Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.
Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.
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DOI：
10.1186/s13073-014-0075-5
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发表时间：
2014
期刊：
影响因子：
12.3
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Tian Y;Voineagu I;Paşca SP;Won H;Chandran V;Horvath S;Dolmetsch RE;Geschwind DH
编码钙通道亚基的基因中的常见遗传变异和罕见突变对多种神经精神疾病的风险具有多效性效应，包括自闭症谱系障碍（ASD）和精神分裂症。为了通过扩展先前的基因表达数据获得进一步的机制见解，我们构建了蒂莫西综合征（TS）的共表达网络，这是一种由L型钙通道Cav1.2突变引起的ASD高表达率的单基因疾病。为了确定转录组组织中的患者特异性改变，我们对来自正常和TS（CACNA 1C中的G406 R）个体的多系诱导多能干细胞（iPSC）的神经祖细胞和神经元进行了全基因组加权共表达网络分析（WGCNA）。我们采用转录因子结合位点富集分析来评估TS相关的共表达变化是否反映了钙依赖的共调节。我们确定了在患者和对照细胞系中保守的可重复的发育和活性依赖性基因共表达模块。通过比较病例组和对照组的细胞系，我们还确定了反映TS不同方面的共表达模块，包括智力残疾和ASD相关表型。此外，通过整合共表达与转录因子结合分析，我们表明TS相关的转录变化被预测为钙依赖性转录调节因子，包括NFAT，MEF 2，CREB和FOXO，从而提供了一种机制，通过该机制改变TS患者中的Ca 2+信号导致观察到的分子失调。我们首次应用WGCNA构建了与TS和对照个体的iPSC衍生神经细胞的神经发育和去极化相关的共表达网络。这些分析说明了基于基因网络的系统生物学方法如何深入了解神经发育和功能的分子机制，并为Ca 2+信号调节异常对转录的下游效应的功能影响提供线索。本文的在线版本（doi：10.1186/s13073-014-0075-5）包含补充材料，可供授权用户使用。
Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Cav1.2. To identify patient-specific alterations in transcriptome organization, we conducted a genome-wide weighted co-expression network analysis (WGCNA) on neural progenitors and neurons from multiple lines of induced pluripotent stem cells (iPSC) derived from normal and TS (G406R in CACNA1C) individuals. We employed transcription factor binding site enrichment analysis to assess whether TS associated co-expression changes reflect calcium-dependent co-regulation. We identified reproducible developmental and activity-dependent gene co-expression modules conserved in patient and control cell lines. By comparing cell lines from case and control subjects, we also identified co-expression modules reflecting distinct aspects of TS, including intellectual disability and ASD-related phenotypes. Moreover, by integrating co-expression with transcription factor binding analysis, we showed the TS-associated transcriptional changes were predicted to be co-regulated by calcium-dependent transcriptional regulators, including NFAT, MEF2, CREB, and FOXO, thus providing a mechanism by which altered Ca2+ signaling in TS patients leads to the observed molecular dysregulation. We applied WGCNA to construct co-expression networks related to neural development and depolarization in iPSC-derived neural cells from TS and control individuals for the first time. These analyses illustrate how a systems biology approach based on gene networks can yield insights into the molecular mechanisms of neural development and function, and provide clues as to the functional impact of the downstream effects of Ca2+ signaling dysregulation on transcription. The online version of this article (doi:10.1186/s13073-014-0075-5) contains supplementary material, which is available to authorized users.
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影响因子：
3.6
作者：
Adams, Dany S.;Levin, Michael
通讯作者：
Levin, Michael
影响因子：
3.7
作者：
Allen JD;Xie Y;Chen M;Girard L;Xiao G
通讯作者：
Xiao G
影响因子：
14.9
作者：
Basu SN;Kollu R;Banerjee-Basu S
通讯作者：
Banerjee-Basu S
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
6.7
作者：
Bhat, Shambhu;Dao, David T.;Terrillion, Chantelle E.;Arad, Michal;Smith, Robert J.;Soldatov, Nikolai M.;Gould, Todd D.
通讯作者：
Gould, Todd D.