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Series GSE57821 Query DataSets for GSE57821
Status Public on Aug 01, 2014
Title Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders.
 
Overall design Two patient derived iPSC lines carrying heterozygous 4bp deletion in DISC1 gene and 1 related control were analyzed in biological triplicate
 
Contributor(s) Wen Z, Nguyen H, Guo Z, Lalli M, Wang X, Su  Y, Kim N, Yoon K, Shin J, Zhang C, Makri G, Nauen D, Guzman E, Yu H, Chiang C, Yoritomo N, Kaibuchi K, Ross C, Zou J, Christian K, Cheng L, Magolis R, Chen G, Kosik K, Ming G, Song H
Citation(s) 25132547
Submission date May 20, 2014
Last update date Mar 01, 2019
Contact name Kenneth Kosik
Organization name University of California Santa Barbara
Department Neuroscience Research Institute
Lab Kosik Lab
Street address 552 University Rd
City Santa Barbara
State/province CA
ZIP/Postal code 93106
Country USA
 
Platforms (1)
GPL17303 Ion Torrent Proton (Homo sapiens)
Samples (9)
GSM1394606 Control 1 RNA-Seq rep1
GSM1394607 Control 1 RNA-Seq rep2
GSM1394608 Control 1 RNA-Seq rep3
Relations
BioProject PRJNA248182
SRA SRP042112

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE57821_RAW.tar 1.5 Mb (http)(custom) TAR (of TSV)
Raw data are available in SRA
Processed data provided as supplementary file

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