TY - JOUR
T1 - Reduced CYFIP1 in human neural progenitors results in dysregulation of schizophrenia and epilepsy gene networks
AU - Nebel, Rebecca A.
AU - Zhao, Dejian
AU - Pedrosa, Erika
AU - Kirschen, Jill
AU - Lachman, Herbert M.
AU - Zheng, Deyou
AU - Abrahams, Brett S.
N1 - Funding Information:
This work was supported through an Albert Einstein New Investigator Development Award, an IDDRC pilot award (P30HD071593; NICHD), and a subcontract from an Autism Center of Excellence Network Award (9R01 MH100027; NIMH) to BSA. Support for RAN was provided through the Training Program in Cellular and Molecular Biology and Genetics (T32 GM007491; NIGMS). Clinical recruitment efforts were supported by CTSA Grants (UL1RR025750, KL2RR025749, and TL1RR025748; NCRR and 8UL1 TR000086; NCATS). Support to HML was provided by the NIMH (MH097893 and MH087840). Support to D. Zheng was provided by the NIMH (MH099452). Thanks to all individuals who provided the biomaterials that enabled us to carry out the experiments described here and to the Simon''s Foundation for Autism Research for granting access to a subset of lymphoblastoid cell lines used. We also thank the Molecular Cytogenetic Core at Einstein for generating lymphoblastoid cell lines, the Analytical Imaging Facility at Einstein for advice and training on image analysis software, and the shRNA Core Facility at Einstein for generating lentiviruses.
Publisher Copyright:
© 2016 Nebel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0148039
DO - 10.1371/journal.pone.0148039
M3 - Article
C2 - 26824476
AN - SCOPUS:84958212527
SN - 1932-6203
VL - 11
JO - PLoS One
JF - PLoS One
IS - 1
M1 - 0148039
ER -
