Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1  gene

Fukumura, Kazuhiro; Kato, Ayako; Jin, Yui; Ideue, Takashi; Hirose, Tetsuro; Kataoka, Naoyuki; Fujiwara, Toshinobu; Sakamoto, Hiroshi; Inoue, Kimiko

doi:10.1093/nar/gkm569

Cited by 41 publications

(47 citation statements)

References 40 publications

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“…In contrast, the mechanisms through which Fox-1/2 block exon recognition might be more heterogeneous. For example, in the context of hF1␥ gene exon 9, Fox-1 binding to a GCAUG element in intron 8 blocks prespliceosomal E-complex formation in intron 9, resulting in skipping of exon 9 (Fukumura et al 2007). We found cases (e.g., exons from Muscleblind-like genes) in which the Fox-1/2-binding sites in the UIF region are very close to the downstream 3Ј splice site.…”

Section: Mechanisms Of Fox-1/2-dependent Exon Activation and Repressionmentioning

confidence: 99%

Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2

Zhang¹,

Zuo²,

Castle³

et al. 2008

Genes Dev.

280

289

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The precise regulation of many alternative splicing (AS) events by specific splicing factors is essential to determine tissue types and developmental stages. However, the molecular basis of tissue-specific AS regulation and the properties of splicing regulatory networks (SRNs) are poorly understood. Here we comprehensively predict the targets of the brain-and muscle-specific splicing factor Fox-1 (A2BP1) and its paralog Fox-2 (RBM9) and systematically define the corresponding SRNs genome-wide. Fox-1/2 are conserved from worm to human, and specifically recognize the RNA element UGCAUG. We integrate Fox-1/2-binding specificity with phylogenetic conservation, splicing microarray data, and additional computational and experimental characterization. We predict thousands of Fox-1/2 targets with conserved binding sites, at a false discovery rate (FDR) of ∼24%, including many validated experimentally, suggesting a surprisingly extensive SRN. The preferred position of the binding sites differs according to AS pattern, and determines either activation or repression of exon recognition by Fox-1/2. Many predicted targets are important for neuromuscular functions, and have been implicated in several genetic diseases. We also identified instances of binding site creation or loss in different vertebrate lineages and human populations, which likely reflect fine-tuning of gene expression regulation during evolution.[Keywords: Tissue-specific alternative splicing; splicing regulatory network; Fox-1/A2BP1; Fox-2/RBM9; UGCAUG; comparative genomics] Supplemental material is available at http://www.genesdev.org.Received June 6, 1007; revised version accepted July 28, 2008.The sequencing of complete genomes revealed that complex metazoans, including mammals, have only slightly more genes than unicellular yeast (International Human Genome Sequencing Consortium 2001). Organismal complexity must have resulted largely from mechanisms for diversifying the expression products, and the temporal and spatial patterns, from a limited set of genes. It is crucial to understand how gene expression is orchestrated to determine developmental stages, specify cell types, and respond to external stimuli (Maniatis and Reed 2002). Alternative splicing (AS), the process for removing introns from pre-mRNA transcripts and joining exons in different combinations, is an essential step of post-transcriptional regulation (Cartegni et al. 2002;Black 2003). In mammals, more than two-thirds of genes are alternatively spliced (Johnson et al. 2003). The choice of exons and splice sites is largely determined by many RNA-binding proteins, or splicing factors, which interact with cis-regulatory elements to activate or repress particular splicing events.Many splicing factors have restricted and dynamic expression patterns, and play important roles in tissue-specific or developmentally regulated splicing of particular transcripts. However, the mechanisms and impact of these AS events remain poorly understood. A well-studied example is Sxl, Tra, Tra-2, and several other s...

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Section: Mechanisms Of Fox-1/2-dependent Exon Activation and Repressionmentioning

confidence: 99%

Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2

Zhang¹,

Zuo²,

Castle³

et al. 2008

Genes Dev.

280

289

View full text Add to dashboard Cite

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“…7 Previously, we showed that Fox-1 represses the formation of E complex and U2AF binding to intron 9. 6 Therefore, it is possible that Fox-1 inhibits the binding of unknown trans-acting factors required for U1-independent 5' splice site recognition, leading to repression of the formation of ΔU1 E complex.…”

Section: Role Of U1-independent Pre-mrna Splicing In the Regulation Omentioning

confidence: 99%

Role and mechanism of U1-independent pre-mRNA splicing in the regulation of alternative splicing

Fukumura

Inoue

2009

RNA Biology

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In metazoan organisms, alternative splicing is a central mechanism for the regulation of gene expression. However, many questions remain about the underlying molecular mechanisms. Our recent work suggests that U1 snRNP-independent premRNA splicing occurs in humans, which contributes to the regulation of alternative splicing. So far it has been reported that several pre-mRNAs were spliced efficiently in a U1 snRNP-independent manner in vitro. Although the molecular mechanism and functional significance of U1-independent pre-mRNA splicing are not well understood, a model of how the 5' splice site is recognized U1-independently has been proposed. In this review, we first overview a model in which the 5' splice site is recognized by SR proteins and U6 snRNA. We then discuss our novel model and the functional significance of U1-independent pre-mRNA splicing in the regulation of alternative splicing, based on our recent work.

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“…RBFOX2 interacts with hnRNP H1 and cooperates with it and with hnRNP F to repress exon IIIc of an FGFR2 minigene by antagonizing the binding of SRSF1 (formerly SF2/ASF) (Mauger et al 2008). The C-terminal domain of RBFOX1 is critical for exon repression in an F1g minigene (Fukumura et al 2007). However, the potential involvement of this domain in alternative exon activation, or in repression of alternative exons flanked by U1-dependent introns, has not been determined.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Sun¹,

Zuo²,

Fregoso³

et al. 2011

RNA

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RBFOX1 and RBFOX2 are alternative splicing factors that are predominantly expressed in the brain and skeletal muscle. They specifically bind the RNA element UGCAUG, and regulate alternative splicing positively or negatively in a position-dependent manner. The molecular basis for the position dependence of these and other splicing factors on alternative splicing of their targets is not known. We explored the mechanisms of RBFOX splicing activation and repression using an MS2-tethering assay. We found that the Ala/Tyr/Gly-rich C-terminal domain is sufficient for exon activation when tethered to the downstream intron, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered to the upstream intron. Using immunoprecipitation and mass spectrometry, we identified hnRNP H1, RALY, and TFG as proteins that specifically interact with the C-terminal domain of RBFOX1 and RBFOX2. RNA interference experiments showed that hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2, whereas RALY had no effect. However, TFG is localized in the cytoplasm, and likely modulates alternative splicing indirectly.

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Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1 gene

Cited by 41 publications

References 40 publications

Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2

Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2

Role and mechanism of U1-independent pre-mRNA splicing in the regulation of alternative splicing

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

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