基于机器学习和实验验证，揭示与HIF1A通路相关的自闭症谱系障碍的发病机制和潜在生物标志物。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease Pub Date : 2025-01-01 DOI:10.1016/j.nbd.2024.106763

Jinru Cui , Heli Li , Cong Hu , Feiyan Zhang , Yunjie Li , Ying Weng , Liping Yang , Yingying Li , Minglan Yao , Hao Li , Xiaoping Luo , Yan Hao

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引用次数: 0

摘要

背景：自闭症谱系障碍（ASD）是一种社会负担高且治疗有限的神经发育障碍。脑缺氧被认为是ASD的重要病理机制。HIF1A是脑缺氧的关键参与者，但其对ASD病理生理景观的贡献尚不清楚。方法：从GEO数据库获取asd相关数据集，从GeneCards获取hif1a相关基因。共表达模块分析鉴定模块基因，与hif1a相关基因交叉鉴定共同基因。机器学习从交叉基因中识别出枢纽基因，并构建PPI网络来探索枢纽与HIF1A之间的关系。单细胞RNA测序分析了枢纽基因在细胞簇中的分布。通过poly（I:C）注射诱导母体免疫激活（MIA），建立ASD小鼠模型，并通过行为实验验证。通过Western Blot、qPCR和免疫荧光在ASD小鼠和小胶质细胞BV-2细胞中证实了HIF1A通路和hub基因的有效性。结果：使用CEMiTool和GeneCards，鉴定出45个与ASD和HIF1A通路相关的基因。机器学习识别出CDKN1A、ETS2、LYN和SLC16A3作为潜在的ASD诊断标记。单细胞测序确定激活的小胶质细胞是关键的免疫细胞。行为测试显示MIA后代小鼠表现出典型的asd样行为。免疫荧光证实ASD小鼠额叶皮层小胶质细胞和HIF1A通路的激活。此外，IL-6通过激活JUN/HIF1A通路，影响小胶质细胞中CDKN1A、LYN和SLC16A3的表达，促进ASD的发生。结论：HIF1A相关基因CDKN1A、ETS2、LYN、SLC16A3是ASD的强诊断标志物，小胶质细胞中IL-6/JUN/HIF1A通路的激活参与了ASD的发病机制。

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Unraveling pathogenesis and potential biomarkers for autism spectrum disorder associated with HIF1A pathway based on machine learning and experiment validation

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high social burden and limited treatments. Hypoxic condition of the brain is considered an important pathological mechanism of ASD. HIF1A is a key participant in brain hypoxia, but its contribution to the pathophysiological landscape of ASD remains unclear.

Methods

ASD-related datasets were obtained from GEO database, and HIF1A-related genes from GeneCards. Co-expression module analysis identified module genes, which were intersected with HIF1A-related genes to identify common genes. Machine learning identified hub genes from intersection genes and PPI networks were constructed to explore relationships among hub and HIF1A. Single-cell RNA sequencing analyzed hub gene distribution across cell clusters. ASD mouse model was created by inducing maternal immune activation (MIA) with poly(I:C) injections, verified through behavioral tests. Validation of HIF1A pathway and hub genes was confirmed through Western Blot, qPCR, and immunofluorescence in ASD mice and microglia BV-2 cells.

Results

Using CEMiTool and GeneCards, 45 genes associated with ASD and HIF1A pathway were identified. Machine learning identified CDKN1A, ETS2, LYN, and SLC16A3 as potential ASD diagnostic markers. Single-cell sequencing pinpointed activated microglia as key immune cells. Behavioral tests showed MIA offspring mice exhibited typical ASD-like behaviors. Immunofluorescence confirmed the activation of microglia and HIF1A pathway in frontal cortex of ASD mice. Additionally, IL-6 contributed to ASD by activating JUN/HIF1A pathway, affecting CDKN1A, LYN, and SLC16A3 expression in microglia.

Conclusions

HIF1A-related genes CDKN1A, ETS2, LYN, and SLC16A3 are strong diagnostic markers for ASD and the activation of IL-6/JUN/HIF1A pathway in microglia contributes to the pathogenesis of ASD.

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来源期刊

Neurobiology of Disease 医学-神经科学

CiteScore

11.20

自引率

3.30%

发文量

270

审稿时长

76 days

期刊介绍： Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.