Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks

PloS One
Rebecca A NebelB S Abrahams

Abstract

Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.

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Citations

Apr 30, 2017·The European Journal of Neuroscience·Yuri BozziSimona Casarosa
Feb 28, 2018·Molecular Psychiatry·Gabriel E HoffmanKristen J Brennand
Jul 12, 2018·Journal of Molecular Neuroscience : MN·Arezou SayadMohammad Taheri
Mar 27, 2019·International Journal of Molecular Sciences·Kyle W DavisMerlin G Butler
Apr 3, 2019·Frontiers in Psychology·Amy Niego, Antonio Benítez-Burraco
Jul 7, 2019·Schizophrenia Research·Prashanth RajarajanKristen J Brennand
Mar 24, 2020·Cell·Alexandros K KanellopoulosClaudia Bagni

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Datasets Mentioned

BETA
GSE70935

Methods Mentioned

BETA
RNA-seq
biopsies
PCR
Protein Assay

Software Mentioned

TopHat
Copy Caller
Ensembl
DESeq2
Volocity
FastQC
ToppGene
HTSeq

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