Abstract
BackgroundCommon 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.MethodsTo 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0075-5) contains supplementary material, which is available to authorized users.
Highlights
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
It has been known that calcium influx triggers massive transcriptional changes by acting through several transcription factors, including calcium response factor (CaRF) [15,16], myocyte enhancer factor-2 (MEF2) [17,18], nuclear factor of activated T-cells (NFAT) [19,20], and cAMP response element-binding proteins (CREB) [21,22,23,24], little is known about their downstream targets in human neurons and how these processes are altered in disease states such as Timothy syndrome (TS)
Using Weighted Gene Co-expression Network Analysis (WGCNA) [27,28], we identified gene co-expression modules associated with neural development, as well as depolarization shared across both patient and control lines
Summary
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. The L-type calcium channel, Cav1.2, plays a central role in regulating an activity-dependent signaling network that is essential for neuronal function [1,2,3,4,5,6]. Given the pleiotropic manifestation of CACNA1C mutations in TS and the recent implication of common variation in CACNA1C across multiple neuropsychiatric disorders [14], we reasoned that characterization of the Cav1.2-dependent signaling network in TS would help elucidate its molecular basis and prioritize genes for therapeutic development. We reasoned that identifying alterations in mRNA transcript levels in TS patient-derived cortical progenitors and developing neurons would help clarify, how calcium regulates gene expression in TS, but more broadly inform our understanding of the molecular mechanism of ASD
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