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Determination of Trunk Neural Crest Cell Fate and Susceptibility to Splicing Perturbation by the DLC1-SF3B1-PHF5A splicing complex

ABSTRACT: How the ubiquitously expressed splicing factors specifically regulate neural crest (NC) development and enhance their vulnerability to splicing perturbations remain poorly understood. Here, we show that NC-specific DLC1, partnering with SF3B1-PHF5A splicing complex, are crucial for determining avian trunk NC cell fate by regulating the splicing of NC specifiers SOX9 and SNAI2 pre-mRNAs rather than their upstream regulators BMP4, WNT1, and PAX7. Mechanistically, SF3B1-PHF5A binds to the intronic branch site (BS) sequences of all factors, while DLC1 interacts with a specific motif near the BS sequences of SOX9 and SNAI2, thereby determining their functional specificity in NC specification. Moreover, DLC1 increases NC cells’ vulnerability to splicing modulator pladienolide B by reducing the binding capacity of the SF3B1-PHF5A splicing complex to the shorter length of both SOX9 intron 2 and SNAI2 intron 1, which possess weaker polypyrimidine tract 3’ of the BS sequence, resulting in intron retention and loss of NC progenitors. Conversely, somite specific SLU7-SF3B1-PHF5A splicing complex regulates SOX9 and SNAI2 expression and imparts resistance to PB. Our data reveal the cell-type specific splicing complexes with distinct vulnerabilities to PB, highlighting the critical role of the DLC1-SF3B1-PHF5A in determining trunk NC cell fate and enhancing its susceptibility to splicing perturbation.

ORGANISM(S): Gallus gallus

PROVIDER: GSE299465 | GEO | 2025/06/17

REPOSITORIES: GEO

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Determination of Trunk Neural Crest Cell Fate and Susceptibility to Splicing Perturbation by the DLC1-SF3B1-PHF5A splicing complex

Project description:How the ubiquitously expressed splicing factors specifically regulate neural crest (NC) development and enhance their vulnerability to splicing perturbations remain poorly understood. Here, we show that NC-specific DLC1, partnering with SF3B1-PHF5A splicing complex, are crucial for determining avian trunk NC cell fate by regulating the splicing of NC specifiers SOX9 and SNAI2 pre-mRNAs rather than their upstream regulators BMP4, WNT1, and PAX7. Mechanistically, SF3B1-PHF5A binds to the intronic branch site (BS) sequences of all factors, while DLC1 interacts with a specific motif near the BS sequences of SOX9 and SNAI2, thereby determining their functional specificity in NC specification. Moreover, DLC1 increases NC cells’ vulnerability to splicing modulator pladienolide B by reducing the binding capacity of the SF3B1-PHF5A splicing complex to the shorter length of both SOX9 intron 2 and SNAI2 intron 1, which possess weaker polypyrimidine tract 3’ of the BS sequence, resulting in intron retention and loss of NC progenitors. Conversely, somite specific SLU7-SF3B1-PHF5A splicing complex regulates SOX9 and SNAI2 expression and imparts resistance to PB. Our data reveal the cell-type specific splicing complexes with distinct vulnerabilities to PB, highlighting the critical role of the DLC1-SF3B1-PHF5A in determining trunk NC cell fate and enhancing its susceptibility to splicing perturbation.

2025-06-09 | PXD064804 |

Splicing Modulators Act at the Branch Point Adenosine Binding Pocket Defined by the PHF5A-SF3b Complex

Project description:Developing small-molecule splicing modulators represents a promising therapeutic approach for various diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that target SF3B1 in the SF3b subcomplex. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to these modulators, suggesting a common site of interaction. Whole-transcriptome RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but alters the action of splicing modulators from inducing intron-retention to exon-skipping. Relative intron strength to splicing inhibition correlates with the differential in GC content between adjacent introns and exons, leading to this differential global splicing pattern. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Structural analysis of the cryo-EM spliceosome Bact complex shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these splicing modulators, which interact with the aromatic side-chain of PHF5A-Y36. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these small-molecule splicing modulators, offering insights to modulate splicing.

2017-05-25 | GSE96917 | GEO

Overlapping roles of spliceosomal components SF3B1 and PHF5A in rice splicing regulation

Project description:The SF3B complex, a multiprotein component of the U2 snRNP of the spliceosome, mediates branch point selection and facilitates spliceosome assembly and activation. Several splicing modulators bind the SF3B1 and PHF5A subunits of the SF3B complex and globally inhibit splicing. Engineered mutant variants of SF3B1 and PHF5A conferred tolerance to splicing inhibitors with only minor effects on gene expression and AS.

2021-04-11 | GSE153234 | GEO

High-throughput mRNA-sequence of CCl4 injected mouse liver

Project description:RNA splicing is an essential step for expression of genes commonly altered in multiple liver diseases. However, how the spliceosomal components participate in the pathogenesis of acute liver failure (ALF) remains poorly defined. Here, we report that KH-type splicing regulatory protein (KSRP) which is downregulated in ALF, regulates RNA splicing in the liver through interacting with the Splicing factor 3b subunit 1 (SF3B1). Overexpression of KSRP resulted in marked amelioration of hepatic injury in vivo. Transcriptomic analysis reveals that KSRP depletion led to severe splicing defects in genes with significant intron retention. Such defects cause substantial loss of proliferation and apoptosis related genes such as EGFR, which further exaggerated liver injury. KSRP promotes RNA splicing of splicing related genes, including SF3B1, PHF5A, and SF3B4, indicating the existence of a positive feedback loop that regulates RNA splicing. Mechanistically, KSRP directly interacts with SF3B1 and enhances binding of SF3B1 to the branch sites located upstream of the exon. Overall, our findings demonstrate a novel mechanism by which KSPR protects against acute liver injury by promoting RNA splicing through interacting with the SF3B complex.

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High-throughput mRNA-sequence of KSRP knock down cells in HL7702 CELLS

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High-throughput sequencing of mouse liver mRNA after treatment with the mRNA splicing inhibitor Pladienolide B

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Determination of Trunk Neural Crest Cell Fate and Susceptibility to Splicing Perturbation by the DLC1-SF3B1-PHF5A splicing complex

Project description:Determination of Trunk Neural Crest Cell Fate and Susceptibility to Splicing Perturbation by the DLC1-SF3B1-PHF5A splicing complex

| PRJNA1274480 | ENA

Transcriptomic Characterization of PRP5 knockdown in HEK293T cells

Project description:Splicing abnormality has been observed in various types of SF3B1-mutated tumors. Aberrant usage of 3’SS has been established as the most frequent splicing defect and is attributed to altered BS selection. In this study, we examined whether reduced PRP5 expression would phenocopy the splicing defects of SF3B1 cancer mutations.

2022-10-01 | GSE185713 | GEO

CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1

Project description:RNA splicing, the process of intron removal from pre-mRNA, is essential for the regulation of gene expression. It is controlled by the spliceosome, a megadalton RNA-protein complex that assembles de novo on each pre-mRNA intron via an ordered assembly of intermediate complexes. Spliceosome activation is a major control step requiring dramatic protein and RNA rearrangements leading to a catalytically active complex. Splicing factor 3B subunit 1 (SF3B1) protein, a subunit of the U2 snRNP, is phosphorylated during spliceosome activation, but the responsible kinase has not been identified. Here we show that cyclin-dependent kinase 11 (CDK11) associates with SF3B1 and phosphorylates threonine residues at its N-terminus during spliceosome activation. The phosphorylation is important for association of SF3B1 with U5 and U6 snRNAs in spliceosome activated Bact complex and it can be blocked by OTS964, a potent and selective inhibitor of CDK11. CDK11 inhibition prevents spliceosomal transition from the precatalytic complex B to the activated complex Bact and leads to widespread intron retention and accumulation of non-functional spliceosomes on pre-mRNAs and chromatin. We characterize OTS964 as a quality chemical biology probe for CDK11 and demonstrate a central role of CDK11 in spliceosome assembly and splicing regulation.

2022-07-09 | MSV000089855 | MassIVE

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