TY - JOUR
T1 - RBFOX1 regulates both splicing and transcriptional networks in human neuronal development
AU - Fogel, Brent L.
AU - Wexler, Eric
AU - Wahnich, Amanda
AU - Friedrich, Tara
AU - Vijayendran, Chandran
AU - Gao, Fuying
AU - Parikshak, Neelroop
AU - Konopka, Genevieve
AU - Geschwind, Daniel H.
N1 - Funding Information:
This work was supported by the National Institute of Mental Health (grants K08MH86297 to B.L.F., R37MH060233 to D.H.G., R01MH081754 to D.H.G., K08MH074362 to E.W., R00MH090238 to G.K. and T32MH073526 to N.P.); the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant p30HD004612 to F.G. and D.H.G.); the UCLA Caltech Medical Scientist Training Program (to N.P.); the Dr Miriam and Sheldon G. Adelson Medical Research Foundation (to C.V.); and the John Douglas French Alzheimer’s Research Foundation (to E.W.).
PY - 2012/10
Y1 - 2012/10
N2 - RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.
AB - RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.
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U2 - 10.1093/hmg/dds240
DO - 10.1093/hmg/dds240
M3 - Article
C2 - 22730494
AN - SCOPUS:84866390941
VL - 21
SP - 4171
EP - 4186
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
M1 - dds240
ER -