Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single-nucleus multiomics

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-10-23 DOI:10.1002/ctm2.70072

Yingying Liu, Yinchao Li, Yaqian Zhang, Yubao Fang, Lei Lei, Jiabin Yu, Hongping Tan, Lisen Sui, Qiang Guo, Liemin Zhou

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引用次数: 0

Abstract

Background

Focal cortical dysplasia (FCD) is a heterogeneous group of cortical developmental malformations that constitute a common cause of medically intractable epilepsy. FCD type IIIa (FCD IIIa) refers to temporal neocortex alterations in architectural organisation or cytoarchitectural composition in the immediate vicinity of hippocampal sclerosis. Slight alterations in the temporal neocortex of FCD IIIa patients pose a challenge for the preoperative diagnosis and definition of the resection range.

Methods

We have performed multimodal integration of single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing in the epileptogenic cortex of four patients with FCD IIIa, and three relatively normal temporal neocortex were chosen as controls.

Results

Our study revealed that the most significant dysregulation occurred in excitatory neurons (ENs) and oligodendrocyte precursor cells (OPCs) in the epileptogenic cortex of FCD IIIa patients. In ENs, we constructed a transcription factor (TF)-hub gene regulatory network and found DAB1^high ENs subpopulation mediates neuronal immunity characteristically in FCD IIIa. Western blotting and immunofluorescence were used to validate the changes in protein expression levels caused by some of the key genes. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa, and TFs regulating reconstructed pseudotime trajectory were identified. Finally, our results revealed aberrant intercellular communication between ENs and OPCs in FCD IIIa patients.

Conclusions

Our study revealed significant and intricate alterations in the transcriptomes and epigenomes in ENs and OPCs of FCD IIIa patients, shedding light on their cell type-specific regulation and potential pathogenic involvement in this disorder. This work will help evaluate the pathogenesis of cortical dysplasia and epilepsy and explore potential therapeutic targets.

Key points

Paired snRNA-seq and snATAC-seq data were intergrated and analysed to identify crucial subpopulations of ENs and OPCs in the epileptogenic cortex of FCD IIIa patients and explore their possible pathogenic role in the disease.
A TF-hub gene regulatory network was constructed in ENs, and the DAB1high Ex-1 mediated neuronal immunity was characterstically in FCD IIIa patients.
The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa patients, and TFs regulating reconstructed pseudotime traectory were identified.
Aberrant intercelluar communications between ENs and OPCs in FCD IIIa patients were identified.

Abstract Image

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单核多组学研究表明，兴奋性神经元和少突胶质细胞前体细胞容易患局灶性皮质发育不良 IIIa 型。

背景：局灶性皮质发育不良（FCD）是一组异质性皮质发育畸形，是医学上难治性癫痫的常见病因。颞叶皮质发育异常 IIIa 型（FCD IIIa）是指紧邻海马硬化的颞叶新皮质的结构组织或细胞结构组成发生改变。FCD IIIa 型患者颞新皮质的轻微改变给术前诊断和确定切除范围带来了挑战：方法：我们在四名 FCD IIIa 患者的致痫皮质中进行了单核 RNA 测序和单核转座酶染色质测序的多模式整合研究，并选择了三个相对正常的颞新皮质作为对照：结果：我们的研究发现，在 FCD IIIa 患者的致痫皮质中，兴奋性神经元（ENs）和少突胶质细胞前体细胞（OPCs）出现了最明显的失调。在ENs中，我们构建了一个转录因子（TF）-枢纽基因调控网络，发现DAB1高的ENs亚群介导了FCD IIIa患者的神经元免疫特征。利用 Western 印迹和免疫荧光验证了一些关键基因引起的蛋白表达水平变化。在 FCD IIIa 中，OPCs 被激活并表现出异常表型，而调节重建假时轨迹的 TFs 也被鉴定出来。最后，我们的研究结果表明，在FCD IIIa患者中，ENs和OPCs之间的细胞间通讯异常：我们的研究揭示了FCD IIIa患者ENs和OPCs的转录组和表观基因组发生了重大而复杂的改变，从而揭示了它们的细胞类型特异性调控以及在这种疾病中的潜在致病作用。这项工作将有助于评估大脑皮层发育不良和癫痫的发病机制，并探索潜在的治疗靶点：通过整合和分析成对的snRNA-seq和snATAC-seq数据，确定了FCD IIIa患者致痫皮质中ENs和OPCs的关键亚群，并探讨了它们在该疾病中可能的致病作用。在ENs中构建了一个TF-hub基因调控网络，DAB1高的Ex-1介导的神经元免疫是FCD IIIa患者的特征。FCD IIIa 患者的 OPCs 被激活并表现出异常的表型，并确定了调节重建假时序的 TFs。在FCD IIIa患者中发现了ENs和OPCs之间异常的细胞间通信。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.