Affinage

SF3B4

Splicing factor 3B subunit 4 · UniProt Q15427

Length
424 aa
Mass
44.4 kDa
Annotated
2026-06-10
55 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SF3B4 (SAP49/SF3b49) is a core RNA-binding subunit of the SF3b complex within the U2 snRNP that acts at the branchpoint recognition step of pre-mRNA splicing, where its loss produces predominantly exon skipping and intron retention across developmental and cancer transcript networks (PMID:39292749, PMID:40126363). The protein contains tandem RNA recognition motifs—RRM2 carries sequence-specific RNA-binding activity, while the canonically folded RRM1 docks onto SF3B145 (SF3B3) through a unique antiparallel helix-helix interaction that anchors SF3B4 within the SF3b complex (PMID:9163526, PMID:27862552). In vivo, SF3B4 governs neural crest cell survival, migration, and differentiation cell-autonomously, and its loss disrupts craniofacial cartilage formation, axial vertebral patterning through Hox-regulating chromatin remodeler splicing, and forebrain development (PMID:26874011, PMID:31900962, PMID:37167859, PMID:39292749, PMID:40126363, PMID:40047147); haploinsufficiency underlies the craniofacial defects modeled by Nager-syndrome mutant mRNAs that fail to rescue SF3B4 loss (PMID:26874011). Beyond canonical splicing, SF3B4 controls isoform switching of multiple cancer-relevant pre-mRNAs—generating high-activity GLS1 GAC, full-length hTERT, exon-2-containing CCND1, and functional RAD52, SPAG5, KAT2A, and KLF4 transcripts [PMID:29397868, PMID:35210412, PMID:35853859, PMID:35852380, PMID:38168564, PMID:41411906, PMID:bio_10.1101_2025.11.25.690515]—and exerts post-splicing control by stabilizing target mRNAs through 3'UTR binding (SREBF1, ENAH), promoting nuclear export of KLF16, and recruiting the NMD factors UPF1, MAGOH, and RNPS1 to drive p21 mRNA decay, thereby restraining senescence (PMID:35030977, PMID:36639679, PMID:39961431, PMID:42255207). Through these activities SF3B4 promotes proliferation and cell-cycle progression, with depletion causing G1/S arrest via p27/p21/p53 induction, in part through interaction with UBE4B (PMID:29397868, PMID:35996826).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1997 Medium

    Established that the SF3B4 ortholog is a genuine sequence-specific RNA-binding protein and localized that activity to a defined domain, framing it as a direct RNA-engaging splicing factor rather than a passive scaffold.

    Evidence In vitro RNA selection (SELEX) on C. elegans SAP49, with domain mapping to RRM2

    PMID:9163526

    Open questions at the time
    • RNA target identity in human SF3B4 not defined
    • single ortholog, single in vitro assay
  2. 1998 Medium

    Linked SF3B4 dynamics to spliceosomal progression, showing its binding changes at the catalytic transitions of splicing.

    Evidence UV cross-linking of SAP49 to retroviral pre-mRNA in a cell-free splicing system under spliceosomal stalling

    PMID:9614130

    Open questions at the time
    • mechanism of altered binding at step 2 not resolved
    • single substrate, single study
  3. 2016 High

    Resolved how SF3B4 is structurally integrated into the SF3b complex by solving its RRM1 fold and the molecular interface with SF3B145.

    Evidence NMR structure of human SF3B4 RRM1, chemical shift mapping, NOESY docking, GST pull-down with mutagenesis

    PMID:27862552

    Open questions at the time
    • functional consequence of RRM1-SF3B145 interaction for splicing not tested in vivo
    • RRM2 RNA-binding role not structurally addressed here
  4. 2016 High

    Demonstrated a direct developmental requirement for SF3B4 in neural crest specification and connected Nager-syndrome mutations to functional loss via rescue discrimination.

    Evidence Morpholino knockdown in Xenopus laevis with in situ hybridization and wild-type vs. mutant mRNA rescue

    PMID:26874011

    Open questions at the time
    • splicing targets mediating the phenotype not identified
    • morpholino specificity relies on rescue alone
  5. 2018 Medium

    Connected SF3B4 to cell-cycle control and tumor biology, identifying KLF4 mis-splicing as a route to p27/Slug dysregulation.

    Evidence siRNA knockdown and overexpression in liver cancer cells, RT-PCR splicing analysis, cell cycle profiling

    PMID:29397868

    Open questions at the time
    • direct SF3B4 binding to KLF4 pre-mRNA not shown
    • single cancer cell context
  6. 2018 Medium

    Identified upstream control of SF3B4 by miR-133b, framing SF3B4 levels as a regulated node in HCC.

    Evidence TargetScan prediction, miRNA mimic transfection, functional and xenograft assays

    PMID:30391496

    Open questions at the time
    • direct miRNA-SF3B4 binding inferred from prediction plus rescue
    • single lab
  7. 2020 High

    Established the in vivo requirement of Sf3b4 for axial skeletal patterning and forebrain development through a mammalian genetic model, with homozygous loss being lethal.

    Evidence CRISPR-Cas9 Sf3b4 knockout mice, phenotypic and histological analysis

    PMID:31900962

    Open questions at the time
    • molecular splicing targets not defined in this study
    • dosage-sensitivity mechanism unresolved
  8. 2020 Medium

    Added a layer of expression control by linking SRSF3 to SF3B4 mRNA stability.

    Evidence siRNA knockdown, RT-qPCR, western blotting, GFP-SF3B4 construct analysis in HCC

    PMID:32234894

    Open questions at the time
    • mRNA decay mechanism inferred not directly measured
    • single method, single lab
  9. 2022 Medium

    Defined a protein-level mechanism by which SF3B4 restrains p53, showing SF3B4-UBE4B interaction sustains p53 polyubiquitination and thereby proliferation.

    Evidence Reciprocal co-IP, double-knockdown epistasis, flow cytometry in A549 NSCLC cells

    PMID:35996826

    Open questions at the time
    • whether interaction is direct or splicing-independent unclear
    • single lab
  10. 2022 Medium

    Built a recurring paradigm of SF3B4-dependent productive splicing of oncogenic targets, here for RAD52 and SPAG5, where loss causes intron retention and PTC generation.

    Evidence 3'UTR luciferase, RNA-seq splicing analysis, knockdown and functional rescue in ovarian and cervical cancer cells

    PMID:35210412 PMID:35853859

    Open questions at the time
    • direct SF3B4 binding to these pre-mRNAs not always shown
    • single lab per target
  11. 2022 Medium

    Extended SF3B4 function beyond splicing into mRNA stabilization via 3'UTR binding, establishing a post-transcriptional regulatory mode (ENAH, GPAA1).

    Evidence RNA immunoprecipitation, actinomycin D decay assays, rescue functional assays in HCC

    PMID:35030977 PMID:35399327

    Open questions at the time
    • how a spliceosomal factor stabilizes cytoplasmic mRNA mechanistically unclear
    • GPAA1 link rests on single RIP plus rescue
  12. 2022 Medium

    Showed SF3B4 acts as a trans-acting splicing factor for hTERT via a defined intronic cis-element, coupling it to telomerase activity.

    Evidence RIP to the DR8 element, hTERT isoform RT-PCR, telomerase and telomere assays in NSCLC

    PMID:35852380

    Open questions at the time
    • structural basis of DR8 recognition unknown
    • single lab
  13. 2023 Medium

    Revealed an mRNA nuclear-export function for SF3B4, driving KLF16-Twist1-mediated EMT.

    Evidence Nuclear/cytoplasmic fractionation, ChIP for KLF16-Twist1, xenograft in ccRCC

    PMID:36639679

    Open questions at the time
    • export machinery SF3B4 engages not identified
    • directness of KLF16 mRNA binding not shown
  14. 2023 Medium

    Connected the in vivo skeletal phenotype to a splicing mechanism, implicating mis-splicing of chromatin remodelers that regulate Hox genes.

    Evidence Heterozygous Sf3b4 knockout mice, RNA-seq of somites, Hox in situ hybridization

    PMID:37167859

    Open questions at the time
    • causal chromatin-remodeler target not pinpointed
    • correlative transcriptomic placement
  15. 2023 Medium

    Broadened the in vivo phenotypic spectrum to retinal degeneration with a metabolic-pathway link, rescued by retinoic acid.

    Evidence sf3b4-null zebrafish, transcriptomics, retinoic acid rescue

    PMID:37263342

    Open questions at the time
    • splicing targets driving retinol metabolism changes not defined
    • single model
  16. 2024 High

    Provided the strongest mechanistic placement of SF3B4 at branchpoint-proximal splicing in vivo, tying neural crest and cardiac developmental gene networks to exon skipping.

    Evidence NCC-specific conditional knockout mice, RNA-seq, branchpoint sequence enrichment analysis

    PMID:39292749

    Open questions at the time
    • individual causal target exons among NCC genes not isolated
    • thymidine/branchpoint enrichment correlative
  17. 2024 Medium

    Added KAT2A isoform control to the SF3B4 splicing-target repertoire in lung adenocarcinoma.

    Evidence siRNA knockdown, alternative 5'-splice-site RT-PCR, functional rescue

    PMID:38168564

    Open questions at the time
    • direct pre-mRNA binding not demonstrated
    • single lab
  18. 2024 Medium

    Layered m6A-dependent stabilization (METTL3) and a downstream LSM4 partnership onto SF3B4 regulation in NSCLC.

    Evidence MeRIP, co-IP for SF3B4-LSM4, rescue, xenograft

    PMID:38462740

    Open questions at the time
    • functional meaning of SF3B4-LSM4 interaction unclear
    • single lab
  19. 2024 Medium

    Defined a direct role for SF3B4 in NMD-mediated p21 mRNA decay, explaining how its loss triggers p53-independent senescence.

    Evidence RIP for UPF1/MAGOH/RNPS1 association with p21 3'UTR, SA-β-Gal, knockdown

    PMID:39961431

    Open questions at the time
    • mechanism of NMD-factor recruitment to p21 3'UTR not structurally resolved
    • single lab
  20. 2024 Medium

    Identified transcriptional activators of SF3B4 (SETDB1; later EP300/CREBBP), establishing how SF3B4 overexpression arises in cancer.

    Evidence Dual-luciferase reporter and ChIP for H3K27ac at the SF3B4 promoter, knockdown functional assays

    PMID:38317200 PMID:40667544

    Open questions at the time
    • EP300/CREBBP link is Low-confidence with autophagy mediation inferred
    • promoter regulation contexts limited to specific cancers
  21. 2025 High

    Consolidated SF3B4 as cell-autonomously required for human neural crest survival and differentiation, with homozygous (not heterozygous) loss causing splicing-driven craniofacial defects across species.

    Evidence siRNA in hESC-derived neural crest; CRISPR sf3b4 knockout in Xenopus tropicalis with temporal RNA-seq

    PMID:40047147 PMID:40126363

    Open questions at the time
    • dosage threshold reconciling haploinsufficiency disease with homozygous-only phenotype unresolved
    • specific causal target exons not isolated
  22. 2025 Medium

    Expanded the SF3B4 oncogenic splicing program to metabolism (GLS1 GAC isoform), cell cycle (CCND1 exon 2 / CDK6 holoenzyme), and migration (Talin1-FAK), each functionally validated by isoform rescue or epistasis.

    Evidence Knockdown with isoform RT-PCR, enzymatic and metabolic flux assays, co-IP for CCND1-CDK6, double-knockdown epistasis (CCND1 study is preprint)

    PMID:41411906 PMID:41771579 PMID:bio_10.1101_2025.11.25.690515

    Open questions at the time
    • direct SF3B4 binding to each pre-mRNA not always shown
    • CCND1 mechanism rests on a single preprint
  23. 2025 Medium

    Identified SF3B4 as an essential HCC survival gene with transcriptome-wide direct targets and additional protein partners, reinforcing its splicing-centered oncogenic role.

    Evidence Genome-wide CRISPR screen in HCC organoids, iRIP-seq/long-read sequencing, co-IP (BUB1, SETD5), SREBF1 3'UTR binding by RIP/pull-down/reporter

    PMID:40234915 PMID:41071884 PMID:42255207

    Open questions at the time
    • functional significance of BUB1 and SETD5 interactions not mechanistically dissected
    • many of the 252 iRIP-seq targets unvalidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SF3B4's branchpoint-step splicing activity is mechanistically partitioned from its non-canonical roles in mRNA stabilization, nuclear export, and NMD-factor recruitment remains unresolved.
  • no structure of full-length SF3B4 on RNA within the spliceosome
  • recruitment determinants for export and NMD machinery unknown
  • the dosage logic linking haploinsufficiency disease to homozygous-only model phenotypes unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140098 catalytic activity, acting on RNA 5 GO:0045182 translation regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 3
Partners
BUB1LSM4MAGOHRNPS1SETD5SF3B3UBE4BUPF1
Complex memberships
SF3b complexU2 snRNP

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 C. elegans SAP49 (SF3B4 ortholog) possesses specific RNA-binding activity residing in its second RNA recognition motif (RRM2), as demonstrated by in vitro RNA selection (SELEX). In vitro RNA selection (SELEX), RNA-binding assay Journal of biochemistry Medium 9163526
1998 SAP49 (SF3B4) cross-linking to retroviral pre-mRNA is enhanced at step 2 of splicing when spliceosomal progression is blocked, indicating SF3B4 regulates late-stage spliceosome transitions; UV cross-linking showed altered SAP49 binding correlates with defective transit through the last spliceosomal complex. UV cross-linking of cellular splicing factors to viral RNA substrates, spliceosomal complex analysis in cell-free splicing system The Journal of biological chemistry Medium 9614130
2016 The solution structure of the first RRM domain (RRM1) of human SF3B4 (SF3b49) was solved by NMR, revealing a canonical β1-α1-β2-β3-α2-β4 fold. RRM1 interacts with residues 607-616 of SF3B145 via a unique antiparallel helix-helix interaction involving SF3B4 α1; this interaction was confirmed by GST pull-down and mutational analysis. NMR structure determination, chemical shift mapping, NOESY-based docking, GST pull-down with mutational analysis Protein science : a publication of the Protein Society High 27862552
2016 Knockdown of Sf3b4 in Xenopus laevis embryos reduces expression of neural crest specifier genes (sox10, snail2, twist) at the neural plate border and decreases neural crest cells in pharyngeal arches, resulting in hypoplasia of neural crest-derived craniofacial cartilages. This phenotype is rescued by wild-type human SF3B4 mRNA but not by Nager syndrome mutant mRNAs, establishing a direct requirement for SF3B4 function in neural crest development. Morpholino antisense knockdown in Xenopus laevis, in situ hybridization, mRNA rescue with wild-type vs. mutant SF3B4 Developmental biology High 26874011
2018 SF3B4 knockdown in liver cancer cells causes G1/S cell cycle arrest by upregulating p27Kip1 and suppressing cyclins and CDKs. SF3B4 overexpression causes aberrant splicing of the KLF4 tumor suppressor pre-mRNA, generating non-functional exon-skipped transcripts, which leads to transcriptional inactivation of p27Kip1 and activation of Slug (SNAI2). siRNA knockdown, western blotting, RT-PCR for alternative splicing, cell cycle analysis BMB reports Medium 29397868
2018 miR-133b directly targets and negatively regulates SF3B4 expression; miR-133b mimics partially abolish the effects of SF3B4 overexpression in HCC cells, and SF3B4 downstream molecules KLF4, KIP1, and SNAI2 are also modulated by miR-133b. TargetScan prediction, miRNA mimic transfection, western blotting, in vitro functional assays, xenograft mouse model EBioMedicine Medium 30391496
2020 Heterozygous knockout of Sf3b4 in mice causes homeotic posteriorization of vertebral morphology, flattened calvaria, and reduced cell proliferation in the forebrain, with homozygous deletion being embryonic lethal; this establishes Sf3b4 as required for axial skeletal patterning and forebrain development in vivo. CRISPR-Cas9 knockout mouse generation, phenotypic analysis of heterozygous and homozygous mutants, histology Developmental dynamics : an official publication of the American Association of Anatomists High 31900962
2020 SRSF3 knockdown significantly increases SF3B4 mRNA and protein levels in HCC cells, likely by retarding SF3B4 mRNA decay rates; the coding region of SF3B4 is involved in SRSF3-mediated regulation of SF3B4 expression. siRNA knockdown, RT-qPCR, western blotting, GFP-SF3B4 fusion construct analysis Anticancer research Medium 32234894
2022 SF3B4 knockdown in A549 NSCLC cells causes G0/G1 arrest, upregulation of p27, p21, and p53. SF3B4 interacts with UBE4B (ubiquitination factor E4B) by co-immunoprecipitation; SF3B4 depletion reduces UBE4B levels, which in turn reduces polyubiquitinated p53, leading to p53 accumulation and p21/p27 induction. Double knockdown of SF3B4 and p53 partially restores p21 expression and cell proliferation. siRNA knockdown, co-immunoprecipitation, western blotting, flow cytometry, double-knockdown epistasis Molecules and cells Medium 35996826
2022 miR-509-3p binds the 3'-UTR of SF3B4 mRNA to decrease its expression. SF3B4 promotes effective splicing of RAD52 pre-mRNA; SF3B4 loss causes intron 8 retention in RAD52 and generation of premature termination codons, reducing RAD52 protein. Decreased RAD52 partially counteracts the tumor-promoting effects of SF3B4 overexpression in ovarian cancer cells. 3'-UTR luciferase reporter assay, RNA-seq/alternative splicing analysis, siRNA knockdown, in vitro and in vivo functional assays Cell death & disease Medium 35210412
2022 SF3B4 promotes effective splicing of SPAG5 pre-mRNA in cervical cancer cells; SF3B4 knockdown causes intron retention and reduced maturation of SPAG5 pre-mRNA. SPAG5 deficiency impairs the oncogenic effects of SF3B4 overexpression. RNA-seq and alternative splicing analysis, siRNA knockdown, rescue experiments, in vitro and in vivo assays Cell death discovery Medium 35853859
2022 SF3B4 binds ENAH mRNA and stabilizes it (as shown by RIP and actinomycin D mRNA decay assay), leading to elevated ENAH protein which activates Notch signaling to promote HCC cell proliferation, invasion, and migration. RNA immunoprecipitation (RIP), actinomycin D mRNA stability assay, western blotting, functional cell assays Bioengineered Medium 35030977
2022 SF3B4 binds GPAA1 mRNA (confirmed by RNA immunoprecipitation), and SF3B4 overexpression reverses the effects of GPAA1 knockdown on HCC cell proliferation, migration, and invasion. RNA immunoprecipitation (RIP), siRNA knockdown, rescue overexpression, functional assays Oncology letters Low 35399327
2022 SF3B4 binds the DR8 intronic cis-element of hTERT pre-mRNA (demonstrated by RNA immunoprecipitation in NSCLC cells); SF3B4 knockdown reduces full-length hTERT splicing, telomerase activity, telomere length, and cancer cell growth, establishing SF3B4 as a trans-acting splicing factor for hTERT in lung cancer. RNA immunoprecipitation (RIP), RT-PCR for hTERT isoforms, telomerase activity assay, telomere length measurement, siRNA knockdown Molecular cancer research : MCR Medium 35852380
2023 SF3B4 promotes KLF16 mRNA export from nucleus to cytoplasm, thereby increasing KLF16 protein expression; elevated KLF16 directly binds the Twist1 promoter to activate its transcription, driving EMT and ccRCC progression. siRNA knockdown, nuclear/cytoplasmic fractionation, western blotting, chromatin immunoprecipitation (ChIP), functional migration/invasion assays, in vivo xenograft Cell death & disease Medium 36639679
2023 Heterozygous Sf3b4 knockout mice exhibit abnormal vertebral development accompanied by changes in Hox gene expression levels and patterns in somites; RNA-seq reveals widespread differential splicing events (predominantly exon skipping and intron retention) in chromatin remodeler transcripts known to regulate Hox expression, suggesting Sf3b4 controls Hox-dependent vertebral patterning via splicing of chromatin remodelers. CRISPR/Cas9 heterozygous knockout mice, RNA-seq of whole embryos and somites, in situ hybridization for Hox genes Differentiation; research in biological diversity Medium 37167859
2023 sf3b4-null zebrafish display retinitis pigmentosa-like phenotypes including retinal pigment epithelium defects and rod degeneration; transcriptome analysis reveals altered retinol metabolism and retinoic acid signaling, and retinoic acid supplementation rescues key cellular phenotypes in sf3b4-/- mutants. sf3b4-/- zebrafish mutants, transcriptome profiling, immunostaining, behavioral analysis, retinoic acid rescue The American journal of pathology Medium 37263342
2024 Conditional homozygous deletion of Sf3b4 in neural crest cells (NCC) in mice causes craniofacial and cardiac malformations; RNA-seq prior to morphological defects reveals exon skipping in NCC regulatory network genes and in histone modifier transcripts, with enrichment of thymidine bases around branch points of affected exons, suggesting Sf3b4 regulates branchpoint-proximal splicing of NCC and cardiac developmental genes. NCC-specific conditional knockout mice, RNA-seq, splicing analysis, branchpoint sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 39292749
2024 SF3B4 knockdown in LUAD cells causes an alternative 5'-splice site in KAT2A pre-mRNA, reducing KAT2A at RNA and protein levels; decreased KAT2A partially reverses SF3B4-dependent LUAD growth promotion, establishing the SF3B4/KAT2A axis in lung adenocarcinoma. siRNA knockdown, RT-PCR for alternative splicing, western blotting, rescue overexpression, functional proliferation/migration assays Scientific reports Medium 38168564
2024 METTL3 promotes SF3B4 mRNA stability through m6A modification (confirmed by MeRIP assay); SF3B4 interacts with LSM4 (confirmed by co-IP); SF3B4 depletion suppresses NSCLC cell functions that are rescued by LSM4 overexpression, placing SF3B4 upstream of LSM4 in a METTL3-SF3B4-LSM4 regulatory axis. MeRIP (m6A RIP), co-immunoprecipitation, siRNA knockdown, rescue overexpression, xenograft mouse model Thoracic cancer Medium 38462740
2024 SF3B4 deficiency leads to dissociation of NMD factors UPF1, MAGOH, and RNPS1 from the 3'UTR of p21 mRNA, thereby stabilizing p21 mRNA and inducing senescence via p53-independent p21 upregulation; SF3B4 recruits these NMD factors to facilitate p21 mRNA decay. siRNA knockdown, SA-β-Gal staining, RT-qPCR, western blotting, RNA immunoprecipitation for NMD factor-mRNA association Cancer letters Medium 39961431
2024 SETDB1 acts as a transcription factor that binds the SF3B4 promoter (confirmed by dual-luciferase reporter assay) to activate SF3B4 expression; SF3B4 knockdown impairs SETDB1-driven ovarian cancer cell proliferation and motility. Cistrome DB analysis, dual-luciferase reporter assay, siRNA knockdown, functional cell assays Journal of ovarian research Medium 38317200
2025 Homozygous deletion of sf3b4 in Xenopus tropicalis causes increased exon-skipping events followed by transcriptional changes affecting cranial neural crest cell migration and survival; loss of one sf3b4 copy is largely inconsequential, but homozygous loss causes major splicing defects disrupting NC-derived craniofacial cartilage. CRISPR/Cas9 sf3b4 knockout in Xenopus tropicalis, temporal RNA-seq, phenotypic characterization Disease models & mechanisms High 40126363
2025 SF3B4 siRNA knockdown in human embryonic stem cell-derived neural crest differentiation reduces neural crest gene expression, increases apoptosis, and causes premature neuronal differentiation, establishing a cell-autonomous requirement for SF3B4 in human neural crest cell survival, maintenance, and differentiation. siRNA knockdown in hESC-derived neural crest differentiation, qRT-PCR for NC markers, apoptosis assays Developmental dynamics : an official publication of the American Association of Anatomists Medium 40047147
2025 SF3B4 interacts with BUB1 (checkpoint protein) and regulates cancer cell mitosis and proliferation in HCC; identified by genome-wide CRISPR KO screening in patient-derived HCC organoids as a top essential survival gene. Genome-wide CRISPR knockout screen in HCC organoids, RNA immunoprecipitation-seq, long-read isoform sequencing, RNA-seq, hydrodynamic tail vein injection HCC model Science advances Medium 41071884
2025 SF3B4 regulates alternative splicing of GLS1 pre-mRNA, preferentially promoting production of the high-activity GAC isoform over the KGA isoform; SF3B4 inhibition reduces GAC expression, decreases GLS enzymatic activity, impairs glutaminolysis, and suppresses glutamine-driven mitochondrial respiration in HCC cells. siRNA/shRNA knockdown, RT-PCR for GLS1 isoforms, GLS enzymatic activity assay, metabolic flux analysis, functional cell assays Biochemical and biophysical research communications Medium 41411906
2025 SF3B4 directly binds the 3'UTR of SREBF1 mRNA (confirmed by RIP, RNA pull-down, and luciferase reporter), enhancing SREBF1 mRNA stability; SREBF1 overexpression partially rescues malignant phenotypes suppressed by SF3B4 knockdown in HCC. RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assay, mRNA stability assay, Oxford Nanopore transcriptome sequencing, xenograft model Frontiers in oncology Medium 42255207
2025 EP300 and CREBBP activate SF3B4 expression by promoting H3K27ac modification on the SF3B4 promoter; SF3B4 knockdown-mediated inhibition of CRC cell proliferation is counteracted by enhanced autophagy. ChIP for H3K27ac at SF3B4 promoter, siRNA knockdown, autophagy assays, functional proliferation assays American journal of cancer research Low 40667544
2025 SF3B4 promotes melanoma cell migration through splicing-dependent regulation of Talin1; SF3B4 knockdown reduces Talin1 mRNA and protein levels, causes Talin1 intron retention, and reduces FAK phosphorylation; combined SF3B4+Talin1 knockdown shows no additive migration defect, placing them in the same pathway. siRNA knockdown, RT-qPCR, western blotting for Talin1 and phospho-FAK, wound healing and transwell migration assays, double knockdown epistasis Cancer genomics & proteomics Medium 41771579
2025 SF3B4 loss triggers skipping of exon 2 in CCND1 pre-mRNA, preventing formation of a CCND1-CDK6 holoenzyme complex and blocking the G1-S transition; rescue with a CCND1 isoform containing the skipped exon restores both CDK6 complex formation and cell proliferation. CRISPore-seq (CRISPR perturbation + long-read single-cell transcriptomics), co-immunoprecipitation for CCND1-CDK6 complex, isoform rescue experiment bioRxivpreprint Medium bio_10.1101_2025.11.25.690515
2025 SF3B4 depletion upregulates natural NMD-targeted mRNA isoforms; among spliceosome components tested, SF3B4 (along with AQR, SF3B1, and CDC40) may have a more direct role in NMD beyond indirect effects from widespread splicing disruption. Analysis of publicly available RNA-seq datasets from cells depleted of 18 spliceosome components (K562 and HepG2) bioRxivpreprint Low bio_10.1101_2024.12.27.630533
2025 SF3B4 regulates HCC cell proliferation and apoptosis through alternative splicing; iRIP-seq identifies 252 direct RNA targets; SF3B4 may bind TRIM28 mRNA to modulate its expression and interact with SETD5 to influence pre-mRNA alternative splicing. iRIP-seq, RNA-seq after SF3B4 knockdown, co-immunoprecipitation Journal of translational medicine Medium 40234915

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. American journal of human genetics 163 22541558
2013 Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clinical genetics 64 24003905
2016 Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome. Developmental biology 63 26874011
2018 SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma. EBioMedicine 46 30391496
2018 SF3B4 as an early-stage diagnostic marker and driver of hepatocellular carcinoma. BMB reports 33 29397868
2020 SF3b4: A Versatile Player in Eukaryotic Cells. Frontiers in cell and developmental biology 28 32083075
2022 SF3B4 promotes ovarian cancer progression by regulating alternative splicing of RAD52. Cell death & disease 26 35210412
2023 SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm. Cell death & disease 23 36639679
2020 SF3B4 Plays an Oncogenic Role in Esophageal Squamous Cell Carcinoma. Anticancer research 22 32366446
2022 Enabled homolog (ENAH) regulated by RNA binding protein splicing factor 3b subunit 4 (SF3B4) exacerbates the proliferation, invasion and migration of hepatocellular carcinoma cells via Notch signaling pathway. Bioengineered 20 35030977
2022 The splicing factor SF3B4 drives proliferation and invasion in cervical cancer by regulating SPAG5. Cell death discovery 20 35853859
2017 SF3B4 is decreased in pancreatic cancer and inhibits the growth and migration of cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 28351319
2016 A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. European journal of human genetics : EJHG 20 27966544
2014 Rodriguez syndrome with SF3B4 mutation: a severe form of Nager syndrome? American journal of medical genetics. Part A 20 24715698
2023 Dysregulation of Spliceosomes Complex Induces Retinitis Pigmentosa-Like Characteristics in sf3b4-Depleted Zebrafish. The American journal of pathology 18 37263342
2020 Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse. Developmental dynamics : an official publication of the American Association of Anatomists 18 31900962
1998 Role of the constitutive splicing factors U2AF65 and SAP49 in suboptimal RNA splicing of novel retroviral mutants. The Journal of biological chemistry 16 9614130
2015 Prenatal diagnosis of Nager syndrome in a 12-week-old fetus with a whole gene deletion of SF3B4 by chromosomal microarray. European journal of medical genetics 15 26679067
2024 Etiology of craniofacial and cardiac malformations in a mouse model of SF3B4-related syndromes. Proceedings of the National Academy of Sciences of the United States of America 14 39292749
2022 SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression. Molecules and cells 13 35996826
2014 A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel SF3B4 Mutation. Molecular syndromology 13 25337072
1997 Polycistronic expression and RNA-binding specificity of the C. elegans homologue of the spliceosome-associated protein SAP49. Journal of biochemistry 12 9163526
2022 SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 11 35331022
2016 Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene. American journal of medical genetics. Part A 11 27642715
2023 Sf3b4 regulates chromatin remodeler splicing and Hox expression. Differentiation; research in biological diversity 10 37167859
2020 Second-trimester prenatal diagnosis of Nager syndrome with a deletion including SF3B4 detected by chromosomal microarray. Clinical case reports 9 32185046
2021 Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4-related disease. American journal of medical genetics. Part A 8 33559401
2020 SRSF3 Depletion Leads to an Increase in SF3B4 Expression in SNU-368 HCC Cells. Anticancer research 8 32234894
2024 SF3B4 downregulation restrains lung adenocarcinoma tumorigenesis via 5' alternative splicing of KAT2A. Scientific reports 7 38168564
2024 METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression. Thoracic cancer 7 38462740
2024 Transcriptomic analysis reveals mitochondrial dysfunction in the pathogenesis of Nager syndrome in sf3b4-depleted zebrafish. Biochimica et biophysica acta. Molecular basis of disease 7 38508476
2021 The Role of Splicing Factor SF3B4 in Congenital Diseases and Tumors. Discovery medicine 7 35220998
2024 Transcriptome alterations in sf3b4-depleted zebrafish: Insights into cataract formation in retinitis pigmentosa model. Experimental eye research 6 38311285
2024 SETDB1 promotes progression through upregulation of SF3B4 expression and regulates the immunity in ovarian cancer. Journal of ovarian research 6 38317200
2024 SF3B4 Regulates Cellular Senescence and Suppresses Therapy-induced Senescence of Cancer Cells. Cancer genomics & proteomics 6 39467623
2022 GPAA1 promotes the proliferation, invasion and migration of hepatocellular carcinoma cells by binding to RNA-binding protein SF3B4. Oncology letters 6 35399327
2016 Solution structure of the first RNA recognition motif domain of human spliceosomal protein SF3b49 and its mode of interaction with a SF3b145 fragment. Protein science : a publication of the Protein Society 6 27862552
2025 Splicing factor SF3B4 acts as a switch in cancer cell senescence by regulating p21 mRNA stability. Cancer letters 5 39961431
2025 Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival. Disease models & mechanisms 5 40126363
2022 Intronic Cis-Element DR8 in hTERT Is Bound by Splicing Factor SF3B4 and Regulates hTERT Splicing in Non-Small Cell Lung Cancer. Molecular cancer research : MCR 5 35852380
2025 Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation. Developmental dynamics : an official publication of the American Association of Anatomists 4 40047147
2025 SF3B4 regulates proliferation and apoptosis in hepatocellular carcinoma via alternative splicing and interaction with TRIM28 and SETD5. Journal of translational medicine 4 40234915
2025 Pan-cancer oncogenic properties and therapeutic potential of SF3B4. Cancer gene therapy 3 40394232
2024 Sf3b4 mutation in Xenopus tropicalis causes RNA splicing defects followed by massive gene dysregulation that disrupt cranial neural crest development. bioRxiv : the preprint server for biology 3 38352410
2025 Splicing factor 3b subunit 4 (SF3b4) is mediated by EP300 and CREBBP to promote colorectal cancer (CRC) proliferation by enhancing autophagy. American journal of cancer research 2 40667544
2025 Genome-wide CRISPR screen identifies splicing factor SF3B4 in driving hepatocellular carcinoma. Science advances 2 41071884
2024 Human stem cell model of neural crest cell differentiation reveals a requirement of SF3B4 in survival, maintenance, and differentiation. bioRxiv : the preprint server for biology 1 38328054
2026 Splicing Factor SF3B4 Suppresses Pancreatic Cancer Growth and Migration by Inhibiting Autophagy. Anticancer research 0 41617440
2026 Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination. WIREs mechanisms of disease 0 41667381
2026 Single-cell RNA sequencing combined with single-cell genome-wide association study identifies SF3B4 as a hub gene in hepatocellular carcinoma progression. Discover oncology 0 41689695
2026 Splicing Factor SF3B4 Promotes Melanoma Migration via Splicing-dependent Regulation of Talin1. Cancer genomics & proteomics 0 41771579
2026 SF3B4-QKI splicing complex generates circ-FNDC3B and mediates breast cancer inhibition. Molecular cancer research : MCR 0 41837881
2026 SF3B4 stabilizes SREBF1 via 3'UTR binding to drive hepatocellular carcinoma progression. Frontiers in oncology 0 42255207
2025 Splicing factor SF3B4 promotes mitochondrial glutamine metabolism in hepatocellular carcinoma by regulating GLS1 isoform switching. Biochemical and biophysical research communications 0 41411906
2025 Likely Pathogenic/Pathogenic Variants in the Spliceosome Complex Genes SNRNP200, SF3B1, SF3B2, and SF3B4 Implicated in Nonsyndromic Orofacial Cleft. Human mutation 0 41427026

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