Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.,Molecular Psychiatry

当前位置： X-MOL 学术 › Mol. Psychiatry › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41380-020-0669-9
K Griesi-Oliveira _{1,

2} , M S Fogo _{1,

2} , B G G Pinto ₁ , A Y Alves ₁ , A M Suzuki ₂ , A G Morales ₂ , S Ezquina ₂ , O J Sosa ₃ , G J Sutton ₄ , D Y Sunaga-Franze ₅ , A P Bueno ₁ , G Seabra ₆ , L Sardinha ₁ , S S Costa ₂ , C Rosenberg ₂ , E C Zachi ₇ , A L Sertie ₁ , D Martins-de-Souza _{6,

8,

9} , E M Reis ₁₀ , I Voineagu ₄ , M R Passos-Bueno ₂

Affiliation

Hospital Israelita Albert Einstein, São Paulo, Brazil.
Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, Brazil.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil.
Núcleo de Neurociências e Comportamento, Departamento de Psicologia Experimental, Instituto de Psicologia, Universidade de São Paulo, São Paulo, Brazil.
Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), São Paulo, Brazil.
Experimental Medicine Research Cluster (EMC), University of Campinas, Campinas, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

中文翻译：

iPSC 衍生的神经元细胞的转录组揭示了与自闭症谱系障碍一致相关的共表达基因模块。

评估自闭症谱系障碍 (ASD) 患者的表达谱是了解可能的相似功能后果的重要方法，这些后果可能是疾病病理生理学的基础，无论其遗传异质性如何。诱导多能干细胞 (iPSC) 衍生的神经元模型有助于探索这个问题，但仍需要研究更大的群体和不同的 ASD 内表型。此外，体外模型中观察到的变化是否反映了自闭症谱系障碍死后大脑的先前发现，以及它们在研究中的一致性仍然是尚未探索的问题。我们检查了来自正常头型 ASD 队列的 iPSC 衍生神经元细胞的转录组，该队列主要由高功能个体和非 ASD 个体组成。ASD 患者表现出参与神经元祖细胞 (NPC) 蛋白质合成的共表达基因模块、与突触/神经传递相关的基因模块和与神经元翻译相关的模块的表达失调。NPC 的蛋白质组学分析揭示了 NPC 和神经元中失调模块之间的潜在分子联系。值得注意的是，我们的结果与一系列转录组研究的比较表明，与突触相关的模块在 iPSC 衍生的神经元（其表达谱与胎儿大脑更密切相关）中一致被发现上调，而在死后脑组织中下调，表明该网络与疾病存在可靠的关联，并表明其失调可能在自闭症谱系障碍个体的发育过程中以不同方向发生。因此，该网络的表达模式可用作 ASD 的生物标志物，并应作为治疗靶标进行实验探索。

更新日期：2020-02-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11