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.
"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
. The protein kinase WNK3 binds to A2BP1 and suppresses its splicing activity through a kinase activity-dependent cytoplasmic re-localization of A2BP1
[Show abstract][Hide abstract] 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.
"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. "
[Show abstract][Hide abstract] 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.
"The numbers of predicted RBFOX1 RNA binding motifs at the 3' untranslated regions (UTRs) of mRNAs positively correlated with the abundance of mRNAs . Using the data of RNA-seq following RBFOX1 knockdown in primary human neural progenitor cells , Ray et al. found that the number of predicted FBFOX1 binding sites in mRNAs also positively correlated with the extent to which RBFOX1 knockdown reduced the expression of the mRNAs , reminiscent of the finding concerning Hsp90 and clients . As reduced RBFOX1 levels in the brains of autism patients had been noted , it was further shown that predicted RBFOX1 targets had progressively lower mRNA expression in these patients . "
[Show abstract][Hide abstract] ABSTRACT: A biological molecule, e.g., an enzyme, tends to interact with its many cognate substrates, targets, or partners differentially. Such a property is termed relative specificity and has been proposed to regulate important physiological functions, even though it has not been examined explicitly in most complex biochemical systems. This essay reviews several recent large-scale studies that investigate protein folding, signal transduction, RNA binding, translation and transcription in the context of relative specificity. These results and others support a pervasive role of relative specificity in diverse biological processes. It is becoming clear that relative specificity contributes fundamentally to the diversity and complexity of biological systems, which has significant implications in disease processes as well.
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