Article

Fogel BL, Wexler E, Wahnich A, et al. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet. 21: 4171-86

Present address: Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2012; 21(19):4171-86. DOI: 10.1093/hmg/dds240
Source: PubMed

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.

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    • "(Cahoy et al., 2008; Vidal et al., 2009). We found that JAKMIP1 was differentially expressed in patients with two syndromic forms of ASD, fragile X and (dup)15q11-13 syndrome, and upon RBFOX1 knockdown (Fogel et al., 2012; Nishimura et al., 2007). To date, 11 ASD subjects have been identified with copy-number variants that contain JAKMIP1 (Szatmari et al., 2007; Kaminsky et al., 2011; Poultney et al., 2013; Tzetis et al., 2012). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.
    Full-text · Article · Nov 2015 · Neuron
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    • "A2BP1 is a neuron-specific splicing factor that promotes either exon inclusion or skipping. It has been implicated in several neurodevelopmental and neuropsychiatric disorders such as autism spectrum disorder, mental retardation, epilepsy, bipolar disorder, and schizophrenia [69]. The protein kinase WNK3 binds to A2BP1 and suppresses its splicing activity through a kinase activity-dependent cytoplasmic re-localization of A2BP1 [70]. "
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    ABSTRACT: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations. We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain. We establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.
    Full-text · Article · Apr 2014 · Genome biology
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    • "The focus of this study is to define and characterize the Rbfox target splicing-regulatory network in the mammalian brain. An important piece of information missing in previous efforts toward this aim (e.g., Fogel et al., 2012; Gehman et al., 2011, 2012; Ray et al., 2013; Zhang et al., 2008) is a genome-wide, high-resolution map of in vivo Rbfox interaction sites in the brain. Such a map is especially essential due to the functional redundancy of different Rbfox family members, so that simultaneous depletion of more than one member is probably required to uncover a majority of Rbfox-dependent exons in a physiologically relevant condition. "
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    ABSTRACT: The RNA binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system, and disruption of Rbfox1 has been implicated in autism. However, comprehensive identification of functional Rbfox targets has been challenging. Here, we perform HITS-CLIP for all three Rbfox family members in order to globally map, at a single-nucleotide resolution, their in vivo RNA interaction sites in the mouse brain. We find that the two guanines in the Rbfox binding motif UGCAUG are critical for protein-RNA interactions and crosslinking. Using integrative modeling, these interaction sites, combined with additional datasets, define 1,059 direct Rbfox target alternative splicing events. Over half of the quantifiable targets show dynamic changes during brain development. Of particular interest are 111 events from 48 candidate autism-susceptibility genes, including syndromic autism genes Shank3, Cacna1c, and Tsc2. Alteration of Rbfox targets in some autistic brains is correlated with downregulation of all three Rbfox proteins, supporting the potential clinical relevance of the splicing-regulatory network.
    Full-text · Article · Mar 2014 · Cell Reports
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