title: Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.
abstract: BACKGROUND
  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 Ca(2+) 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 Ca(2+) signaling dysregulation on transcription.
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 USA ; Interdepartmental Ph.D. Program in Bioinformatics, University of California, Los Angeles, CA 90095 USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Voineagu
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Sergiu P
authors.initials: SP
authors.lastname: Paşca
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 USA.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Won
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 USA.
authors.forename: Vijayendran
authors.initials: V
authors.lastname: Chandran
authors.affiliation: Department of Human Genetics, David Geffen Sch. of Medicine, UCLA, Los Angeles, CA USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345 USA ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139 USA.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 USA ; Interdepartmental Ph.D. Program in Bioinformatics, University of California, Los Angeles, CA 90095 USA ; Department of Human Genetics, David Geffen Sch. of Medicine, UCLA, Los Angeles, CA USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind