HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism
Open accessAbstract
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.
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- Findingown data
BrdU-CLIP data yielded 6,606 robust CITS (p<0.001).
“Overall, 6,606 robust CITS were identified (p<0.001; Table S3).”
Quote in the paperSubstantial claim - Findingown data
Reproducible deletion sites showed substantial enrichment of the Rbfox motif GCAUG nearby.
“A substantial enrichment of the Rbfox binding motif GCAUG was observed in the immediate vicinity of the reproducible deletion sites (Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
Within the UGCAUG motif, the two guanine nucleotides are essential for Rbfox-RNA interaction and crosslinking.
“We found that the two guanines in the Rbfox-binding motif UGCAUG are critical for protein-RNA interactions and crosslinking.”
- Also stated in: § A single-nucleotide resolution map of Rbfox binding sites by CIMS and CITS analysis · hedged
“Together, our data suggest that the two guanines G2 and G6 in the (U)GCAUG motif are particularly prone to crosslinking with the Rbfox protein.”
Quote in the paperSubstantial claim - Also stated in: § A single-nucleotide resolution map of Rbfox binding sites by CIMS and CITS analysis · hedged
- Findingown data
More than half of the Rbfox targets that could be quantified display developmental changes in splicing in the brain.
“Over half of the quantifiable targets show dynamic changes during brain development.”
- Also stated in: § Rbfox regulates global dynamic splicing changes during brain development · plain
“55% of Rbfox target exons with sufficient read coverage to quantify splicing show splicing changes between the two developmentalstages, as compared to 32% for exons not regulated by Rbfox (odds ratio=2.4, p<7.6×10−16; Fisher’s exact test; Figure 5B).”
Quote in the paperSubstantial claim - Also stated in: § Rbfox regulates global dynamic splicing changes during brain development · plain
- Findingown data
VGCAUG showed its strongest enrichment at position -1 relative to the crosslink site (64-fold), corresponding to crosslinking of G2.
“Interestingly, enrichment of VGCAUG is most predominant at position −1 relative to the crosslink site (64 fold), corresponding to crosslinking of G2 (Figure 2C).”
Quote in the paperNot a substantial claim
- Findingown data
Using 10-fold cross validation, the model predicted 772 cassette exons as direct Rbfox targets (FDR<0.05).
“After using 10-fold cross validation to ensure the model was not overfit (Figure S3F), we predicted 772 cassette exons as direct Rbfox targets (FDR<0.05; Table S6).”
Quote in the paperSubstantial claim - Findingown data
In Rbfox CLIP, crosslinking mainly causes deletions, not insertions or substitutions.
“when we analyzed substitutions and insertions using the same method, we did not observe elevated motif enrichment near the mutation sites (data not shown), suggesting that crosslinking predominantly, if not exclusively, introduces deletions rather than insertions or substitutions in Rbfox CLIP.”
Quote in the paperSubstantial claim - Findingreasoning
In total, 587 genes contain at least one alternative splicing event directly regulated by Rbfox.
“Altogether, 587 genes have one or more alternative splicing events directly regulated by Rbfox.”
Quote in the paperSubstantial claim - Findingown data
Between E17 and adult cortex, 55% of Rbfox target exons with sufficient coverage show splicing changes, versus 32% of exons not regulated by Rbfox (odds ratio=2.4, p<7.6×10−16).
“55% of Rbfox target exons with sufficient read coverage to quantify splicing show splicing changes between the two developmentalstages, as compared to 32% for exons not regulated by Rbfox (odds ratio=2.4, p<7.6×10−16; Fisher’s exact test; Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
In brain tissue, Rbfox proteins bind the predicted site at Gabrg2 exon 9.
“Our CLIP data now confirmed that Rbfox proteins indeed bind to the expected site in vivo inthe brain (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
Among Rbfox targets are 111 events from 48 genes proposed as autism susceptibility candidates, such as Shank3, Cacna1c, and Tsc2.
“Of particular interest are 111 events from 48 candidate autism-susceptibility genes, including syndromic autism genes Shank3, Cacna1c, and Tsc2.”
Quote in the paperSubstantial claim- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
- Findingown data
Relative to the crosslink site, UGCAUG was enriched 28-41 fold at positions -5, -4, and -1, corresponding to crosslinking at G2, U5, and G6.
“UGCAUG isenriched 28-41 fold at positions −5, −4, and −1 relative to the crosslink site, corresponding to crosslinking at G2, U5, and G6 of the UGCAUG element.”
Quote in the paperSubstantial claim - Findingown data
Rbfox is more likely to bind motif sites with stronger scores.
“strongermotif sites are more likely to be bound by the protein (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
In a subset of autistic brains, changes in Rbfox target splicing are correlated with reduced levels of all three Rbfox proteins.
“Alteration of Rbfox targets in some autistic brains is correlated with down-regulation of all three Rbfox proteins”
- Also stated in: § Rbfox target genes are linked to autism · plain
“we found that the expression of the other two family members, Rbfox2 and Rbfox3, was also down-regulated 3.3 fold (p<0.05; t-test) and 3.2 fold (p<0.09; t-test), respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
- Also stated in: § Rbfox target genes are linked to autism · plain
- Findingown data
By integrating interaction sites with other datasets, the authors identified 1,059 alternative splicing events directly targeted by Rbfox.
“Using integrative modeling, these interaction sites combined with additional datasets defined 1,059 direct Rbfox target alternative splicing events.”
Quote in the paperSubstantial claim - Findingown data
De novo motif analysis of sequences around CIMS found (U)GCAUG as the sole strongly enriched motif (36% of 1,158 non-repetitive CIMS in [-10,10], E<3.7×10−320).
“De novo motif analysis using sequences [−10,10] around CIMS uncovered (U)GCAUG as the only motif with strong enrichment (36% of 1,158 non-repetitive CIMS in [−10,10], E<3.7×10−320; Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
RNA-Seq identified 126 cassette exons, 17 tandem cassette events, and 4 mutually exclusive events with Rbfox2-dependent inclusion or exclusion (FDR ≤ 0.1 and |ΔI|≥0.1).
“we were able to identify 126 cassette exons, 17 tandem cassette exon events, and 4 mutually exclusive exon events showing Rbfox2-dependent inclusion or exclusion [FDR ≤ 0.1 and proportional change of exon inclusion |ΔI|≥0.1 (Ule et al., 2005b)]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ule et al., 2005b
Not checked in the free run.
- Findingown data
VGCAUG was crosslinked at the same position as UGCAUG, though with lower enrichment (88-fold).
“The same position was crosslinked in the VGCAUG element, although there is less enrichment of the motif (88 fold; Figure 2F).”
Quote in the paperNot a substantial claim - Findingown data
Regions predicted to be Rbfox-bound contain more CLIP tags than regions predicted not to be bound.
“regions inferred to be bound by Rbfox have more CLIP tags than those inferred not to be bound (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
De novo motif analysis around CITS confirmed UGCAUG enrichment (60% of 1000 randomly sampled non-repetitive sites; E<1.9×10−631).
“Analysis of the base composition [−10,10] around CITS revealed the UGCAUG motif directly (Figure S2C), and this was confirmed by de novo motif analysis (60% of 1000 randomly sampled non-repetitive sites; E<1.9×10−631; Figure S2D).”
Quote in the paperSubstantial claim - Findingown data
Within the (U)GCAUG motif, G2 and G6 are especially prone to crosslinking with Rbfox.
“Together, our data suggest that the two guanines G2 and G6 in the (U)GCAUG motif are particularly prone to crosslinking with the Rbfox protein.”
Quote in the paperSubstantial claim - Findingcitation
Analysis of a published RNA-Seq dataset showed dynamic expression changes for Rbfox family members between E17 and adult mouse cortex.
“We found that Rbfox family members undergodynamic expression change between E17 and adult mouse cortex, as evaluated from a published RNA-Seq dataset (Dillman et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dillman et al., 2013 source
Not checked in the free run.
- Findingown data
Standard CLIP data, which lacked truncated tags, showed no (U)GCAUG enrichment at the CITS positions.
“As a control, we repeated the same analysis in the standard CLIP data, which presumably lacked truncated tags, and did not observe enrichment of the (U)GCAUG motif in these specific positions (Figure S2 H,I).”
Quote in the paperSubstantial claim - Findingown data
Rbfox target transcripts encode proteins enriched in PDZ domains (Benjamini FDR < 7.2×10−8).
“proteins encoded by Rbfox target transcripts are enriched in PDZ domains that are known to be important for anchoring transmembrane proteins to the cytoskeleton and for functioning as scaffolds for signaling complexes (Benjamini FDR < 7.2×10−8) (Ranganathan and Ross, 1997).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ranganathan and Ross, 1997
Not checked in the free run.
- Findingown data
All Rbfox family members are down-regulated in some autistic brains.
“Importantly, we found that all Rbfox family members are down-regulated in some autistic brains, underscoring the potential clinical relevance of the Rbfox target network in autism.”
Quote in the paperSubstantial claim - Findingown data
CIMS and CITS analysis indicated that Rbfox and substrate RNA predominantly crosslink at the two guanines in the (U)GCAUG motif.
“Therefore, the predominant crosslinking of Rbfox and substrate RNA at the two guanines in the (U)GCAUG motif, as suggested by CIMS and CITS analysis, is somewhat unexpected, especially given the presence oftwo uridines in the motif.”
Quote in the paperSubstantial claim - Findingown data
When these non-canonical sites were included, the base composition at CIMS in Rbfox CLIP data showed a slight bias toward uridine.
“Paradoxically, when these sites were included for analysis, the base composition at CIMS identified in Rbfox CLIP data is slightly biased toward uridine.”
Quote in the paperNot a substantial claim - Findingown data
In Scn2a1, Rbfox is predicted to activate a cryptic exon containing an in-frame premature stop codon through extensive binding to the downstream intron.
“In Scn2a1 for instance, Rbfox is predicted to activate a cryptic exon harboring an in-frame premature stop codon via extensive binding to the downstream intron (Figure 6D).”
Quote in the paperSubstantial claim - Findingown data
Using the SFARI autism gene database, the authors found that 48 of 519 candidate autism genes with mouse orthologs were Rbfox targets according to Bayesian network analysis (odds ratio 2.8, p<9.6×10−18, Fisher's exact test).
“Among the 519 candidate autism-susceptibility genes with mouse orthologs, 48 were identified as Rbfox targets by Bayesian network analysis (odds ratio=2.8, p<9.6×10−18, Fisher’s exact test; Table 1 and Table S6).”
- Also stated in: § Discussion · plain
“In addition, we were able to highlight 48 genesin the SFARI autism gene database as direct Rbfox targets.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Basu et al., 2009 source
Not checked in the free run.
- Also stated in: § Discussion · plain
- Findingown data
The study identified more than 40,000 robust Rbfox binding sites by applying two HITS-CLIP protocols in parallel to each of the three Rbfox family members.
“A critical aspect of this work is our ability to identify over 40,000 robust Rbfox binding sites using two HITS-CLIP protocols applied in parallel to each of the three Rbfox family members.”
Quote in the paperSubstantial claim - Findingown data
The authors identified several genes (Fat1, St7, Scn2a1, Scn8a) where alternative splicing may be coupled to nonsense-mediated mRNA decay.
“However, we identified several cases (Fat1, St7, Scn2a1, and Scn8a) in which alternative splicing is potentially coupled with non-sensemediated mRNA decay [NMD; ref. (Maquat, 2004)].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Maquat, 2004 source
Not checked in the free run.
- Findingown data
Differential Rbfox expression is paralleled by developmental splicing changes in more than half of quantifiable Rbfox target exons, often in the direction expected from direct Rbfox regulation.
“Importantly, differential expression of Rbfox is paralleled by developmental splicing changes in over half of the quantifiable Rbfox target exons, frequently in the direction consistent with direct Rbfox regulation.”
Quote in the paperSubstantial claim - Findingnone given
The Scn2a1 alternative exon is conserved across vertebrates.
“Interestingly, while this alternative exon is conserved in vertebrates, compensatory mutations in the stop codon have accumulated.”
Quote in the paperNot a substantial claim - Findingcitation
The autistic brains in the comparison were chosen for low Rbfox1 expression, which was 4.1-fold lower than controls by RNA-Seq (p<0.05).
“The autistic brains compared here were selected to have low expression level of Rbfox1 (Voineagu et al., 2011) (4.1-fold down-regulation compared to control brains as measured by RNA-Seq; p<0.05, t-test; Figure 6B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al., 2011 source
Not checked in the free run.
- Findingown data
A substantial fraction of Rbfox-RNA crosslink sites do not overlap the canonical Rbfox (U)GCAUG motif.
“On the other hand, we also observed that a substantial proportion of Rbfox-RNA crosslink sites do not overlap with the canonical Rbfox (U)GCAUG motif.”
Quote in the paperSubstantial claim - Findingown data
The model predicts that Rbfox activates inclusion of alternative exon 25 in Tsc2, an exon conserved between human and mouse.
“For a specific example, Rbfox is predicted to activate the inclusion of alternative exon 25 in the Tsc2 gene, which isconserved between human and mouse (Figure 6C).”
Quote in the paperNot a substantial claim - Findingown data
From the relative frequency of deletions in Rbfox CLIP tags from standard and BrdU-CLIP protocols (14% vs 6.2%), the authors estimated that 57% of Rbfox CLIP tags are truncated at crosslink sites.
“Based on the relative frequency of deletions in Rbfox CLIP tags obtained with standard and BrdU-CLIP protocols (14% vs. 6.2%), we estimated that 57% of Rbfox CLIP tags are truncated at the crosslink sites (Experimental Procedures).”
Quote in the paperNot a substantial claim - Findingown data
Compensatory mutations in the stop codon have accumulated, producing different stop codons in different species.
“This has resulted in different stop codons in different species, suggesting an evolutionary selection pressure to preserve a stop codon.”
Quote in the paperNot a substantial claim - Findingown data
Most Rbfox target exons, when included or excluded, alter only local amino acid sequences.
“Inclusion or exclusion of Rbfox target exons mostly introduces alteration in local amino acid sequences.”
Quote in the paperNot a substantial claim - Premisecitation
Rbfox1, Rbfox2, and Rbfox3 regulate alternative splicing in the nervous system.
“The RNA-binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system”
- Also stated in: § Introduction · boosted
“Rbfox proteins are known as tissue-specific splicing factors which bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § Introduction · boosted
- Premisecitation
CNS depletion of Rbfox2 causes cerebellar developmental defects.
“CNS depletion of Rbfox2 results in defects in cerebellar development (Gehman et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gehman et al., 2012 source
Not checked in the free run.
- Study design and conductown data
The two CLIP protocols produced highly reproducible global profiles (R=0.97).
“In addition, we confirmed that the two CLIP protocols gave very reproducible results inthe global profiles (R=0.97; Figure 1G).”
Quote in the paperSubstantial claim - Interpretationown data
The Rbfox splicing regulatory network may have clinical importance.
“supporting the potential clinical relevance of the splicing- regulatory network.”
Quote in the paperSubstantial claim- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
- Interpretationown data
On a genome-wide scale, the three Rbfox family members show similar RNA interaction profiles.
“Based on these observations, we conclude that the three Rbfox family members have similar RNA-interaction profiles on a genome-wide scale, consistent with the notion that their binding specificity is largely determined by their very similar RRMs.”
Quote in the paperSubstantial claim - Premisecitation
Disruption of Rbfox1 has been implicated in autism.
“disruption of Rbfox1 has been implicated in autism”
- Also stated in: § Introduction · plain
“In humans, chromosomal translocation or copy number variation affecting RBFOX1has been found in patients with several neurological disorders, including epilepsy, intellectual disability (Bhalla et al., 2004), schizophrenia (Xu et al., 2008), and autism (Martin et al., 2007; Sebat et al., 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § Introduction · plain
- Premisecitation
WT versus Rbfox1 or Rbfox2 KO brain exon-junction microarray studies identified only 20 and 29 Rbfox-dependent exons, respectively.
“Comparison of wild type (WT) versus Rbfox1 or Rbfox2 KO brains using exon-junction microarrays has identified multiple Rbfox-dependent exons (Gehman et al., 2012; Gehman et al., 2011). However, the number of exons identified using this approach is quite small (20 and 29 exons, respectively)”
Quote in the paperSubstantial claim0 of 2 sources checked - Study design and conductown data
Comparison with previously validated Rbfox-regulated exons gave the Bayesian network an estimated sensitivity of 73-79%.
“Based on comparison of the predicted exons with previously validated Rbfox-regulated exons compiled from the literature, we estimated that our Bayesian network analysis has a sensitivity of 73-79% (Supplementary Notes, Figure S4 and Table S7).”
Quote in the paperSubstantial claim - Premisecitation
Bioinformatically predicted Rbfox target transcripts based on conserved motif sites significantly overlap with autism-implicated genes.
“We previously demonstrated that Rbfox target transcripts predicted bioinformatically based on conserved motif sites have significant overlap with genes implicated in autism, supporting the notion that disruption of either Rbfox1 itself or of its targets observed in autism patients is likely pathogenic (Zhang et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2010 source
Not checked in the free run.
- Premiseown data
The integrative modeling approach employs a Bayesian network to weigh and combine several complementary data types probabilistically.
“This method uses a Bayesian network to probabilistically weigh and combine multiple types of data complementary to each other: bioinformatically predicted motif sites represented by MECS scores, protein-RNA interaction sites mapped by Rbfox HITS-CLIP, Rbfox1-dependent splicing identified by comparison of WT with Rbfox1 KO mouse brain using exon-junction microarrays (Gehman et al., 2011), Rbfox2-”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
The concurrent reduction of all Rbfox family members could account for the extensive splicing misregulation of Rbfox target exons seen in these autism patients.
“Therefore, simultaneous down-regulation of all Rbfox family members might explain the massive splicing misregulation of Rbfox target exons observed in these autism patients.”
Quote in the paperSubstantial claim- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
- Premisecitation
Scn2a1 is among the few genes with recurrent de novo gene-disrupting mutations in ASD patients, based on exome sequencing.
“Scn2a1 is one of the few genes with recurrent de novo gene-disrupting mutations according to exome-sequencing of ASD patients (Sanders et al., 2012), and our analysis suggests that the same gene can potentially be disrupted in autism by different mechanisms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sanders et al., 2012
Not checked in the free run.
- Interpretationreasoning
Such an integrative method has the unique advantage of identifying direct, functional target transcripts with high specificity and sensitivity at the same time.
“As increasing amounts of high-throughput data are being produced for different RBPs, interrogating RNA regulation from different perspectives, such a method has the unique advantage of being able to identify direct, functional target transcripts with high specificity and sensitivity simultaneously.”
Quote in the paperSubstantial claim - Premisecitation
In cell culture models of epithelial-to-mesenchymal transition, inclusion of the Tsc2 alternative exon was shown to require Rbfox2.
“Although the function of this alternative exon has not been characterized, its inclusion was recently shown to be dependent on Rbfox2 using cell culture models of epithelial-to-mesenchymal transition (Braeutigam et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Braeutigam et al., 2013
Not checked in the free run.
- Premisecitation
Additional support for this argument comes from predominant crosslinking to different nucleotides for several other RBPs with distinct binding specificities.
“Additional evidence supporting this argument comes from predominant crosslinking to different nucleotides for several other RBPs with distinct binding specificity (Moore et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Moore et al., 2014 source
Not checked in the free run.
- Interpretationreasoning
Because Rbfox family members are functionally redundant, depleting more than one member is likely necessary to reveal most Rbfox-dependent exons under physiological conditions.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Together with neuro-developmental defects seen in cell cultures, animal models, and human patients with disrupted Rbfox proteins, this provides a compelling case that Rbfox proteins play critical roles in driving the global dynamic change of the developmental splicing-regulatory program.
“Combined with neuro-developmental defects observed in cell cultures (Kim et al., 2013), animal models (Gehman et al., 2012; Gehman et al., 2011; Kim et al., 2013), and human patients (Bhalla et al., 2004) where Rbfox proteins are disrupted, this presents a compelling case for Rbfox proteins playing critical roles in driving the global dynamic change of the developmentalsplicing-regulatory program.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The presence of different stop codons across species suggests evolutionary selection to maintain a stop codon.
“This has resulted in different stop codons in different species, suggesting an evolutionary selection pressure to preserve a stop codon.”
Quote in the paperNot a substantial claim - Interpretationown data
The functions of the 48 SFARI genes, including cytoskeleton and scaffolding, synaptic transmission, ion channels, and transcription regulation, are potentially relevant to the neurobiology underlying autism.
“The functions of these genes, which include cytoskeleton and scaffolding, synaptic transmission, ion channels and transcription regulation, are potentially relevant to the neurobiology underlying autism.”
Quote in the paperNot a substantial claim- Rests on an assumption: Three genes in the Rbfox target list—Shank3, Cacna1c, and Tsc2—are causal in syndromic autism spectrum disorders.
- Interpretationcitation
The small number of validated exons is probably explained by Rbfox protein redundancy and a compensatory rise in Rbfox2 in Rbfox1 knockout animals.
“The relatively small number of validated exons is likely due to the redundancy of Rbfox proteins and the compensatory increase of Rbfox2 protein expression in Rbfox1 KO animals (Gehman et al., 2011), although it is possible that some of the predicted targets might represent false positives.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gehman et al., 2011 source
Not checked in the free run.
- Interpretationreasoning
The analysis suggests that Scn2a1 can potentially be disrupted in autism through mechanisms other than those already known.
“Scn2a1 is one of the few genes with recurrent de novo gene-disrupting mutations according to exome-sequencing of ASD patients (Sanders et al., 2012), and our analysis suggests that the same gene can potentially be disrupted in autism by different mechanisms.”
Quote in the paperSubstantial claim - Interpretationreasoning
This truncation parameter could vary substantially across proteins, depending on the amino acids and nucleotides at crosslink sites and possibly on experimental conditions.
“Therefore, this parameter could vary substantially for different proteins, depending on the specific amino acid(s) and nucleotide(s) at the crosslink sites, and possibly also on different experimental conditions.”
Quote in the paperNot a substantial claim - Premisecitation
Previous efforts lacked a genome-wide, high-resolution map of in vivo Rbfox interaction sites in the brain.
“An important piece of information missing in previous efforts toward this aim [e.g., (Fogel et al., 2012; Gehman et al., 2012; Gehman et al., 2011; Ray et al., 2013; Zhang et al., 2008)] is a genome-wide, high-resolution map ofin vivo Rbfox interaction sites in the brain.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
For high-affinity protein-RNA interactions, such background preference does not prevent UV crosslinking at specific nucleotides in the core motif.
“However, for high-affinity protein-RNA interactions, such “background” preference does not prevent UV crosslinking at specific nucleotides in the core motif.”
Quote in the paperNot a substantial claim - Study design and conductcitation
The study used an integrative modeling approach that combines multiple complementary data types to make strong predictions of Rbfox targets.
“The second critical aspect of this study is the use of an integrative modeling approach to combine multiple complementary types of data, so that individually weak bits of information can be integrated to make strong predictions of Rbfox targets (Zhang et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2010 source
Not checked in the free run.
- Study design and conductreasoning
The study is currently limited in its ability to comprehensively identify target transcripts differentially regulated by each of the three Rbfox family members individually.
“We are currently limitedin our ability to comprehensively identify target transcripts differentially regulated bythe three family members individually.”
Quote in the paperSubstantial claim
- May combine two claims. 36
- Classified as probably not a substantial claim. 10
May combine two claims.
Findingown dataPairwise comparisons of CLIP tags across Rbfox members showed strong correlation, particularly Rbfox1 versus Rbfox3 (Pearson R=0.97), while Rbfox2 correlations were lower (R=0.76-0.80).
“CLIP tags for different members are very well correlated in each pairwise comparison, especially between Rbfox1 and Rbfox3 (Pearson correlation R=0.97); the correlation between Rbfox2 and the other two members is somewhat lower (R=0.76-0.80; Figure 1F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBrdU-CLIP tags had deletions in 6.2% of cases, and combining standard and BrdU-CLIP tags defined 2,298 CIMS (FDR<0.001).
“Finally, we observed deletions in 6.2% of BrdU-CLIP tags, and analysis combining standard and BrdU-CLIP tags defined 2,298 CIMS (FDR<0.001; Table S2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRelative to CITS, UGCAUG was enriched 319-fold at position -5, corresponding to predominant crosslinking at G6.
“Among these, the UGCAUG element is enriched 319-fold at a single position (−5) relative to CITS, corresponding to predominant crosslinking at G6 of the motif (Figure 2E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA stringent set of 41,182 genic CLIP tag clusters, each with at least one significant peak (p<0.01), was obtained; 70% were intronic and 30% exonic.
“A stringent set of 41,182genic CLIP tag clusters with at least one statistically significant peak (p<0.01) was obtained (Table S1), 70% of which are located in introns and the other 30% are in exons (Figure 1E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataStandard CLIP tags showed nucleotide deletions in 14% of cases, from which 1,424 reproducible CIMS were identified (FDR<0.001).
“Nucleotide deletions were observed in 14% of standard CLIP tags, from which 1,424 reproducible CIMS were identified (FDR<0.001).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIntrons contained 59-65% of CLIP tags, while exons contained 23-28%, mostly in 3′ UTRs.
“Between 59-65% of these CLIP tags arelocated in introns, consistent with the known role of Rbfox proteins in regulating alternative splicing; an additional 23-28% unique CLIP tags are located in exons, mostly in the 3′ UTRs.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe model predicted 212 tandem cassette events (300 exons) and 75 mutually exclusive events (107 exons) as direct Rbfox targets.
“we applied the model toother types of alternative splicing events, and predicted 212 events of tandem cassette exons (300 exons, Table S6) and 75 events of mutually exclusive exons (107 exons, Table S6) as direct Rbfox targets.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOf the 772 predicted cassette exon targets, Rbfox was predicted to activate 421 and repress 113 (probability >0.7), with direction unassigned for 238.
“Among these targets, Rbfox was predicted to activate 421 exons (probability of activation>0.7) and repress 113 exons (probability of repression>0.7), respectively. For the remaining 238 exons predicted as Rbfox targets, the Bayesian network was unable to assign the direction of regulation unambiguously”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFiltering yielded 4.6 million unique CLIP tags: 1,460,387 for Rbfox1, 868,366 for Rbfox2, and 2,308,632 for Rbfox3.
“we obtained a total of 4.6 million unique CLIP tags that represent independent captures of protein-RNA interactions, including 1,460,387 tags for Rbfox1, 868,366 tags for Rbfox2, and 2,308,632 tags for Rbfox3.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNear the Rbfox1 cassette exon, all three family members bind upstream intronic sequences with clustered conserved UGCAUG elements, suggesting auto- and cross-regulation.
“Our CLIP data show that all three Rbfox family members bind to the upstream intronic sequences harboring a cluster of conserved UGCAUG elements, suggesting that this exon is under both auto-and cross-regulation by all family members.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe model quantified the position-dependent RNA map: downstream intron binding predicts inclusion at probability 0.99; upstream intron or exon binding predicts repression at 0.75 and 0.61; binding in both exon and upstream intron raises repression probability to 0.84.
“binding of Rbfox in the downstream intron is predicted to result in Rbfox-dependent inclusion with a probability of 0.99, while binding of Rbfox in the upstream intron or exon is predicted to result in repression with a probability of 0.75 and 0.61, respectively. Binding of Rbfox in both exon and upstream intron is expected to increase the probability of repression to 0.84 (Figure 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCompared with all brain-expressing genes, Rbfox target genes are significantly enriched for cytoskeleton (Benjamini FDR < 3.8×10−17) and neuron projection (Benjamini FDR < 3.8×10−8) functions.
“we performed gene ontology (GO) analysis, and found very significant enrichment of genes with annotated function in “cytoskeleton” (Benjamini FDR < 3.8×10−17) and “neuron projection” (Benjamini FDR < 3.8×10−8), compared to all brain-expressing genes (Table S8).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn adult cortex compared with E17, Rbfox1 and Rbfox3 increase 1.6-fold (p<0.02) and 3.1-fold (p<10−6), while Rbfox2 decreases 3.1-fold (p<10−4).
“Rbfox1 and Rbfox3 show 1.6-fold (p<0.02; t-test) and 3.1-fold (p<10−6; t-test) increases in the adult cortex compared to E17 cortex, respectively, while the expression of Rbfox2 is reduced 3.1-fold (p<10−4; t-test; Figure 5A).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationOf 235 human-conserved Rbfox target cassette exons with enough RNA-Seq coverage, 97 (41%) show altered splicing in autistic brains (|ΔI|≥0.1, FDR≤0.05), significantly more than expected by chance (odds ratio=3.4, p<1.4×10−16).
“Among the 235 Rbfox target cassette exons that are conserved in human and that havesufficient RNA-Seq read coverage to evaluate splicing change in autistic versus control brains (Voineagu et al., 2011), 97 (41%) show alteration of splicing in autistic brains (|ΔI|≥0.1, and FDR≤0.05), a very significant overlap compared to random chance (odds ratio=3.4, p<1.4×10−16; Fisher’s exact test; Figure 6A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al., 2011 source
Not checked in the free run.
- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
May combine two claims.
Findingown dataThe current data supporting Rbfox roles in these processes are largely correlative, but they are corroborated by the observation that almost 30% of Rbfox binding sites are in 3′ UTRs.
“Although the current data supporting the role of Rbfox in these processes are largely correlative, they are corroborated by our observation that almost 30% of Rbfox binding sites are in 3′ UTRs.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOf eight exons with detectable inclusion and exclusion isoforms, three showed altered splicing after Rbfox1 depletion (ΔI≥0.1), and these exons were not identified as Rbfox1 targets in a prior genome-wide study.
“Among eight exons for which both the inclusion and exclusion isoforms can be detected, three exons showed altered splicing upon Rbfox1 depletion (ΔI≥0.1; Figure S6 and Table S5), and these were not identified as Rbfox1 targets in the previous genome-wide analysis (Gehman et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gehman et al., 2011 source
Not checked in the free run.
May combine two claims.
Findingown dataThe direction of Rbfox regulation was assigned for most Rbfox targets (69% of cassette exons), enabling evaluation of splicing regulation's impact in different physiological contexts, including brain development and autism.
“We were able to assign the direction of Rbfox regulation for a majority of Rbfox targets (69% of cassette exons), which allowed us to evaluate the impact of splicing regulation by Rbfox proteins in different physiological contexts, including brain development and autism.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn these autistic brains, Rbfox2 and Rbfox3 were also reduced, by 3.3-fold (p<0.05) and 3.2-fold (p<0.09), respectively.
“we found that the expression of the other two family members, Rbfox2 and Rbfox3, was also down-regulated 3.3 fold (p<0.05; t-test) and 3.2 fold (p<0.09; t-test), respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong these, 8,811 sites (2,298 CIMS and 6,606 CITS, with 93 shared) allow deduction of the exact protein-RNA crosslinking site, enabling single-nucleotide resolution of interactions.
“These include 8,811 sites (2,298 CIMS and 6,606 CITS with 93 common sites) for which the exact site of protein-RNA crosslinking can be deduced, allowing for determination of protein-RNA interactions at a single nucleotide resolution.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe analysis showed increased expression of Rbfox1 and Rbfox3 and decreased expression of Rbfox2 in adult compared to a late prenatal stage.
“Our analysis extends previous observations regarding the differential expression ofRbfox family members during brain development (Hammock and Levitt, 2011; Kim et al., 2013; Tang et al., 2009) by showing increased expression of Rbfox1 and Rbfox3 and decreased expression of Rbfox2 in adult compared to a late prenatal stage.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCLIP data suggest that all three Rbfox members have very similar protein-RNA interaction profiles, indicating that the highly conserved RRM is the major determinant of targeting specificity.
“Our CLIP data suggest that all three members have very similar protein-RNA interaction profiles, indicating that the highly conserved RRM is the major determinant of targeting specificity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn co-expression networks from microarray profiling of postmortem autistic and control human brains, RBFOX1 is a hub gene, and its reduced expression in some autism patients correlates with altered splicing of predicted Rbfox target exons.
“This hypothesis was further supported by recent findings that RBFOX1 lies in a hub in gene co-expression networks based on microarray profiling of autistic and control postmortem human brains and its reduced expression in a subset of autism patients is correlated with altered splicingof predicted Rbfox target exons (Voineagu et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al., 2011 source
Not checked in the free run.
May combine two claims.
Study design and conductown dataRT-PCR testing of 22 alternative exons found 21 with Rbfox2-dependent splicing, a 95% validation rate.
“Among the 22 cases of alternative exons we tested by RT-PCR (which includes 3 cases with a read coverage slightly below the threshold we used), 21 showed Rbfox2-dependent splicing (Figure 3C,D; Tables S4 and S5), giving a validation rate of 95%.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationRbfox binding downstream of an exon activates inclusion, while binding in the alternative exon or upstream intron represses inclusion.
“According to this map, Rbfox binding in the downstream intron activates exon inclusion and binding in the alternative exon or upstream intron represses exon inclusion, consistent with observations from several tissue-specific exons (Jin et al., 2003; Underwood et al., 2005).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataThe direction of Rbfox2-dependent splicing for these exons is predictable from the position-dependent RNA map using either mouse brain CLIP data or predicted motif sites, suggesting they are enriched for direct Rbfox targets in brain.
“The direction of Rbfox2-dependent splicing of these exons can be predicted by the position-dependent RNA map based on either the CLIP data derived from mouse brain or the bioinformatically predicted motif sites (data not shown), indicating that these Rbfox2-dependent exons are enriched in direct Rbfox targets in the brain.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCNS-specific depletion of Rbfox1 increases seizure susceptibility and neuronal over-excitability in the dentate gyrus.
“Central nervous system (CNS)-specific depletion of Rbfox1 results in an increased susceptibility of mice to seizures and in over-excitability of neurons in the dentate gyrus (Gehman et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gehman et al., 2011 source
Not checked in the free run.
May combine two claims.
PremisecitationDifferent Rbfox family members have highly similar protein sequences, especially in the RRM-type RBD (≥94% amino acid identity), and are expected to bind and regulate largely overlapping transcript sets.
“Since different Rbfox family members have highly similar protein sequences, especially in their RNA-recognition motif (RRM)-type RNA-binding domain (RBD; ≥94% amino acid identity), they are expected to bind and regulate largely overlapping sets of transcripts (Gallagher et al., 2010; Gehman et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gallagher et al., 2010
Not checked in the free run.
- cites Gehman et al., 2012 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe developmental splicing changes of Rbfox targets are dominated by increased Rbfox1 and Rbfox3 expression, which generally drive the switch to the adult splicing program via direct regulation.
“This asymmetry indicates that increased expression of Rbfox1 and Rbfox3 predominates the developmental splicing change of their targets, and in general they promote the switch to the adult splicing program through direct regulation.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataIn HeLa cells, Rbfox2 was specifically reduced 3.3-fold, matching protein-level changes seen by immunoblot.
“Examination of the gene-expression level confirmed that Rbfox2 was specifically knocked down 3.3-fold (Figure 3A, right panel), consistent with the protein level changes observed from immunoblot analysis.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAn NMR structure of the Rbfox1 RRM bound to UGCAUGU RNA shows G2 and G6 buried in two RRM pockets, stabilized by hydrogen bonds and stacking, and mutations at these positions produce the largest increases in binding free energy.
“examination of a previously determined NMR structure of the Rbfox1 RRM in complex with UGCAUGU RNA revealed that these two guanines are buried in two pockets of the RRM, and are stabilized by multiple hydrogen bonds and stacking interactions (Figure 2G); mutations in each of these two nucleotides resulted in the largest increases in the free energy of binding (Auweter et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Auweter et al., 2006 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationRbfox proteins bind the (U)GCAUG element, which is frequently conserved across vertebrates.
“Rbfox proteins are known as tissue-specific splicing factors which bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Study design and conductown dataThe antibodies used in Rbfox1/2/3 HITS-CLIP were specific to their intended family member and immunoprecipitated the target protein efficiently with little background.
“We firstconfirmed that the antibodies we used did not cross-react with different members and that they efficiently immunoprecipitated (IP) the targeted protein with minimal background under standard CLIP conditions (Figure S1; Supplementary Notes).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataFor Rbfox1, Rbfox2, and Rbfox3, the HITS-CLIP libraries had 4, 4, and 5 biological replicates, respectively.
“we prepared HITS-CLIP libraries for Rbfox1, Rbfox2, and Rbfox3 with 4, 4, and 5 biological replicates, respectively”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationHITS-CLIP isolates RNA fragments directly bound by an RBP of interest.
“crosslinking and immunoprecipitation followed by high-throughput sequencing (HITS-CLIP) has been developed to isolate RNA fragments directly bound by an RBP of interest (Darnell, 2010; Licatalosi et al., 2008; Moore et al., 2014; Ule et al., 2005a).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
InterpretationcitationThese crosslink sites probably reflect the residues in closest contact with the protein or those interacting with specific amino acids.
“We argue that these crosslink sites likely reflect the residues in closest contact with the protein or those interacting with specific amino acids, which agrees very well with a structure study of the protein-RNA complex (Auweter et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Auweter et al., 2006 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent findings propose that Rbfox can also regulate alternative polyadenylation and mRNA stability, based on analysis of Rbfox motif sites in 3′ UTRs correlated with transcript abundance in different tissues.
“Several recent findingspropose that Rbfox can also regulate alternative polyadenylation (Wang et al., 2008) and mRNA stability (Ray et al., 2013), based on analysis of Rbfox motif sites in 3′ UTRs that are correlated with transcript abundance in different tissues.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe rate of cDNA truncation at the crosslink site during reverse transcription has been reported as high as 82% for Nova and over 95% for several other RBPs.
“It has been reported that the rate of cDNA truncation at the crosslink site during reverse transcription is as high as 82% for Nova and over 95% for several other RBPs(Sugimoto et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sugimoto et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenMany of the splicing changes seen in autism patients may not be under direct Rbfox regulation.
“On the other hand, many of thesplicing changes observed in autism patients may not be regulated by Rbfox proteins directly.”
Quote in the paperNot a substantial claim- Rests on an assumption: The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationFunctional divergence among Rbfox members could arise from increased variation in their N-terminal and C-terminal regions, which have been shown to be important in splicing regulation.
“However, the functional divergence of the different members could arise from the increased variation in the N terminal and Cterminal regions, which were shown to also be important in splicing regulation (Jin et al., 2003; Nakahata and Kawamoto, 2005; Sun et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Jin et al., 2003 source
Not checked in the free run.
- cites Nakahata and Kawamoto, 2005
Not checked in the free run.
- cites Sun et al., 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar dynamic changes in Rbfox1 and Rbfox2 expression were previously observed in the heart during postnatal development.
“Similar dynamic changes in Rbfox1 and Rbfox2 expression were previously observed in the heart during postnatal development (Kalsotra et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kalsotra et al., 2008 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenAntibodies used in HITS-CLIP for individual Rbfox members were tested to ensure no or minimal cross-reactivity between family members and to optimize signal-to-noise ratios of IP in the CLIP condition.
“Antibodies used in HITS-CLIP experiments for individual Rbfox members were tested to ensure that there is no or minimal cross-reactivity between family members and to optimize the signal-to-noise ratios of IP in the CLIP condition.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe hypothesis that many autism genes can be disrupted in cis by mutations or in trans by disruption of upstream regulators such as Rbfox1 was supported by significant overlap between candidate autism-susceptibility genes and Rbfox targets, and by overlap between predicted Rbfox target exons and exons altered in autistic brains with Rbfox1 down-regulation.
“This hypothesis was supported both by the significant overlap between candidate autism-susceptibility genes and Rbfox target genes and by the significant overlap of predicted Rbfox target exons and exons altered in autistic brains with down-regulation of Rbfox1 (Voineagu et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al., 2011 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe Scn2a1 cryptic exon's inclusion is not detectable in brain RNA-Seq data, likely because the inclusion isoform is degraded by NMD.
“Inclusion of this exon is undetectable in the brain from RNA-Seq data, presumably due to NMD of the inclusion isoform.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The Rbfox regulatory network and its target exons are sufficiently conserved between mouse and human for mouse CLIP and RNA-Seq findings to inform human autism.
“Among the 235 Rbfox target cassette exons that are conserved in human and that havesufficient RNA-Seq read coverage to evaluate splicing change in autistic versus control brains”
“The comprehensive Rbfox target network defined by integrative modeling now allows us to examine the link between RBFOX1 and autism in more detail.”
The paper relies on this without support.
Three genes in the Rbfox target list—Shank3, Cacna1c, and Tsc2—are causal in syndromic autism spectrum disorders.
“The list includes three genes that are currently regarded as causal in syndromic autism spectrum disorders (ASD): Shank3 (Phelan-McDermid Syndrome), Cacna1c (Timothy syndrome), and Tsc2 (tuberous sclerosis complex).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several genes that cause rare forms of autism spectrum disorder regulate expression or splicing of many genes associated with psychiatric disorders.
“Several genes that cause rare forms of ASD (e.g., FMR1, CACNA1C, and TCF4) regulate expression or splicing of many genes associated with psychiatric disorders (Tian et al., 2014; Weyn-Vanhentenryck et al., 2014).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Weyn-Vanhentenryck et al., 2014
RBFOX targets are frequently dysregulated in autism.
“RBFOX targets are also frequently dysregulated in autism, highlighting the critical role of alternative splicing in brain development and function (De Rubeis et al., 2014; Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Weyn-Vanhentenryck et al., 2014
Human mutations in RBFOX1 have been identified in patients with autism spectrum disorder.
“and autism spectrum disorder129–131.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [131]
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“HITS-CLIP has been used to map the Rbfox2 binding sites in thousands of genes in human embryonic stem cells, including those important for splicing regulation as predicted by the RNA map (Yeo et al., 2009).”
Probing tumor phenotypes using stable and regulated synthetic microRNA precursors
Dickins, R., Hemann, M., Zilfou, J. T., Simpson, D. R., Ibarra, I., Hannon, G., & Lowe, S. (2005) · Nature Genetics · doi:10.1038/ng1651 · Cited by 561 · cited 1× · see citing works
“Briefly, an shRNA against human Rbfox2 (shRbfox2) was cloned into the MSCV retroviral vector (Dickins et al., 2005).”
An RNA map predicting Nova-dependent splicing regulation
Ule, J., Stefani, G., Mele, A., Ruggiu, M., Wang, X., Taneri, B., Gaasterland, T., Blencowe, B. J., & Darnell, R. B. (2006) · Nature · doi:10.1038/nature05304 · Cited by 528 · cited 2× · see citing works
“Such a map was previously found for another neuron-specific splicing factor Nova and is now recognized as a more general rule of alternative splicing regulation (Licatalosi et al., 2008; Ule et al., 2006).”
Self-citationNova regulates brain-specific splicing to shape the synapse
Ule, J., Ule, A., Spencer, J., Williams, A., Hu, J.-S., Cline, M., Wang, H., Clark, T., Fraser, C., Ruggiu, M., et al. (2005) · Nature Genetics · doi:10.1038/ng1610 · Cited by 509 · see citing works
Self-citationA postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart
Kalsotra, A., Xiao, X., Ward, A. J., Castle, J. C., Johnson, J. M., Burge, C. B., & Cooper, T. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809045105 · Cited by 508 · cited 2× · see citing works
“Similar dynamic changes in Rbfox1 and Rbfox2 expression were previously observed in the heart during postnatal development (Kalsotra et al., 2008 ).”
Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data
Zhang, C., & Darnell, R. B. (2011) · Nature Biotechnology · doi:10.1038/nbt.1873 · Cited by 405 · cited 7× · see citing works
“CIMS analysis was performed as described previously (Moore et al., 2014; Zhang and Darnell, 2011).”
InfluentialSelf-citationAutDB: a gene reference resource for autism research
Basu, S. N., Kollu, R., & Banerjee-Basu, S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn835 · Cited by 394 · cited 2× · see citing works
“To focus on Rbfox target genes that are likely genetic risk factors of autism, we examined candidate autism-susceptibility genes in the SFARI autism gene database (Basu et al., 2009).”
The role of de novo mutations in the genetics of autism spectrum disorders
Ronemus, M., Iossifov, I., Levy, D., & Wigler, M. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3585 · Cited by 390 · cited 1× · see citing works
“Scn2a1 is one of the few genes with recurrent de novo gene-disrupting mutations according to exome sequencing of ASD patients (Ronemus et al., 2014), and our analysis suggests that the same gene can potentially be disrupted in autism by different mechanisms.”
Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
Lovci, M. T., Ghanem, D., Marr, H., Arnold, J., Gee, S., Parra, M., Liang, T. Y., Stark, T. J., Gehman, L. T., Hoon, S., et al. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2699 · Cited by 385 · cited 1× · see citing works
“The overall distribution of Rbfox binding sites defined by HITS-CLIP is generally consistent with a recently published independent study (Lovci et al., 2013).”
HITS-CLIP: panoramic views of protein-RNA regulation in living cells
Darnell, R. B. (2010) · WIREs RNA · doi:10.1002/wrna.31 · Cited by 382 · cited 5× · see citing works
“The standard CLIP libraries were prepared as described previously (Darnell, 2010; Licatalosi et al., 2008; Moore et al., 2014).”
InfluentialSelf-citationGranneman, S., Kudla, G., Petfalski, E., & Tollervey, D. W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901997106 · Cited by 364 · cited 2× · see citing works
“…previously noted that after proteinase K digestion of the crosslinked protein-RNA complex, one or a few amino acids might remain attached to the RNA at the crosslink site, which causes informative errors at the crosslink site during reverse transcription (Granneman et al., 2009; Ule et al., 2005a).”
The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain
Gehman, L. T., Stoilov, P., Maguire, J., Damianov, A., Lin, C.-H., Shiue, L., Ares, M., Mody, I., & Black, D. L. (2011) · Nature Genetics · doi:10.1038/ng.841 · Cited by 331 · see citing works
Charizanis, K., Lee, K.-Y., Batra, R., Goodwin, M., Zhang, C., Yuan, Y., Shiue, L., Cline, M., Scotti, M. M., Xia, G., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.05.029 · Cited by 324 · see citing works
Self-citationJin, Y., Suzuki, H., Maegawa, S., Endo, H., Sugano, S., Hashimoto, K., Yasuda, K., & Inoue, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg089 · Cited by 311 · cited 4× · see citing works
“The first position of the motif is the most variable, which is consistent with previous findings that Rbfox binds to both UGCAUG and VGCAUG with high affinity (Jin et al., 2003; Ponthier et al., 2006).”
InfluentialDefining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2
Zhang, C., Zhang, Z., Castle, J., Sun, S., Johnson, J., Krainer, A. R., & Zhang, M. Q. (2008) · Genes & Development · doi:10.1101/gad.1703108 · Cited by 300 · cited 16× · see citing works
“%) of bioinformatically predicted Rbfox target alternative exons tested with RT-PCR (Zhang et al., 2008).”
InfluentialSelf-citationIntegrative Modeling Defines the Nova Splicing-Regulatory Network and Its Combinatorial Controls
Zhang, C., Frias, M. A., Mele, A., Ruggiu, M., Eom, T., Marney, C. B., Wang, H., Licatalosi, D. D., Fak, J. J., & Darnell, R. B. (2010) · Science · doi:10.1126/science.1191150 · Cited by 294 · cited 13× · see citing works
“We used our established Bayesian network framework with some modifications (Zhang et al., 2010).”
InfluentialSelf-citationUnderwood, J. G., Boutz, P. L., Dougherty, J. D., Stoilov, P., & Black, D. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.22.10005-10016.2005 · Cited by 272 · cited 2× · see citing works
“At the molecular level, Rbfox proteins are known as tissuespecific splicing factors that bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
Molecular basis of RNA recognition by the human alternative splicing factor Fox-1
Auweter, S. D., Fasan, R., Reymond, L., Underwood, J. G., Black, D. L., Pitsch, S., & Allain, F. H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600918 · Cited by 264 · cited 5× · see citing works
“Consistent with this finding, examination of a previously determined NMR structure of the Rbfox1 RRM in complex with UGCAUGU RNA revealed that these two guanines are buried in two pockets of the RRM and are stabilized by multiple hydrogen bonds and stacking interactions (Figure 2G); mutations in each of these two nucl…”
InfluentialMoore, M. J., Zhang, C., Gantman, E. C., Mele, A., Darnell, J. C., & Darnell, R. B. (2014) · Nature Protocols · doi:10.1038/nprot.2014.012 · Cited by 251 · cited 18× · see citing works
“CIMS analysis was performed as described previously (Moore et al., 2014; Zhang and Darnell, 2011).”
InfluentialSelf-citationiCLIP Predicts the Dual Splicing Effects of TIA-RNA Interactions
Wang, Z., Kayikci, M., Briese, M., Zarnack, K., Luscombe, N. M., Rot, G., Zupan, B., Curk, T., & Ule, J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000530 · Cited by 242 · cited 4× · see citing works
“This was done using a random redistribution of potential truncations in each CLIP tag cluster, which is more stringent than the gene-by-gene permutation used in the previous analyses (Konig et al., 2010; Wang et al., 2010).”
InfluentialAnalysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions
Sugimoto, Y., König, J., Hussain, S., Zupan, B., Curk, T., Frye, M., & Ule, J. (2012) · Genome Biology · doi:10.1186/gb-2012-13-8-r67 · Cited by 234 · see citing works
RBFOX1 regulates both splicing and transcriptional networks in human neuronal development
Fogel, B. L., Wexler, E., Wahnich, A., Friedrich, T., Vijayendran, C., Gao, F., Parikshak, N., Konopka, G., & Geschwind, D. H. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds240 · Cited by 216 · cited 1× · see citing works
“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.”
The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function
Gehman, L. T., Meera, P., Stoilov, P., Shiue, L., O'Brien, J. E., Meisler, M. H., Ares, M., Otis, T. S., & Black, D. L. (2012) · Genes & Development · doi:10.1101/gad.182477.111 · Cited by 213 · cited 7× · see citing works
“…Rbfox family members have highly similar protein sequences, especially in their RNA-recognition motif (RRM)-type RNA binding domain (RBD; R94% amino acid identity), they are expected to bind and regulate largely overlapping sets of transcripts (Gallagher et al., 2011; Gehman et al., 2012).”
InfluentialMartin, C. L., Duvall, J. A., Ilkin, Y., Simon, J. S., Arreaza, M. G., Wilkes, K., Alvarez‐Retuerto, A., Whichello, A., Powell, C. M., Rao, K., et al. (2007) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30530 · Cited by 198 · cited 2× · see citing works
“, 2008), and autism (Martin et al., 2007; Sebat et al., 2007).”
Nakahata, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki338 · Cited by 184 · cited 1× · see citing works
“However, the functional divergence of the different members could arise from the increased variation in the N-terminal and C-terminal regions, which were shown to also be important in splicing regulation (Jin et al., 2003; Nakahata and Kawamoto, 2005; Sun et al., 2012).”
Bräutigam, C., Rago, L., Rolke, A., Waldmeier, L., Christofori, G., & Winter, J. (2013) · Oncogene · doi:10.1038/onc.2013.50 · Cited by 174 · see citing works
PDZ domain proteins: Scaffolds for signaling complexes
Ranganathan, R., & Ross, E. M. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00401-5 · Cited by 167 · cited 1× · see citing works
“In addition, proteins encoded by Rbfox target transcripts are enriched in PDZ domains that are known to be important for anchoring transmembrane proteins to the cytoskeleton and for functioning as scaffolds for signaling complexes (Benjamini FDR 7.2 3 10 À8 ) (Ranganathan and Ross, 1997).”
InfluentialmRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex
Dillman, A. A., Hauser, D. N., Gibbs, J. R., Nalls, M. A., McCoy, M. K., Rudenko, I. N., Galter, D., & Cookson, M. R. (2013) · Nature Neuroscience · doi:10.1038/nn.3332 · Cited by 148 · see citing works
Bhalla, K., Phillips, H. A., Crawford, J., McKenzie, O. L. D., Mulley, J. C., Eyre, H., Gardner, A. E., Kremmidiotis, G., & Callen, D. F. (2004) · Journal of Human Genetics · doi:10.1007/s10038-004-0145-4 · Cited by 146 · cited 4× · see citing works
“…defects observed in cell cultures (Kim et al., 2013 ), animal models (Gehman et al., 2011, 2012; Kim et al., 2013), and human patients (Bhalla et al., 2004) where Rbfox proteins are disrupted, this presents a compelling case for Rbfox proteins playing critical roles in driving the…”
InfluentialOLego: fast and sensitive mapping of spliced mRNA-Seq reads using small seeds
Wu, J., Anczuków, O., Krainer, A. R., Zhang, M. Q., & Zhang, C. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt216 · Cited by 123 · cited 1× · see citing works
“Reads in each dataset were mapped to the mouse (mm10) or human (hg19) genome by OLego (http://zhanglab.c2b2.columbia.edu/index.php/OLego) (Wu et al., 2013) with 14-nt non-overlapping seeds, requiring ≤ 3 mismatches per read.”
Self-citationDredge, B. K., & Darnell, R. B. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.13.4687-4700.2003 · Cited by 120 · cited 1× · see citing works
“…2 subunit (Gabrg2) exon 9 is under the synergistic regulation of Rbfox and Nova when they bind near the 5 0 and 3 0 splice sites of the downstream intron, respectively , based on detailed mutation analysis and splicing reporter assays in cell culture (Dredge and Darnell, 2003; Zhang et al., 2010).”
Self-citationAutoregulation of Fox protein expression to produce dominant negative splicing factors
Damianov, A., & Black, D. L. (2010) · RNA · doi:10.1261/rna.1838210 · Cited by 120 · cited 1× · see citing works
“Its skipping as a result of autoregulation generates a dominantnegative form that lacks RNA binding capability (Baraniak et al., 2006; Damianov and Black, 2010).”
Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development
Kim, K. K., Nam, J., Mukouyama, Y.-S., & Kawamoto, S. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201206146 · Cited by 120 · cited 3× · see citing works
“Combined with neurodevelopmental defects observed in cell cultures (Kim et al., 2013 ), animal models (Gehman et al., 2011, 2012; Kim et al., 2013), and human patients (Bhalla et al., 2004) where Rbfox proteins are disrupted, this presents a compelling case for Rbfox proteins playing critical roles…”
Ponthier, J. L., Schluepen, C., Chen, W., Lersch, R., Gee, S. L., Hou, V., Lo, A., Short, S. A., Chasis, J. A., Winkelmann, J. C., et al. (2006) · eScholarship (California Digital Library) · Cited by 119 · see citing works
Fox-2 Mediates Epithelial Cell-Specific Fibroblast Growth Factor Receptor 2 Exon Choice
Baraniak, A. P., Chen, J. R., & García-Blanco, M. A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1209-1222.2006 · Cited by 117 · see citing works
Minovitsky, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki210 · Cited by 103 · see citing works
Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2
Sun, S., Zhang, Z., Fregoso, O. I., & Krainer, A. R. (2011) · RNA · doi:10.1261/rna.030486.111 · Cited by 103 · cited 1× · see citing works
“However, the functional divergence of the different members could arise from the increased variation in the N-terminal and C-terminal regions, which were shown to also be important in splicing regulation (Jin et al., 2003; Nakahata and Kawamoto, 2005; Sun et al., 2012).”
Self-citationDredge, B. K., & Jensen, K. B. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021585 · Cited by 99 · see citing works
Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins
Tang, Z. Z., Zheng, S., Nikolic, J. M., & Black, D. L. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00608-09 · Cited by 82 · cited 4× · see citing works
“…observations regarding the differential expression of Rbfox family members during brain development (Hammock and Levitt, 2011; Kim et al., 2013; Tang et al., 2009) by showing increased expression of Rbfox1 and Rbfox3 and decreased expression of Rbfox2 in adult compared to a late prenatal stage.”
InfluentialPrediction of clustered RNA-binding protein motif sites in the mammalian genome
Zhang, C., Lee, K., Swanson, M. S., & Darnell, R. B. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt421 · Cited by 65 · cited 1× · see citing works
“Despite recent progress (Barash et al., 2010; Ray et al., 2013; Ule et al., 2006; Zhang et al., 2013), the small sizes of RBP binding motifs limit the ability of motif-based bioinformatic target prediction to achieve both high specificity and sensitivity.”
Self-citationHammock, E. A. D., & Levitt, P. (2011) · Developmental Neuroscience · doi:10.1159/000323732 · Cited by 21 · cited 4× · see citing works
“Our analysis extends previous observations regarding the differential expression of Rbfox family members during brain development (Hammock and Levitt, 2011; Kim et al., 2013; Tang et al., 2009) by showing increased expression of Rbfox1 and Rbfox3 and decreased expression of Rbfox2 in adult compared…”
InfluentialGallagher, T. L., Arribere, J. A., Adkar, S. S., et al. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.05.432 · Cited by 1 · cited 2× · see citing works
“Given that different Rbfox family members have highly similar protein sequences, especially in their RNA-recognition motif (RRM)-type RNA binding domain (RBD; R94% amino acid identity), they are expected to bind and regulate largely overlapping sets of transcripts (Gallagher et al., 2011; Gehman et al., 2012).”
Ponthier, J. L., Schluepen, C., Chen, W., Lersch, R. A., Gee, S. L., Hou, V. C., Lo, A. J., Short, S. A., Chasis, J. A., Winkelmann, J. C., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511556200
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Synaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
m6A RNA methylation promotes XIST-mediated transcriptional repression
Patil, D. P., Chen, C.-K., Pickering, B. F., Chow, A., Jackson, C., Guttman, M., & Jaffrey, S. R. (2016) · Nature · doi:10.1038/nature19342 · Cited by 1,747 · see citing works
Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome
Linder, B., Grozhik, A. V., Olarerin-George, A. O., Meydan, C., Mason, C. E., & Jaffrey, S. R. (2015) · Nature Methods · doi:10.1038/nmeth.3453 · Cited by 1,569 · see citing works
Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP)
Van Nostrand, E. L., Pratt, G. A., Shishkin, A. A., Gelboin-Burkhart, C., Fang, M. Y., Sundararaman, B., Blue, S. M., Nguyen, T. B., Surka, C., Elkins, K., et al. (2016) · Nature Methods · doi:10.1038/nmeth.3810 · Cited by 1,397 · see citing works
Alternative splicing as a regulator of development and tissue identity
Baralle, F. E., & Giudice, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.27 · Cited by 1,333 · see citing works
Mechanisms and Regulation of Alternative Pre-mRNA Splicing
Lee, Y., & Rio, D. C. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034316 · Cited by 1,291 · see citing works
Scotti, M. M., & Swanson, M. S. (2015) · Nature Reviews Genetics · doi:10.1038/nrg.2015.3 · Cited by 1,130 · see citing works
Context-dependent control of alternative splicing by RNA-binding proteins
Fu, X.-D., & Ares, M. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3778 · Cited by 1,044 · see citing works
A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulationPreprint
Ke, S., Alemu, E. A., Mertens, C., Gantman, E. C., Fak, J. J., Mele, A., Haripal, B., Zucker-Scharff, I., Moore, M. J., Park, C. Y., et al. (2015) · Genes & Development · doi:10.1101/gad.269415.115 · Cited by 815 · see citing works
“Similar to Weyn-Vanhentenryck et al. (2014), we removed all m6A-CLIP reads with UV-induced CIMSs, as most of them were reads in which the cross-link sites were read through during reverse transcription.”
BackgroundMethodInfluentialSelf-citationGenome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism
Parikshak, N. N., Swarup, V., Belgard, T. G., Irimia, M., Ramaswami, G., Gandal, M. J., Hartl, C., Leppa, V., Ubieta, L. D. L. T., Huang, J., et al. (2016) · Nature · doi:10.1038/nature20612 · Cited by 685 · see citing works
“Previous studies have evaluated alternative splicing in ASD and its relation to specific splicing regulators in small sets of selected samples across individuals 8,13,14 .”
Genetic identification of brain cell types underlying schizophrenia
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Skene, N. G., Bryois, J., Bakken, T. E., Breen, G., Crowley, J. J., Gaspar, H. A., Giusti-Rodriguez, P., Hodge, R. D., Miller, J. A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0129-5 · Cited by 651 · see citing works
m6A modulates haematopoietic stem and progenitor cell specification
Zhang, C., Chen, Y., Sun, B., Wang, L., Yang, Y., Ma, D., Lv, J., Heng, J., Ding, Y., Xue, Y., et al. (2017) · Nature · doi:10.1038/nature23883 · Cited by 579 · see citing works
Self-citationRaj, B., & Blencowe, B. J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.004 · Cited by 475 · see citing works
“Previously, downregulation of RBFOX expression and misregulation of the RBFOX splicing regulatory network—comprising mostly longer alternative exons—were also observed in ASD patients (Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
BackgroundInfluentialInherited and de novo genetic risk for autism impacts shared networks
Ruzzo, E. K., Pérez-Cano, L., Jung, J.-Y., Wang, L.-K., Kashef-Haghighi, D., Hartl, C., Singh, C., Xu, J., Hoekstra, J. N., Leventhal, O., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.015 · Cited by 457 · see citing works
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
Genovese, G., Fromer, M., Stahl, E. A., Ruderfer, D. M., Chambert, K., Landén, M., Moran, J. L., Purcell, S. M., Sklar, P., Sullivan, P. F., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4402 · Cited by 444 · see citing works
Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation
Xu, K., Yang, Y., Feng, G.-H., Sun, B., Chen, J., Li, Y., Chen, Y., Zhang, X.-X., Wang, C.-X., Jiang, L.-Y., et al. (2017) · Cell Research · doi:10.1038/cr.2017.100 · Cited by 449 · see citing works
Self-citationDefining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders
Sullivan, P. F., & Geschwind, D. H. (2019) · Cell · doi:10.1016/j.cell.2019.01.015 · Cited by 452 · see citing works
“, 2014), splicing (Berto et al., 2016; Fogel et al., 2012; Weyn-Vanhentenryck et al., 2014), or signaling (Tian et al.”
BackgroundZhou, X., Feliciano, P., Shu, C., Wang, T., Astrovskaya, I., Hall, J. B., Obiajulu, J. U., Wright, J. R., Murali, S. C., Xu, S. X., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01148-2 · Cited by 453 · see citing works
Methods to study RNA–protein interactions
Ramanathan, M., Porter, D. F., & Khavari, P. A. (2019) · Nature Methods · doi:10.1038/s41592-019-0330-1 · Cited by 380 · see citing works
Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex
Zhang, X., Chen, M. H., Wu, X., Kodani, A., Fan, J., Doan, R. N., Ozawa, M., Ma, J., Yoshida, N., Reiter, J. F., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.025 · Cited by 343 · see citing works
“Re-analysis of Rbfox-1/2/3 HITS-CLIP datasets from P15 mouse brains (Weyn-Vanhentenryck et al., 2014) revealed that Rbfox1 and Rbfox3 bound to a conserved GCAUG motif, and Rbfox2 CLIP tags mapped to a different but adjacent GCAUG motif (Figure 6J and S6I).”
BackgroundMethodThe neurogenetics of alternative splicing
Vuong, C. K., Black, D. L., & Zheng, S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.27 · Cited by 340 · see citing works
Hepatitis C Virus RNA Functionally Sequesters miR-122
Luna, J. M., Scheel, T. K. H., Danino, T., Shaw, K. S., Mele, A., Fak, J. J., Nishiuchi, E., Takacs, C. N., Catanese, M. T., de Jong, Y. P., et al. (2015) · Cell · doi:10.1016/j.cell.2015.02.025 · Cited by 332 · see citing works
“Poly-G CLIP is a direct adaptation of the single linker ligation BrdU CLIP protocol (Weyn-Vanhentenryck et al., 2014).”
BackgroundSelf-citationAdvances in CLIP Technologies for Studies of Protein-RNA Interactions
Lee, F. C. Y., & Ule, J. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.01.005 · Cited by 288 · see citing works
Kwart, D., Gregg, A., Scheckel, C., Murphy, E. A., Paquet, D., Duffield, M. D., Fak, J. J., Olsen, O., Darnell, R. B., & Tessier‐Lavigne, M. (2019) · Neuron · doi:10.1016/j.neuron.2019.07.010 · Cited by 317 · see citing works
Self-citationDynamic methylome of internal mRNA N7-methylguanosine and its regulatory role in translation
Malbec, L., Zhang, T., Chen, Y., Zhang, Y., Sun, B., Shi, B., Zhao, Y., Yang, Y., & Yang, Y. (2019) · Cell Research · doi:10.1038/s41422-019-0230-z · Cited by 304 · see citing works
Moore, M. J., Scheel, T. K. H., Luna, J. M., Park, C. Y., Fak, J. J., Nishiuchi, E., Rice, C. M., & Darnell, R. B. (2015) · Nature Communications · doi:10.1038/ncomms9864 · Cited by 326 · see citing works
Self-citationSplicing-factor alterations in cancers
Anczuków, O., & Krainer, A. R. (2016) · RNA · doi:10.1261/rna.057919.116 · Cited by 297 · see citing works
“Mutations or deletions in RBFOX1 and RBFOX3 are found in epilepsy patients (Bhalla et al. 2004; Lal et al. 2013a,b), whereas copy-number variations in RBFOX1 are associated with autism spectrum disorders and spinocerebellar ataxias (Bill et al. 2013; Weyn-Vanhentenryck et al. 2014).”
Self-citationPrecise temporal regulation of alternative splicing during neural development
Weyn‐Vanhentenryck, S. M., Feng, H., Ustianenko, D., Duffié, R., Yan, Q., Jacko, M., Martinez, J. C., Goodwin, M., Zhang, X., Hengst, U., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04559-0 · Cited by 271 · see citing works
“%) of cases, while Ptbp mostly suppresses the mature splicing pattern (80% of cases), confirming and extending previous studies (Charizanis et al. 2012; Li et al. 2014; Weyn-Vanhentenryck et al. 2014) (Fig.”
BackgroundMethodResultInfluentialSelf-citationPhase Separation as a Missing Mechanism for Interpretation of Disease Mutations
Tsang, B., Pritišanac, I., Scherer, S. W., Moses, A. M., & Forman-Kay, J. D. (2020) · Cell · doi:10.1016/j.cell.2020.11.050 · Cited by 273 · see citing works
“The splicing factor protein RBFOX1 regulates alternative splicing of neuronal gene networks enriched with ASD candidate genes (Lee et al., 2016; Weyn-Vanhentenryck et al., 2014).”
BackgroundDisruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions
Nussbacher, J. K., Tabet, R., Yeo, G. W.-M., & Lagier‐Tourenne, C. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.014 · Cited by 264 · see citing works
“The predominant nuclear isoform of RBFOX1 is necessary for appropriate neuronal excitation through control of the alternative splicing of numerous transcripts, including genes associated with increased susceptibility to autism (Weyn-Vanhentenryck et al., 2014).”
BackgroundirCLIP platform for efficient characterization of protein–RNA interactions
Zarnegar, B. J., Flynn, R. A., Shen, Y., Do, B. T., Chang, H. Y., & Khavari, P. A. (2016) · Nature Methods · doi:10.1038/nmeth.3840 · Cited by 264 · see citing works
N6-Methyladenosine Inhibits Local Ribonucleolytic Cleavage to Stabilize mRNAs in Arabidopsis
Anderson, S. J., Kramer, M. C., Gosai, S. J., Yu, X., Vandivier, L. E., Nelson, A. D. L., Anderson, Z. D., Beilstein, M. A., Fray, R. G., Lyons, E. H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.020 · Cited by 265 · see citing works
CLIPdb: a CLIP-seq database for protein-RNA interactions
Yang, Y., Di, C., Hu, B., Zhou, M., Liu, Y., Song, N., Li, Y., Umetsu, J., & Lu, Z. J. (2015) · BMC Genomics · doi:10.1186/s12864-015-1273-2 · Cited by 238 · see citing works
“3) to discriminate the truncation sties [22].”
Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes
Lee, J.-A., Damianov, A., Lin, C.-H., Fontes, M., Parikshak, N. N., Anderson, E. S., Geschwind, D. H., Black, D. L., & Martin, K. C. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.025 · Cited by 232 · see citing works
“targets using CLIP-seq were done in whole tissue and thus could not differentiate between nuclear and cytoplasmic targets of Rbfox1 (Lovci et al., 2013; Weyn-Vanhentenryck et al., 2014).”
BackgroundMethodInfluentialRbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR
Damianov, A., Yi, Y., Lin, C.-H., Lee, J.-A., Tran, D., Vashisht, A. A., Bahrami‐Samani, E., Xing, Y., Martin, K. C., Wohlschlegel, J. A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.040 · Cited by 204 · see citing works
“However, as seen previously, many iCLIP clusters did not contain the GCAUG motif 612 Cell 165, 606–619, April 21, 2016 (Jangi et al., 2014; Lovci et al., 2013; Weyn-Vanhentenryck et al., 2014; Yeo et al., 2009).”
InfluentialSingh, T., Walters, J. T. R., Johnstone, M., Curtis, D., Suvisaari, J., Torniainen, M., Rees, E., Iyegbe, C., Blackwood, D., McIntosh, A. M., et al. (2017) · Nature Genetics · doi:10.1038/ng.3903 · Cited by 231 · see citing works
RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcriptsPreprint
Li, Y., Sánchez‐Pulido, L., Haerty, W., & Ponting, C. P. (2014) · Genome Research · doi:10.1101/gr.181990.114 · Cited by 231 · see citing works
“Additionally, aberrant splicing induced by RBFOX dysregulation is associated with a variety of brain-related disorders including autism, mental retardation, and epilepsy (Gehman et al. 2012; Weyn-Vanhentenryck et al. 2014).”
BackgroundMethodInfluentialExome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
Palmer, D. S., Howrigan, D. P., Chapman, S. B., Adolfsson, R., Bass, N. J., Blackwood, D., Boks, M. P., Chen, C., Churchhouse, C. L., Corvin, A. P., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01034-x · Cited by 196 · see citing works
Defective control of pre–messenger RNA splicing in human disease
Chabot, B., & Shkreta, L. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201510032 · Cited by 209 · see citing works
“Consistent with this view, repression of PRPF8 alters the splicing of introns with weak 5′ss (Wickramasinghe et al., 2015).”
Backgroundm6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation
Jia, R., Chai, P., Wang, S., Sun, B., Xu, Y., Yang, Y., Ge, S., Jia, R., Yang, Y., & Fan, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1088-x · Cited by 191 · see citing works
“pl [29] was used to determine the coverage of the tag number (k) and mutations (m) for each mutation position.”
MethodCLIP Tool Kit (CTK): a flexible and robust pipeline to analyze CLIP sequencing data
Shah, A., Qian, Y., Weyn‐Vanhentenryck, S. M., & Zhang, C. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw653 · Cited by 182 · see citing works
Self-citationYan, Q., Weyn‐Vanhentenryck, S. M., Wu, J., Sloan, S. A., Zhang, Y., Chen, K., Wu, J. Q., Barres, B. A., & Zhang, C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502849112 · Cited by 167 · see citing works
Self-citationPOSTAR: a platform for exploring post-transcriptional regulation coordinated by RNA-binding proteins
Hu, B., Yang, Y., Huang, Y., Zhu, Y., & Lu, Z. J. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw888 · Cited by 174 · see citing works
Krakau, S., Richard, H., & Marsico, A. (2017) · Genome biology · doi:10.1186/s13059-017-1364-2 · Cited by 156 · see citing works
“These crosslinking patterns are in agreement with previous studies [31] [30] and, since crosslinks do not preferentially occur at guanines, are most likely caused by target-specific protein-RNA interactions.”
MethodResultInfluentialAutism spectrum disorder: insights into convergent mechanisms from transcriptomics
Quesnel-Vallières, M., Weatheritt, R. J., Cordes, S. P., & Blencowe, B. J. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0066-2 · Cited by 160 · see citing works
Quesnel-Vallières, M., Dargaei, Z., Irimia, M., Gonatopoulos-Pournatzis, T., Ip, J. Y., Wu, M., Sterne-Weiler, T., Nakagawa, S., Woodin, M. A., Blencowe, B. J., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.033 · Cited by 178 · see citing works
“These and a subsequent study also revealed misregulation of 5%–10% of alternative exons in patients with reduced levels of transcripts encoding members of the Rbfox family of RNA-binding splicing regulators (Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
BackgroundPOSTAR2: deciphering the post-transcriptional regulatory logics
Zhu, Y., Xu, G., Yang, Y., Xu, Z., Chen, X., Shi, B., Xie, D., Lu, Z. J., & Wang, P. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky830 · Cited by 152 · see citing works
“We also applied CLIP technology-specific tools for binding site identification with default parameters: using PARalyzer (18) for PAR-CLIP datasets, using CIMS (19) for HITS-CLIP datasets and using CITS (a module in CIMS software) (19,20) for iCLIP datasets.”
MethodZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity
Moore, M. J., Blachère, N. E., Fak, J. J., Park, C. Y., Sawicka, K., Parveen, S., Zucker-Scharff, I., Moltedo, B., Rudensky, A. Y., & Darnell, R. B. (2018) · eLife · doi:10.7554/elife.33057 · Cited by 158 · see citing works
Self-citationUnusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins
Wu, H., Yin, Q.-F., Luo, Z., Yao, R.-W., Zheng, C.-C., Zhang, J., Xiang, J., Yang, L. C., & Chen, L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.007 · Cited by 154 · see citing works
“Their aberrant localization and expression have been reported to be associated with neurogenetic disorders, such as Amyotrophic Lateral Sclerosis (Lagier-Tourenne et al., 2012; Tollervey et al., 2011) and autism (Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
BackgroundFunctional roles of alternative splicing factors in human disease
Cieply, B. W., & Carstens, R. P. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1276 · Cited by 142 · see citing works
Wang, Q., Chen, R., Cheng, F., Wei, Q., Ji, Y., Hai, Y., Zhong, X. Y., Tao, R., Wen, Z., Sutcliffe, J. S., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0382-7 · Cited by 130 · see citing works
Vanharanta, S., Marney, C. B., Shu, W., Valiente, M., Zou, Y., Mele, A., Darnell, R. B., & Massagué, J. (2014) · eLife · doi:10.7554/elife.02734 · Cited by 143 · see citing works
Self-citationPredicting dynamic cellular protein–RNA interactions by deep learning using in vivo RNA structures
Sun, L., Xu, K., Huang, W., Yang, Y., Li, P., Tang, L., Xiong, T., & Zhang, Q. C. (2021) · Cell Research · doi:10.1038/s41422-021-00476-y · Cited by 141 · see citing works
Bridging the gap betweenin vitroandin vivoRNA folding
Leamy, K. A., Assmann, S. M., Mathews, D. H., & Bevilacqua, P. C. (2016) · Quarterly Reviews of Biophysics · doi:10.1017/s003358351600007x · Cited by 134 · see citing works
“…protein sites transcriptome wide in HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) and PAR-CLIP (photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation) (Hafner et al. 2010; Licatalosi et al. 2008; Weyn-Vanhentenryck et al. 2014).”
MethodDevelopmental regulation of RNA processing by Rbfox proteins
Conboy, J. G. (2016) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1398 · Cited by 134 · see citing works
Genetic Changes Shaping the Human Brain
Bae, B.-I., Jayaraman, D., & Walsh, C. A. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.035 · Cited by 135 · see citing works
Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly
Jacko, M., Weyn‐Vanhentenryck, S. M., Smerdon, J. W., Yan, R., Feng, H., Williams, D. J., Pai, J. A., Xu, K., Wichterle, H., & Zhang, C. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.020 · Cited by 126 · see citing works
“…and immunoprecipitation followed by highthroughput sequencing (HITS-CLIP) (Licatalosi et al., 2008), we predicted over a thousand exons as potential Rbfox targets, many in transcripts with known functions in the adult neurons and muscle (Weyn-Vanhentenryck et al., 2014, 2018; Zhang et al., 2008).”
InfluentialSelf-citationFeng, H., Bao, S., Rahman, M. A., Weyn‐Vanhentenryck, S. M., Khan, A., Wong, J., Shah, A., Flynn, E. D., Krainer, A. R., & Zhang, C. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.002 · Cited by 119 · see citing works
Self-citationAlternative splicing: the pledge, the turn, and the prestige
Gallego-Paez, L. M., Bordone, M. C., Leote, A. C., Saraiva-Agostinho, N., Ascensão-Ferreira, M., & Barbosa‐Morais, N. L. (2017) · Human Genetics · doi:10.1007/s00439-017-1790-y · Cited by 133 · see citing works
“Regarding the RBFOX family, RBFOX1 is expressed in neurons, heart and muscle and its absence in mouse, especially of isoform Rbfox1-iso2, causes defects during corticogenesis due to impairments in migration, axon growth and dendrite development of excitatory neurons (Hamada et al. 2015).”
RNA-binding proteins in neurological development and disease
Prashad, S., & Gopal, P. P. (2020) · RNA Biology · doi:10.1080/15476286.2020.1809186 · Cited by 119 · see citing works
“a critical role in alternative splicing and stabilization of transcripts encoding proteins important for neurotransmission [48-50].”
BackgroundAlkallas, R., Fish, L., Goodarzi, H., & Najafabadi, H. (2017) · Nature Communications · doi:10.1038/s41467-017-00867-z · Cited by 102 · see citing works
Binding specificities of human RNA-binding proteins toward structured and linear RNA sequencesPreprint
Jolma, A., Zhang, J., Mondragón, E., Morgunova, E. Y., Kivioja, T., Laverty, K. U., Yin, Y., Zhu, F., Bourenkov, G. P., Morris, Q., et al. (2020) · Genome Research · doi:10.1101/gr.258848.119 · Cited by 121 · see citing works
“…by HTR-SELEX were also observed in sites bound in vivo, we compared our data against existing in vivo data for four RBPs for which high-quality PAR-CLIP and HITSCLIP derived data were available from previous studies (Hafner et al. 2010; Farazi et al. 2014; Weyn-Vanhentenryck et al. 2014).”
Gonatopoulos-Pournatzis, T., Niibori, R., Salter, E. W., Weatheritt, R. J., Tsang, B., Farhangmehr, S., Liang, X., Braunschweig, U., Roth, J. F., Zhang, S., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.006 · Cited by 119 · see citing works
“Moreover, consistent with its distinct binding map and mechanism of action (Lee et al., 2016; Lovci et al., 2013; Weyn-Vanhentenryck et al., 2014), Rbfox forms spatially distinct binding peaks downstream of the Eif4g1 and Eif4g3 microexons (Figures 2D and S2E).”
BackgroundSplicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain
Yi, Y., Wang, X., Vuong, C. K., Lin, C.-H., Damianov, A., & Black, D. L. (2017) · Cell · doi:10.1016/j.cell.2017.06.022 · Cited by 104 · see citing works
Ajiro, M., Jia, R., Yang, Y., Zhu, J., & Zheng, Z. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1500 · Cited by 116 · see citing works
“Aberrant RNA splicing is often associated with various pathological conditions in human, such as myotonic dystrophy (1,2), autism (3), spinal muscular atrophy (4), tauopathies (5) and numerous types of cancer (6).”
BackgroundUnderstanding Long Noncoding RNA and Chromatin Interactions: What We Know So Far
Mishra, K., & Kanduri, C. (2019) · Non-Coding RNA · doi:10.3390/ncrna5040054 · Cited by 111 · see citing works
“• BrdU-CLIP: BrdU-CLIP built on the same principle as that of CLIP and iCLIP but employs a nucleotide analogue BrdUTP in reverse transcription to capture truncated and non-truncated cDNA products using BrdU antibody [79].”
MethodLIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs
Ustianenko, D., Chiu, H., Treiber, T., Weyn‐Vanhentenryck, S. M., Treiber, N., Meister, G., Sumazin, P., & Zhang, C. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.06.029 · Cited by 108 · see citing works
Self-citationRNA-binding proteins in neurodegeneration: Seq and you shall receive
Nussbacher, J. K., Batra, R., Lagier-Tourenne, C., & Yeo, G. W. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.02.003 · Cited by 115 · see citing works
Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons
Wamsley, B., Jaglin, X. H., Favuzzi, E., Quattrocolo, G., Nigro, M. J., Yusuf, N., Khodadadi‐Jamayran, A., Rudy, B., & Fishell, G. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.026 · Cited by 100 · see citing works
Genetic and epigenetic mechanisms of epilepsy: a review
Chen, T., Giri, M., Xia, Z., Subedi, Y. N., & Li, Y. (2017) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s142032 · Cited by 105 · see citing works
“Aberrant splicing induced by RBFOX dysregulation is associated with a variety of brain-related disorders, including autism, mental retardation, and epilepsy.(150,151)”
Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1
Vuong, C. K., Wei, W., Lee, J.-A., Lin, C.-H., Damianov, A., de la Torre-Ubieta, L., Halabi, R., Otis, K. O., Martin, K. C., O’Dell, T. J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.03.008 · Cited by 102 · see citing works
Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders
Andrade, A., Brennecke, A., Mallat, S., Brown, J., Gomez-Rivadeneira, J., Czepiel, N., & Londrigan, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143537 · Cited by 127 · see citing works
“Interestingly alterations in the relative abundance of several alternatively spliced exons in CACNA1D have been observed cortical samples of patients with ASD [215].”
BackgroundMicroexons: discovery, regulation, and function
Ustianenko, D., Weyn‐Vanhentenryck, S. M., & Zhang, C. (2017) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1418 · Cited by 98 · see citing works
Self-citationNguyen, H. T., Bryois, J., Kim, A., Dobbyn, A. L., Huckins, L. M., Muñoz‐Manchado, A. B., Ruderfer, D. M., Genovese, G., Fromer, M., Xu, X., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0497-y · Cited by 86 · see citing works
“We assigned 1/10 of the minimum non-zero mutation rate to genes with calculated mutation rates equal to zero.”
MethodInsights into the design and interpretation of iCLIP experiments
Haberman, N., Huppertz, I., Attig, J., König, J., Wang, Z., Hauer, C., Hentze, M. W., Kulozik, A. E., Hir, H. L., Curk, T., et al. (2017) · Genome biology · doi:10.1186/s13059-016-1130-x · Cited by 84 · see citing works
“Recently, further variants were developed that also amplify truncated cDNAs, including BrdU-CLIP [5], eCLIP [6] and irCLIP [7].”
BackgroundHamada, N., Ito, H., Nishijo, T., Iwamoto, I., Morishita, R., Tabata, H., Momiyama, T., & Nagata, K.-I. (2016) · Scientific Reports · doi:10.1038/srep30805 · Cited by 86 · see citing works
Advances in the profiling of N6-methyladenosine (m6A) modifications
Zheng, H., Zhang, X., & Sui, N. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107656 · Cited by 98 · see citing works
Lin, L., Göke, J., Cukuroglu, E., Dranias, M. R., VanDongen, A. M. J., & Stanton, L. W. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.022 · Cited by 92 · see citing works
Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation
Carreira-Rosario, A., Bhargava, V., Hillebrand, J., Kollipara, R. K., Ramaswami, M., & Buszczak, M. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.02.010 · Cited by 89 · see citing works
“Strikingly, Rbfox1, Rbfox2 and Rbfox3 also physically associate with Pumilio1 and Pumilio2 mRNA in the mouse nervous system (Weyn-Vanhentenryck et al., 2014).”
BackgroundSatellite-like cells contribute to pax7-dependent skeletal muscle repair in adult zebrafish
Berberoglu, M. A., Gallagher, T. L., Morrow, Z. T., Talbot, J. C., Hromowyk, K. J., Tenente, I. M., Langenau, D. M., & Amacher, S. L. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.03.004 · Cited by 85 · see citing works
Microexons: at the nexus of nervous system development, behaviour and autism spectrum disorder
Gonatopoulos-Pournatzis, T., & Blencowe, B. J. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.03.007 · Cited by 77 · see citing works
“Current Opinion in Genetics & Development 2020, 65:22–33 www.sciencedirect.com Serine/Arginine Repetitive Matrix 4 protein (SRRM4; also knownasnSR100),RBFOXandPTBP1,followedbyRNASeq analysis, revealed that these factors extensively regulate microexon splicing, with SRRM4 and RBFOX predominantly activating – and PTBP1…”
BackgroundPorter, R. S., Jaamour, F., & Iwase, S. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.10.006 · Cited by 80 · see citing works
Halvorsen, M., Huh, R., Oskolkov, N., Wen, J., Netotea, S., Giusti‐Rodríguez, P., Karlsson, R., Bryois, J., Nystedt, B., Ameur, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15707-w · Cited by 81 · see citing works
The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina
Murphy, D., Cieply, B. W., Carstens, R. P., Ramamurthy, V., & Stoilov, P. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006256 · Cited by 78 · see citing works
Saito, Y., Yuan, Y., Zucker-Scharff, I., Fak, J. J., Jereb, S., Tajima, Y., Licatalosi, D. D., & Darnell, R. B. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.019 · Cited by 77 · see citing works
Self-citationRBP-Maps enables robust generation of splicing regulatory maps
Yee, B. A., Pratt, G. A., Graveley, B. R., Nostrand, E. L. V., & Yeo, G. W.-M. (2018) · RNA · doi:10.1261/rna.069237.118 · Cited by 78 · see citing works
“However, for other RBPs (even those such as RBFOX2, which has previously been shown to crosslink directly to its in vitro binding motif [Weyn-Vanhentenryck et al. 2014]) we observed that using 5′ read ends yielded a similar structure with dramatically increased noise relative to using whole-reads…”
RNA ‐binding proteins, neural development and the addictions
Bryant, C. D., & Yazdani, N. (2015) · Genes Brain & Behavior · doi:10.1111/gbb.12273 · Cited by 79 · see citing works
“Increased expression of RBFOX1 and RBFOX3 and decreased expression of RBFOX2 were associated with a change in the RBFOX spliceome programs from E17 to adulthood (Weyn-Vanhentenryck et al. 2014).”
BackgroundBerto, S., Usui, N., Konopka, G., & Fogel, B. L. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw110 · Cited by 80 · see citing works
“As the nELAVL family has been linked to neuronal physiology and brain function (17,18,23,53), we examined whether any of the DEGs are linked with ASD.”
BackgroundResultInfluentialHwang, H., Park, C. Y., Goodarzi, H., Fak, J. J., Mele, A., Moore, M. J., Saito, Y., & Darnell, R. B. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.023 · Cited by 72 · see citing works
“The sequencing library was constructed using BrdU-CLIP method (Weyn-Vanhentenryck et al., 2014) with modification to improve sensitivity.”
MethodSelf-citationThe kinetic landscape of an RNA binding protein in cells
Sharma, D., Zagore, L. L., Brister, M., Ye, X., Crespo-Hernández, C., Licatalosi, D. D., & Jankowsky, E. (2020) · Nature · doi:10.1038/s41586-021-03222-x · Cited by 75 · see citing works
“Crosslink Induced Truncation Site (CITS) analysis was performed as described 28,29 .”
Design and bioinformatics analysis of genome-wide CLIP experiments
Wang, T., Xiao, G., Chu, Y., Zhang, M. Q., Corey, D. R., & Xie, Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv439 · Cited by 75 · see citing works
Self-citationDissecting noncoding and pathogen RNA–protein interactomes
Flynn, R. A., Martin, L., Spitale, R. C., Do, B. T., Sagan, S. M., Zarnegar, B. J., Qu, K., Khavari, P. A., Quake, S. R., Sarnow, P., et al. (2014) · RNA · doi:10.1261/rna.047803.114 · Cited by 78 · see citing works
Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT
Harvey, S. E., Xu, Y., Lin, X., et al. (2018) · RNA · doi:10.1261/rna.066712.118 · Cited by 78 · see citing works
Sellier, C., Cerro-Herreros, E., Blatter, M., Freyermuth, F., Gaucherot, A., Ruffenach, F., Sarkar, P. S., Puymirat, J., Udd, B., Day, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04370-x · Cited by 74 · see citing works
Feng, H., Moakley, D. F., Chen, S., McKenzie, M. G., Menon, V., & Zhang, C. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013056118 · Cited by 70 · see citing works
Self-citationGlobal identification of hnRNP A1 binding sites for SSO-based splicing modulation
Bruun, G. H., Doktor, T. K., Borch-Jensen, J., Masuda, A., Krainer, A. R., Ohno, K., & Andresen, B. S. (2016) · BMC Biology · doi:10.1186/s12915-016-0279-9 · Cited by 70 · see citing works
“To identify in vivo binding sites, a number of RNA binding proteins have been subjected to crosslinking and immunoprecipitation (CLIP) analysis [16–24].”
MethodSelf-citationAn alternative splicing program promotes adipose tissue thermogenesis
Vernia, S., Edwards, Y. J. K., Han, M. S., Cavanagh, J., Barrett, T., Kim, J. K., & Davis, R. J. (2016) · eLife · doi:10.7554/elife.17672 · Cited by 71 · see citing works
“Recent studies have identified changes in pre-mRNA splicing associated with autism ( Irimia et al., 2014 ; Weyn-Vanhentenryck et al., 2014 ), cardiac hypertrophy ( Mirtschink et al., 2015 ), embryonic stem cell re-programming ( Han et al., 2013a ), tumorigenesis ( Oltean and Bates, 2014 ; Hsu et…”
BackgroundDevelopmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms
Patowary, A., Zhang, P., Jops, C. T., Vuong, C. K., Ge, X., Hou, K., Kim, M., Gong, N. N., Margolis, M. P., Vo, D., et al. (2024) · Science · doi:10.1126/science.adh7688 · Cited by 87 · see citing works
Chen, Y., Chen, C.-Y., Mai, T., Chuang, C.-F., Chen, Y., Gupta, S. K., Yen, L., Wang, Y.-D., & Chuang, T. (2020) · Genome Research · doi:10.1101/gr.255463.119 · Cited by 67 · see citing works
“S9; Darnell et al. 2011; Mukherjee et al. 2011; Weyn-Vanhentenryck et al. 2014).”
Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival
Juan‐Mateu, J., Rech, T. H., Villate, O., Lizárraga-Mollinedo, E., Wendt, A., Turatsinze, J., Brondani, L. D. A., Nardelli, T. R., Nogueira, T. C., Esguerra, J. L. S., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.748335 · Cited by 70 · see citing works
“In line with the present findings, Rbfox1 targets in brain and muscle are enriched in genes involved in cytoskeleton organization and actin filament-based processes (28, 57).”
BackgroundResult
- Authors
- Weyn-Vanhentenryck, S. M., Mele, A., Yan, Q., Sun, S., Farny, N., Zhang, Z., Xue, C., Herre, M., Silver, P. A., Zhang, M. Q., Krainer, A. R., Darnell, R. B., & Zhang, C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Columbia University (US)
- Cold Spring Harbor Laboratory (US)
- Harvard University (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- The University of Texas at Dallas (US)
- Corresponding author
- Darnell, Robert B.
- Zhang, Chaolin
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 6
- Issue
- 6
- Pages
- 1139-1152
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3992522
- OpenAlex
- W2114893730
- Cited by
- 333
- References
- 63
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 18 · 2023: 20 · 2022: 24 · 2021: 25 · 2020: 30 · 2019: 32 · 2018: 43 · 2017: 35 · 2016: 38 · 2015: 24 · 2014: 10 · 2013: 1
- FWCI
- 14.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p30ca045508-35)
- National Human Genome Research Institute (R01HG001696, HG001696)
- National Institute of General Medical Sciences (GM74688, R37GM042699, R01GM074688, R00GM095713, GM 42699, R01GM042699)
- National Institute of Neurological Disorders and Stroke (R01NS081706, NS34389, NS81706, R01NS034389, R56NS034389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- RBFOX1, RBFOX2, NeuN, alternative splicing, RNA-binding proteins, HITS-CLIP, RNA-protein interactions, brain development, autism spectrum disorder, autism susceptibility genes, SHANK3, CACNA1C, TSC2, integrative modeling, mouse brain
- MeSH terms
- Animals, Autistic Disorder, Base Sequence, Brain, Exons, Humans, Models, Genetic, Models, Molecular, Molecular Sequence Data, Repressor Proteins, RNA, RNA-Binding Proteins, Alternative Splicing, Genetic Predisposition to Disease, Immunoprecipitation, Mice, Gene Regulatory Networks
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
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