Affinage

SRRM4

Serine/arginine repetitive matrix protein 4 · UniProt A7MD48

Length
611 aa
Mass
68.6 kDa
Annotated
2026-06-10
24 papers in source corpus 18 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SRRM4 (nSR100) is a vertebrate neural-specific RNA splicing factor that governs a program of neural microexon (3–27 nt) inclusion essential for nervous system development, with knockout disrupting neurite outgrowth, cortical layering, and axon guidance, and inclusion of a single Unc13b microexon sufficient to rescue neuritogenesis (PMID:25838543). Mechanistically, SRRM4 recognizes UGC motifs in the polypyrimidine tract immediately upstream of a regulated microexon (PMID:28106138, PMID:31559909), and its primary action is to accelerate co-transcriptional removal of the upstream intron before the downstream intron is synthesized, eliminating competition for the microexon's non-canonical downstream 5' splice site rather than directly stabilizing the microexon (PMID:42146467). Loss of SRRM4 in Bronx waltzer mice causes widespread exon skipping in sensory hair cells of transcripts encoding secretion and neurotransmission proteins, and minigene mutagenesis confirmed a cis motif required for SRRM4-dependent inclusion (PMID:23055939). Validated targets span protrudin (exon L, enhancing neurite outgrowth) (PMID:28106138), a neuronal TAF1 microexon generating a neuron-specific TFIID complex (PMID:31559909), and the REST gene, where SRRM4 generates a truncated REST4/sREST isoform lacking the transcriptional repressor domain to de-repress neuronal genes (PMID:27180064, PMID:23928058). Aberrant SRRM4 activity drives neuroendocrine transdifferentiation of prostate cancer through REST splicing—potentiated by androgen receptor inhibition and TP53 loss (PMID:27180064)—and through an additional program including SOX2-dependent pluripotency gene induction (PMID:30100395), anti-apoptotic Bif-1 isoform switching (PMID:29759485), and an NEPC-specific LSD1+8a isoform (PMID:32403054); ASO knockdown of SRRM4 or REST splice-switching oligonucleotides reduce cancer cell viability, establishing REST splicing as a key survival mechanism (PMID:36650528). De novo splice-donor variants in SRRM4 cause a neurodevelopmental disorder with dystonia and chorea by producing aberrant SRRM4 isoforms that alter downstream microexon splicing (PMID:41958152).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2012 High

    Established that SRRM4 is required in vivo for inclusion of specific alternative exons, defining it as a tissue-specific splicing activator acting through a discrete cis element.

    Evidence Positional cloning, transgenic rescue, and minigene mutagenesis in Bronx waltzer mice with sensory hair cell transcriptome analysis

    PMID:23055939

    Open questions at the time
    • Did not define the molecular nature of the cis motif at nucleotide resolution
    • Mechanism of how SRRM4 promotes inclusion not addressed
  2. 2013 Medium

    Linked SRRM4 to cancer by showing it directly splices REST to a repressor-deficient isoform in SCLC, embedded in MEK/ERK- and PI3K-regulated feedback control.

    Evidence siRNA knockdown and overexpression with RT-PCR splicing readout and pharmacological pathway inhibitors in SCLC cells

    PMID:23928058

    Open questions at the time
    • Single lab
    • Did not establish functional consequence of REST splicing on tumor phenotype
  3. 2015 High

    Defined SRRM4 as the master regulator of neural microexons whose loss causes specific neurodevelopmental defects, with single-microexon rescue proving microexons are functionally causal.

    Evidence Mouse knockout, transcriptome-wide splicing analysis, and Unc13b microexon rescue in primary neurons

    PMID:25838543

    Open questions at the time
    • Did not resolve the biochemical mechanism of microexon recognition
    • Direct RNA binding not mapped
  4. 2015 Medium

    Connected SRRM4-driven REST4 splicing to the neuroendocrine phenotype of castration-resistant prostate cancer in patient-derived models.

    Evidence REST splicing PCR, whole-genome microarray, and IHC across LuCaP xenografts

    PMID:26071481

    Open questions at the time
    • Correlative only; no direct SRRM4 manipulation
    • Causality not established in this study
  5. 2016 High

    Demonstrated causally that SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma via REST splicing, contextualized by AR inhibition and TP53 loss.

    Evidence SRRM4 overexpression in prostate cell lines, xenograft models, and biochemical validation

    PMID:27180064

    Open questions at the time
    • Full set of effector splicing targets beyond REST not enumerated
    • Mechanism of synergy with AR/TP53 not resolved
  6. 2017 High

    Provided the first nucleotide-level mechanism showing SRRM4 recognizes an upstream UGC motif to promote a functional protrudin microexon controlling neurite outgrowth.

    Evidence Depletion/overexpression, minigene assay with UGC deletion, and neurite outgrowth assays in Neuro2A and ES cells

    PMID:28106138

    Open questions at the time
    • Whether UGC recognition is direct binding not biochemically demonstrated
    • Generalizability of the UGC rule to all targets unaddressed
  7. 2018 Medium

    Expanded the oncogenic SRRM4 program beyond REST to SOX2-dependent pluripotency induction and anti-apoptotic Bif-1 isoform switching.

    Evidence Lentiviral SRRM4 overexpression with SOX2 knockdown epistasis and apoptosis assays in NEPC models and xenografts

    PMID:29759485 PMID:30100395

    Open questions at the time
    • Whether SOX2 induction is splicing-dependent unclear
    • Single lab for both findings
  8. 2019 Medium

    Generalized the UGC-polypyrimidine-tract recognition mechanism to TAF1, showing SRRM4 builds a neuron-specific TFIID complex via microexon inclusion.

    Evidence Reciprocal knockdown/overexpression with isoform-specific probes and UGC motif analysis in neuronal cells

    PMID:31559909

    Open questions at the time
    • Functional consequence of neuronal TFIID not characterized
    • Single lab
  9. 2020 Medium

    Identified the NEPC-specific LSD1+8a isoform as an SRRM4 splicing product that co-regulates a distinct gene set, broadening the chromatin-level effects of SRRM4.

    Evidence SRRM4-overexpressing cell lines, RT-PCR splicing assays, and clinical xenograft/biopsy validation

    PMID:32403054

    Open questions at the time
    • Mechanism by which LSD1+8a redirects target specificity not resolved
    • Single lab
  10. 2021 Medium

    Reframed SRRM4 as a pan-cancer proliferation brake whose silencing permits mitotic gene expression, and distinguished SRRM3 as the dominant REST splicing factor in SRRM4-negative early NE differentiation.

    Evidence Dose-response SRRM4 overexpression with xenograft growth and pan-cancer transcriptomics; SRRM3 splicing assays in CRPC models

    PMID:33621242 PMID:34312180

    Open questions at the time
    • Mechanistic basis of proliferation suppression unclear
    • Redundancy/division of labor between SRRM3 and SRRM4 incompletely mapped
  11. 2023 Medium

    Validated REST splicing as a therapeutically actionable downstream node by showing SRRM4 ASO knockdown and REST splice-switching oligonucleotides reduce cancer cell viability.

    Evidence Gapmer ASO knockdown, splice-switching oligonucleotide, FLAG-REST reconstitution, and viability assays in SCLC and prostate cancer cells

    PMID:36650528

    Open questions at the time
    • In vivo therapeutic efficacy not established
    • Single lab
  12. 2024 Medium

    Established a Mendelian disease link, showing de novo SRRM4 splice-donor variants disrupt downstream microexon splicing and cause a neurodevelopmental movement disorder.

    Evidence Exome/genome sequencing with short- and long-read RNA-seq in patient fibroblasts with CRISPR-induced SRRM4 expression

    PMID:41958152

    Open questions at the time
    • Single study cohort
    • Causal mechanism linking specific microexon changes to neurological phenotype not resolved
  13. 2024 Medium

    Showed microexon sensitivity to SRRM4 is determined largely by core splice-site architecture conserved across vertebrates, not by SRRM4 binding alone.

    Evidence Massively parallel splicing assay of 28,535 variants with computational modeling (preprint)

    PMID:bio_10.1101_2024.09.17.613571

    Open questions at the time
    • Preprint, not peer-reviewed
    • Single lab
  14. 2026 Medium

    Resolved the kinetic mechanism: SRRM4 accelerates upstream intron removal co-transcriptionally to eliminate competition for the microexon's weak downstream 5' splice site, rather than directly stabilizing the microexon.

    Evidence Nascent RNA sequencing and 5' splice site mutagenesis in neuronal cells (preprint)

    PMID:42146467

    Open questions at the time
    • Preprint, single lab
    • Direct biochemical demonstration of SRRM4 binding to the spliceosome not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SRRM4 physically engages the spliceosome and its co-factors to accelerate upstream intron removal, and the structural basis of UGC recognition, remain undefined.
  • No structure of SRRM4 bound to RNA or spliceosome
  • Direct RNA-binding biochemistry not established
  • Full spliceosomal co-factor set incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1266738 Developmental Biology 2
Partners
PRPF40A

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 SRRM4/nSR100 knockout in mice disrupts alternative splicing of neural microexons (3–27 nt), causing shifts to non-neural splicing patterns, and impairs neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Inclusion of a 6-nt nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. Mouse knockout, whole-transcriptome splicing analysis, rescue experiment with Unc13b microexon in primary neurons Genes & development High 25838543
2012 A loss-of-function mutation in Srrm4 in Bronx waltzer mice causes widespread alternative exon skipping in sensory hair cells of the inner ear; minigene experiments confirmed that skipped exons require Srrm4 for inclusion. The affected transcripts share a novel cis motif necessary for Srrm4-dependent splicing. Affected transcripts encode proteins in secretion and neurotransmission pathways. Positional cloning, transgenic rescue, transcriptome-wide splicing analysis, minigene assay with mutagenesis of cis motif PLoS genetics High 23055939
2016 SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma cells; one key target is the REST gene, where SRRM4 promotes alternative splicing to generate a REST isoform lacking the transcriptional repressor domain. This effect is exacerbated by androgen receptor pathway inhibition and enhanced by TP53 loss of function. RNA-seq/bioinformatics (COMPAS), in vitro overexpression of SRRM4 in prostate cell lines, in vivo xenograft models, biochemical validation European urology High 27180064
2015 SRRM4 expression in neuroendocrine LuCaP xenografts correlates with a splice variant of REST (REST4) that lacks the transcriptional repressor domain, suggesting SRRM4-mediated REST splicing promotes the neuroendocrine phenotype in castration-resistant prostate cancer. PCR-based REST splicing verification, whole-genome microarray analysis, IHC on patient-derived xenografts Clinical cancer research Medium 26071481
2013 nSR100/SRRM4 is highly expressed in SCLC cells and directly mediates alternative splicing of REST to generate the sREST isoform. Knockdown of nSR100 by siRNA represses sREST and reciprocally increases full-length REST. The MEK/ERK pathway positively regulates nSR100 expression, and PI3K/Akt/mTOR inhibition also induces nSR100 expression. REST contains an RE1 element that represses nSR100, forming a feedback loop. siRNA knockdown, overexpression, RT-PCR splicing assay, pharmacological inhibitors (LY294002, U0126) Molecular cancer research Medium 23928058
2017 SRRM4 promotes neuron-specific inclusion of a microexon (exon L, encoding 7 amino acids) in protrudin (Zfyve27) pre-mRNA by recognizing a UGC motif immediately upstream of exon L. The resulting long isoform (protrudin-L) promotes neurite outgrowth more effectively than the short isoform (protrudin-S). Deletion of exon L inhibited neurite outgrowth in Neuro2A and embryonic stem cells. SRRM4 depletion and overexpression in neuronal cells, minigene assay, UGC motif deletion mutagenesis, neurite outgrowth assay Scientific reports High 28106138
2019 SRRM4/nSR100 directly promotes inclusion of the 6-nt microexon 34' in TAF1 mRNA through recognition of UGC sequences in the polypyrimidine tract upstream of the regulated microexon, generating a neuronal-specific TFIID complex. Knockdown and ectopic expression experiments confirmed SRRM4 is both necessary and sufficient for microexon 34' inclusion. SRRM4 knockdown and ectopic expression in neuronal cells, isoform-specific RNA probes and antibodies, UGC motif analysis RNA biology Medium 31559909
2018 SRRM4 drives NEPC progression in part via induction of a pluripotency gene network including SOX2. SRRM4 overexpression enhances SOX2 expression in a time- and dose-dependent manner, and RNA depletion of SOX2 compromises SRRM4-mediated stimulation of pluripotency genes, placing SOX2 downstream of SRRM4. Lentiviral SRRM4 overexpression, qPCR, immunoblotting, siRNA knockdown of SOX2, xenograft models, whole transcriptome analysis (AmpliSeq) EBioMedicine Medium 30100395
2018 SRRM4 promotes alternative RNA splicing of the Bif-1 gene from the pro-apoptotic isoform Bif-1a to the neural-specific anti-apoptotic isoforms Bif-1b and Bif-1c in neuroendocrine prostate cancer. This splicing switch confers resistance to apoptosis under camptothecin and UV treatment. Whole transcriptome comparison, SRRM4 overexpression cell models, functional apoptosis assays (camptothecin, UV irradiation), correlation in patient xenografts EBioMedicine Medium 29759485
2020 SRRM4 mediates alternative splicing of LSD1 (KDM1A) to include exon 8a (LSD1+8a) in neuroendocrine prostate cancer. LSD1+8a and SRRM4 co-regulate target genes distinct from those regulated by canonical LSD1. LSD1+8a expression is exclusive to NEPC and significantly correlated with SRRM4 levels. SRRM4-overexpressing cell lines, RT-PCR splicing assay, gene expression analysis, patient-derived xenografts and metastatic biopsies Neoplasia Medium 32403054
2021 SRRM4 overexpression in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model, inducing neural-like expression and splicing patterns. SRRM4 is the most consistently silenced splicing factor across tumor types, and its silencing correlates with increased mitotic gene expression, establishing SRRM4 as a proliferation brake. SRRM4 overexpression in cancer cell lines (dose-response), mouse xenograft tumor growth assay, transcriptome analysis PLoS biology Medium 33621242
2021 SRRM3 (not only SRRM4) can induce alternative splicing of REST to REST4 in CRPC cell lines and drive neuroendocrine differentiation. SRRM3 is expressed in REST4-positive, SRRM4-negative cases, identifying it as the principal REST splicing factor in early neuroendocrine differentiation where SRRM4 is absent. SRRM3 expression in cell lines, patient-derived xenografts, mCRPC specimens; SRRM3-induced REST splicing assay Cancer research Medium 34312180
2023 SRRM4 antisense oligonucleotide (ASO) knockdown reduces cell viability of SCLC and prostate cancer cells by modifying alternative splicing of REST (shifting toward full-length REST), and REST splice-switching oligonucleotides phenocopy this effect. This establishes REST splicing as a key downstream mechanism of SRRM4-dependent cancer cell survival. Gapmer ASO knockdown, RT-PCR splicing assay, FLAG-REST reconstitution, splice-switching oligonucleotide, cell viability assay Cancer cell international Medium 36650528
2024 De novo splice-donor-site variants in SRRM4 (c.464+2T>C, c.464+2T>A) produce aberrant SRRM4 mRNA isoforms and alter splicing of known SRRM4 downstream substrates (including the AP1S2 microexon) in patient fibroblasts with induced SRRM4 expression, causing a neurodevelopmental disorder with dystonia and chorea. Exome/genome sequencing, short-read and long-read RNA-seq in patient fibroblasts with CRISPR-induced SRRM4 expression, transcriptomic analysis of downstream microexon splicing Movement disorders Medium 41958152
2023 In Bronx waltzer (bv) mice carrying an Srrm4 mutation, GABAergic postsynaptic transmission is abnormal and GABAA receptor blockage reveals increased cortical excitability; however, Srrm4 is expressed in pyramidal neurons (not interneurons), and Kcc2 (a downstream Srrm4 target regulating chloride flux) shows no gross expression change, suggesting a postsynaptic rather than interneuron-intrinsic mechanism for the anxiety phenotype. In situ hybridization for Srrm4 in cortex, electrophysiology, pharmacological GABAA receptor blockade, Kcc2 expression analysis in bv/bv mice IBRO neuroscience reports Low 38229888
2025 Loss of TDP-43 unmasks a binding site for SRRM4 within intron 2 of G3BP1 in neurons, enabling SRRM4-dependent inclusion of a cryptic exon. The resulting CRYPTIC G3BP1 protein (10 extra amino acids in the NTF2L domain) acts as a dominant negative and disrupts stress granule dynamics, linking TDP-43 pathology to SRRM4 activity in ALS/FTD. iPSC-derived neurons, multi-omics ALS/FTD patient data, TDP-43 depletion, RNA binding site analysis, stress granule functional assay bioRxivpreprint Low 42146467
2026 Co-transcriptional splicing analysis shows that SRRM4-dependent microexon inclusion occurs by rapid removal of the upstream intron before the downstream intron is synthesized, eliminating competition for the microexon's non-canonical downstream 5' splice site. Strengthening this 5' splice site promoted constitutive microexon inclusion independently of SRRM4, demonstrating that SRRM4's primary role is to accelerate upstream intron removal rather than directly stabilize the microexon. Nascent RNA sequencing in neuronal cells, 5' splice site mutagenesis, SRRM4-dependent microexon co-transcriptional splicing kinetics analysis bioRxivpreprint Medium 42146467
2024 Massively parallel splicing assays of 28,535 variants show that microexon sensitivity to SRRM4 is conserved across vertebrates and is largely determined by core splicing architecture (interplay between upstream 3' splice site strength, microexon length, and downstream 5' splice site), not only by SRRM4 binding per se. Massively parallel splicing assay (MPSA), computational modeling, comparison across vertebrate sequences bioRxivpreprint Medium bio_10.1101_2024.09.17.613571
2024 PRPF40A (U1 spliceosome component) co-regulates microexon splicing with SRRM4 in mouse neuroblastoma cells. SRRM4-dependent microexons show a size threshold (~30 nt) while PRPF40A-dependence is graded, indicating distinct but overlapping mechanisms for microexon recognition. PRPF40A and SRRM4 knockdown in mouse neuroblastoma cells, transcriptome-wide splicing analysis bioRxivpreprint Low bio_10.1101_2024.09.26.615222

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition. European urology 150 27180064
2015 SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 148 26071481
2015 Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. Genes & development 123 25838543
2012 A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse. PLoS genetics 80 23055939
2018 A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network. EBioMedicine 45 30100395
2017 SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth. Scientific reports 39 28106138
2021 RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer. Cancer research 34 34312180
2019 A gapmer antisense oligonucleotide targeting SRRM4 is a novel therapeutic medicine for lung cancer. Scientific reports 31 31110284
2013 The small cell lung cancer-specific isoform of RE1-silencing transcription factor (REST) is regulated by neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100). Molecular cancer research : MCR 29 23928058
2021 Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers. PLoS biology 26 33621242
2020 Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4. Neoplasia (New York, N.Y.) 26 32403054
2019 Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100. RNA biology 22 31559909
2017 Establishment of a neuroendocrine prostate cancer model driven by the RNA splicing factor SRRM4. Oncotarget 22 28978002
2022 CircRNA SRRM4 affects glucose metabolism by regulating PKM alternative splicing via SRSF3 deubiquitination in epilepsy. Neuropathology and applied neurobiology 19 36168302
2018 Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer. EBioMedicine 19 29759485
2020 SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion. Cells 18 33207694
2023 An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells. Cancer cell international 13 36650528
2024 SRRM4-mediated REST to REST4 dysregulation promotes tumor growth and neural adaptation in breast cancer leading to brain metastasis. Neuro-oncology 12 37716001
2025 Mutations in the microexon splicing regulator srrm4 have minor phenotypic effects on zebrafish neural development. G3 (Bethesda, Md.) 2 40053833
2023 Abnormality in GABAergic postsynaptic transmission associated with anxiety in Bronx waltzer mice with an Srrm4 mutation. IBRO neuroscience reports 1 38229888
2026 The castration-resistant prostate cancer-associated SNP rs11067228 facilitates neuroendocrine differentiation through an enhancer-mediated chromatin interaction with SRRM4. International journal of biological sciences 0 41608622
2026 Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4. Movement disorders : official journal of the Movement Disorder Society 0 41958152
2026 Efficient co-transcriptional splicing enforces rapid microexon definition and inclusion by SRRM4. bioRxiv : the preprint server for biology 0 42146467
2025 SRRM4 Knockout Helps the Human Mesenchymal Stem Cell Line to Penetrate Decellularized Cancellous Bone. Bioengineering (Basel, Switzerland) 0 41463596

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