Comprehensive transcriptome analysis and lncRNA-miRNA-mRNA establishment of schizophrenia based on induced pluripotent stem cells

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research Pub Date : 2025-04-30 DOI:10.1016/j.schres.2025.04.027

Ningning Jia , Xuyuan Yin , Zhenhua Zhu , Wenlong Hou , Qing Yang , Hongliang Zhu , Huiping Zhang , Xin Yu , Qiong Yu , Li Hui

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Abstract

Background

Schizophrenia (SCZ) is a complex and heterogeneous disorder with unclear underlying mechanisms. Identifying key gene diseases and constructing biological regulatory networks were beneficial in expanding our understanding of the pathogenesis of SCZ.

Methods

We conducted whole transcriptome sequencing of induced pluripotent stem cells (iPSCs) derived from 5 SCZ patients and 5 healthy controls to analyze differences in mRNA and non-coding RNA expression profiles. Differentially expressed mRNAs (DE mRNAs) were explored for their functions and pathways, and lncRNA-miRNA-mRNA regulatory networks were constructed to understand post-transcriptional regulation mechanisms. Additionally, correlation analyses between competitive endogenous RNAs (ceRNAs), hub genes, and clinical phenotypes of SCZ patients (positive/negative and cognitive symptoms) were performed.

Results

We identified 139 DE mRNAs, 154 lncRNAs, and 19 miRNAs. Significant enrichment of pathways related to apoptosis, inflammatory response, hypoxia, KRAS signaling, and IL6_JAK_STAT3 signaling were observed. Ten hub genes, CCK, CCNA1, CDH5, GATA2, GRPR, NPY, PRKG2, TLE6, ZEB1and ZEB2, were identified, of which ZEB1 and GATA2 were positively correlated with positive symptoms of SCZ, while CDH5 and GRPR were associated with memory. The ceRNA regulatory network (TPM1-AS/ADPGK-AS1/MIRLET7BHG-hsa-mir-3180/3180-3p-LRRC15/TUBA8 and MIRLET7BHG- hsa-mir-3187-3p- CCDC92/ TDRD6/ TMEM26/ ATP1A2) was established, which was also significantly associated with positive, negative and cognitive symptoms of SCZ.

Conclusions

This study identified potential hub genes, pathways, and lncRNA-miRNA-mRNA regulatory networks in iPSCs that provide new insights into the molecular mechanisms of SCZ. The identified hub genes and ceRNA showed significant correlations with various clinical phenotypes of SCZ, offering potential biomarkers and therapeutic targets.

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基于诱导多能干细胞的精神分裂症综合转录组分析及lncRNA-miRNA-mRNA构建

精神分裂症（SCZ）是一种复杂的异质性疾病，其潜在机制尚不清楚。识别关键基因疾病，构建生物调控网络，有助于扩大对SCZ发病机制的认识。方法对5例SCZ患者和5例健康对照的诱导多能干细胞（iPSCs）进行全转录组测序，分析mRNA和非编码RNA表达谱的差异。探索差异表达mrna （DE mrna）的功能和途径，构建lncRNA-miRNA-mRNA调控网络，了解转录后调控机制。此外，我们还分析了竞争性内源性rna （ceRNAs）、枢纽基因与SCZ患者临床表型（阳性/阴性和认知症状）之间的相关性。结果共鉴定出139个DE mrna、154个lncrna和19个mirna。观察到细胞凋亡、炎症反应、缺氧、KRAS信号和IL6_JAK_STAT3信号通路的显著富集。共鉴定出CCK、CCNA1、CDH5、GATA2、GRPR、NPY、PRKG2、TLE6、ZEB1和ZEB2 10个枢纽基因，其中ZEB1和GATA2与SCZ阳性症状呈正相关，CDH5和GRPR与记忆相关。ceRNA调控网络（TPM1-AS/ADPGK-AS1/MIRLET7BHG-hsa-mir-3180/3180-3p- lrrc15 /TUBA8和MIRLET7BHG- hsa-mir-3187-3p- CCDC92/ TDRD6/ TMEM26/ ATP1A2）的建立也与SCZ的阳性、阴性和认知症状显著相关。结论本研究发现了iPSCs中潜在的中枢基因、通路和lncRNA-miRNA-mRNA调控网络，为研究SCZ的分子机制提供了新的思路。所鉴定的枢纽基因和ceRNA与SCZ的各种临床表型具有显著相关性，为SCZ提供了潜在的生物标志物和治疗靶点。

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来源期刊

Schizophrenia Research 医学-精神病学

CiteScore

7.50

自引率

8.90%

发文量

429

审稿时长

10.2 weeks

期刊介绍： As official journal of the Schizophrenia International Research Society (SIRS) Schizophrenia Research is THE journal of choice for international researchers and clinicians to share their work with the global schizophrenia research community. More than 6000 institutes have online or print (or both) access to this journal - the largest specialist journal in the field, with the largest readership! Schizophrenia Research''s time to first decision is as fast as 6 weeks and its publishing speed is as fast as 4 weeks until online publication (corrected proof/Article in Press) after acceptance and 14 weeks from acceptance until publication in a printed issue. The journal publishes novel papers that really contribute to understanding the biology and treatment of schizophrenic disorders; Schizophrenia Research brings together biological, clinical and psychological research in order to stimulate the synthesis of findings from all disciplines involved in improving patient outcomes in schizophrenia.