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Developmental regulation of RNA processing by Rbfox proteins

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The Rbfox genes encode an ancient family of sequence‐specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high‐affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre‐mRNA introns, mRNA 3’UTRs, and pre‐miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre‐mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing. Complex Rbfox expression is encoded in large genes encompassing multiple promoters and alternative splicing options that govern spatiotemporal expression of structurally distinct and tissue‐specific protein isoforms with different classes of RNA targets. Nuclear Rbfox1 is a candidate master regulator that binds intronic UGCAUG elements to impact splicing efficiency of target alternative exons, many in transcripts for other splicing regulators. Tissue‐specificity of Rbfox‐mediated alternative splicing is executed by combinatorial regulation through the integrated activity of Rbfox proteins and synergistic or antagonistic splicing factors. Studies in animal models show that Rbfox1‐related genes are critical for diverse developmental processes including germ cell differentiation and memory in Drosophila, neuronal migration and function in mouse brain, myoblast fusion and skeletal muscle function, and normal heart function. Finally, genetic and biochemical evidence suggest that aberrations in Rbfox‐regulated circuitry are risk factors for multiple human disorders, especially neurodevelopmental disorders including epilepsy and autism, and cardiac hypertrophy. WIREs RNA 2017, 8:e1398. doi: 10.1002/wrna.1398 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing
Sites of Rbfox function in the transcriptome. (a) Binding of Rbfox proteins upstream inhibits, while binding downstream enhances, inclusion of the adjacent alternative exon. (b) Binding of Rbfox proteins to 3′UTR elements can enhance or inhibit RNA stability and/or translation. (c) Binding to a specific subset of sno‐lncRNAs can reduce the amount of Rbfox2 protein available for other nuclear functions. (d) Binding of Rbfox3 to the hairpin loop of pre‐miRNAs can promote or repress processing. (e) Binding of Rbfox2 to nascent promoter‐proximal transcripts can recruit PRC2 complexes that repress transcription. Black arrow indicates transcription start site; curved green arrow indicates enhancer activity; curved red arrow represents silencer activity. (Adapted from Ref. 25).
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Rbfox1 gene architecture encodes diverse protein isoforms. (a) In the long 5′ region, multiple promoters operating at distinct first exons provide potential for independent regulation by various physiological signals. In the RRM region, exons of 54 and 93 nucleotide are conserved from Drosophila to humans; the 93 nt exon is deleted in some isoforms to generate isoforms with non‐functional RRMs. Mutually exclusive exons B40 (brain‐expressed 40 nt exon) and M43 (muscle‐expressed 43 nt exon) are differentially spliced to generate tissue‐specific protein isoforms. In the 3′ region, inclusion of exon A53 (alternative 53 nt exon), also designated as exon 19, shifts the translational reading frame of the downstream exons and results in loss of the NLS. White box, untranslated sequence; black boxes, translated sequence; gray boxes, alternative N‐terminal sequences predicted by reading frame analysis. Alternative C‐terminal reading frames are generated by inclusion or exclusion of A53 (Rbfox1) or 32 nt exon (Rbfox2). n.d., not determined. (b) Organization of Rbfox family genes. Rbfox2 and Rbfox3 are also encoded by large complex genes with many of the same features as Rbfox1. Excluding genome browser annotations only represented once in the database, Rbfox2 and Rbfox3 have 5 and 3 promoters, respectively, spanning ~200–300 kb of 5′ sequence. In the core coding region between alternative N‐ and C‐terminal domains, paralogous exons of the three genes are aligned (intron lengths not to scale). Highly conserved RRM domains and RF(A/T)PY nuclear localization signals are indicated by shaded regions.
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Rbfox1 regulatory circuitry. The top half of the figure indicates multiple steps of gene expression at which the expression of Rbfox1 proteins is regulated, while the lower half depicts some of the functional outputs manifested by these proteins. ** Alternative splicing regulates coding exons in many target transcripts, but also noncoding exons in others that can induce NMD and reduced transcript levels.
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Rbfox1 deletions associated with neurodevelopmental disorders in humans. Below are Rbfox1 annotations with arrows depicting presumed promoter locations as described in Figure . Green bars, deletions that span promoters; blue bars, deletions that span internal exons likely translated in some contexts as shown in Figure . Red lines indicate deletions apparently in introns only. Other Rbfox1 deletions have also been reported. Numbers at the right margin indicate the relevant citations for deletions as follows: group 1; group 2; group 3; group 4; group 5; group 6; group 7.
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Coordinate determination of lineage‐specific alternative splicing by Rbfox and other RBPs. (a) Model based on co‐regulation by Rbfox1 and Mbnl1 in a muscle cell line. (b) Model based on the common overlap between Rbfox‐ and Nova‐regulated exons in brain. (c) Model of dual specificity by intersection of muscle‐ and brain‐specific regulatory patterns. (d) Model based on co‐regulation by Rbfox1 and Mbnl1 in a muscle cell line and correlation of exon inclusion with number of UGCAUG motifs. (e) Demonstrated antagonistic effects on splicing for an alternative exon in Arhgef12. (f) Coordinated repression by SUP12 and the Rbfox‐related gene ASD‐1 of exon 5B in the egl‐15 gene in C. elegans. (g) Antagonistic effects on splicing of brain microexons H. Brain‐specific enhancer activity by looping across the intron, proposed for Gabrg2 exon 9. Green arrows indicate enhancer activity; red arrows indicate silencer activity.
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