y,Smolen P,Baxter DA, et al.Biphasic regulation of p38 MAPK by serotonin contributes to the efficacy of stimulus protocols that induce longterm synaptic facilitation［J］.eNeuro,2017,4(1):ENEURO.0373-16.

［11］Zhou XM,Liu CY,Liu YY, et al.Xiaoyaosan alleviates hippocampal glutamate-induced toxicity in the CUMS rats via NR2B and PI3K/Akt signaling pathway［J］.Front Pharmacol,2021,12:586788.

［12］Zhao YN, Chen GZh, Chen ChX, et al. p38MAPK is involved in the cognition injury after sleep deprivation in rats ［J］. Acta Anatomica Sinica, 2011,42(1):32-37. (in Chinese)

赵雅宁,陈桂芝,陈长香,等.p38MAPK信号通路参与睡眠剥夺大鼠认知功能的损害［J］.解剖学报,2011,42(1):32-37.

［13］Zhang L,Zhang P,Wang G, et al.Ras and rap signal bidirectional synaptic plasticity via distinct subcellular microdomains［J］.Neuron,2018,98(4):783-800.

［14］Liu W,Ge T,Leng Y, et al.The role of neural plasticity in depression: from hippocampus to prefrontal cortex［J］.Neural Plast,2017,2017:6871089.

［15］Gruzdev SK,Yakovlev AA,Druzhkova TA, et al.The missing link: how exosomes and mirnas can help in bridging psychiatry and molecular biology in the context of depression, bipolar disorder and schizophrenia［J］.Cell Mol Neurobiol,2019,39(6):729-750.

［16］Ahmed M,Marziali LN,Arenas E, et al.Laminin α2 controls mouse and human stem cell behaviour during midbrain dopaminergic neuron development［J］.Development,2019,146(16): 172668-172679.

［17］Nakamura Y,Nakatochi M,Kunimoto S, et al.Methylation analysis for postpartum depression: a case control study［J］.BMC Psychiatry,2019,19(1):190-199.

［18］Roy B,Dunbar M,Agrawal J, et al.Amygdala-based altered mirnome and epigenetic contribution of mir-128-3p in conferring susceptibility to depression-like behavior via wnt signaling［J］.Int J Neuropsychopharmacol,2020,23(3):165-177.

［19］Kaufman J,Wymbs NF,Montalvo-Ortiz JL, et al.Methylation in OTX2 and related genes, maltreatment, and depression in children［J］.Neuropsychopharmacology,2018,43(11):2204-2211.

［20］Shi Y,Song R,Wang Z, et al.Potential clinical value of circular RNAs as peripheral biomarkers for the diagnosis and treatment of major depressive disorder［J］.EBioMedicine,2021,66:103337-103351.