原文作者：Yuan Tian, Irina Voineagu, Sergiu P Pa?ca, Hyejung Won, Vijayendran Chandran, Steve Horvath, Ricardo E Dolmetsch and Daniel H Geschwind
编码钙信号通路亚基的基因中常见的遗传变异和罕见突变对患多种神经精神疾病的风险具有多重影响，其中包括自闭症谱系障碍（autism spectrum disorder, ASD）和精神分裂症。为了进一步扩展已有基因的表达数据从而探寻其中的机理，来自美国加州大学洛杉矶分校的Daniel H Geschwind及其研究团队在Genome Medicine上发表了一篇名为Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome的文章，构建了一个Timothy综合征（TS）的共表达网络。
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.
Methods
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.
Results
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.
Conclusions
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.
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