RBFOX1 regulates both splicing and transcriptional networks in human neuronal development

Brent L. Fogel, Eric Wexler, Amanda Wahnich, Tara Friedrich, Chandran Vijayendran, Fuying Gao, Neelroop Parikshak, Genevieve Konopka, Daniel H. Geschwind

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberdds240
Pages (from-to)4171-4186
Number of pages16
JournalHuman Molecular Genetics
Volume21
Issue number19
DOIs
StatePublished - Oct 2012

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Gene Regulatory Networks
Human Development
Alternative Splicing
RNA Splicing
RNA Sequence Analysis
Gene Expression
Neurons
RNA-Binding Proteins
Neural Stem Cells
Genes
Cell Differentiation
Transcription Factors
Genome
Proteins
RNA Splicing Factors
Autism Spectrum Disorder

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Fogel, B. L., Wexler, E., Wahnich, A., Friedrich, T., Vijayendran, C., Gao, F., ... Geschwind, D. H. (2012). RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Human Molecular Genetics, 21(19), 4171-4186. [dds240]. https://doi.org/10.1093/hmg/dds240

RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. / Fogel, Brent L.; Wexler, Eric; Wahnich, Amanda; Friedrich, Tara; Vijayendran, Chandran; Gao, Fuying; Parikshak, Neelroop; Konopka, Genevieve; Geschwind, Daniel H.

In: Human Molecular Genetics, Vol. 21, No. 19, dds240, 10.2012, p. 4171-4186.

Research output: Contribution to journalArticle

Fogel, BL, Wexler, E, Wahnich, A, Friedrich, T, Vijayendran, C, Gao, F, Parikshak, N, Konopka, G & Geschwind, DH 2012, 'RBFOX1 regulates both splicing and transcriptional networks in human neuronal development', Human Molecular Genetics, vol. 21, no. 19, dds240, pp. 4171-4186. https://doi.org/10.1093/hmg/dds240
Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C, Gao F et al. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Human Molecular Genetics. 2012 Oct;21(19):4171-4186. dds240. https://doi.org/10.1093/hmg/dds240
Fogel, Brent L. ; Wexler, Eric ; Wahnich, Amanda ; Friedrich, Tara ; Vijayendran, Chandran ; Gao, Fuying ; Parikshak, Neelroop ; Konopka, Genevieve ; Geschwind, Daniel H. / RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 19. pp. 4171-4186.
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