{"gene":"SRRM4","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2015,"finding":"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.","method":"Mouse knockout, whole-transcriptome splicing analysis, rescue experiment with Unc13b microexon in primary neurons","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — loss-of-function mouse model with defined cellular phenotypes, transcriptome-wide splicing analysis, and single-microexon rescue experiment providing orthogonal mechanistic validation","pmids":["25838543"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Positional cloning, transgenic rescue, transcriptome-wide splicing analysis, minigene assay with mutagenesis of cis motif","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — positional cloning, transgenic rescue, minigene assay, and mutagenesis in one study, replicated by the Bronx waltzer phenotype","pmids":["23055939"],"is_preprint":false},{"year":2016,"finding":"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.","method":"RNA-seq/bioinformatics (COMPAS), in vitro overexpression of SRRM4 in prostate cell lines, in vivo xenograft models, biochemical validation","journal":"European urology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo evidence across multiple models with specific mechanistic target (REST splicing), independently corroborated by other labs","pmids":["27180064"],"is_preprint":false},{"year":2015,"finding":"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.","method":"PCR-based REST splicing verification, whole-genome microarray analysis, IHC on patient-derived xenografts","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlative splicing PCR and arrays across multiple xenograft models, but no direct manipulation of SRRM4 in this study","pmids":["26071481"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown, overexpression, RT-PCR splicing assay, pharmacological inhibitors (LY294002, U0126)","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown + overexpression with defined splicing readout, pharmacological pathway probing; single lab","pmids":["23928058"],"is_preprint":false},{"year":2017,"finding":"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.","method":"SRRM4 depletion and overexpression in neuronal cells, minigene assay, UGC motif deletion mutagenesis, neurite outgrowth assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro splicing assay with mutagenesis of cis element, loss-of-function and gain-of-function experiments, functional phenotype readout; single lab but multiple orthogonal methods","pmids":["28106138"],"is_preprint":false},{"year":2019,"finding":"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.","method":"SRRM4 knockdown and ectopic expression in neuronal cells, isoform-specific RNA probes and antibodies, UGC motif analysis","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdown/overexpression with defined splicing outcome and UGC motif characterization; single lab","pmids":["31559909"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Lentiviral SRRM4 overexpression, qPCR, immunoblotting, siRNA knockdown of SOX2, xenograft models, whole transcriptome analysis (AmpliSeq)","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SRRM4 overexpression with SOX2 knockdown epistasis, in vivo xenograft; single lab","pmids":["30100395"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Whole transcriptome comparison, SRRM4 overexpression cell models, functional apoptosis assays (camptothecin, UV irradiation), correlation in patient xenografts","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined splicing event, gain-of-function model, functional apoptosis readout; single lab","pmids":["29759485"],"is_preprint":false},{"year":2020,"finding":"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.","method":"SRRM4-overexpressing cell lines, RT-PCR splicing assay, gene expression analysis, patient-derived xenografts and metastatic biopsies","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function SRRM4 with defined splicing outcome and co-regulation readout; single lab, validated in clinical samples","pmids":["32403054"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SRRM4 overexpression in cancer cell lines (dose-response), mouse xenograft tumor growth assay, transcriptome analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in vitro and in vivo with dose-response; single lab with pan-cancer transcriptomic support","pmids":["33621242"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SRRM3 expression in cell lines, patient-derived xenografts, mCRPC specimens; SRRM3-induced REST splicing assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defines functional distinction between SRRM3 and SRRM4 via cell-line splicing assays and multi-model validation; relevant to SRRM4 mechanism by comparison","pmids":["34312180"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Gapmer ASO knockdown, RT-PCR splicing assay, FLAG-REST reconstitution, splice-switching oligonucleotide, cell viability assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ASO knockdown and splice-switching rescue with defined mechanistic readout; single lab","pmids":["36650528"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Exome/genome sequencing, short-read and long-read RNA-seq in patient fibroblasts with CRISPR-induced SRRM4 expression, transcriptomic analysis of downstream microexon splicing","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived functional genomics with defined splicing outcomes in SRRM4-expressing cells; single study","pmids":["41958152"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In situ hybridization for Srrm4 in cortex, electrophysiology, pharmacological GABAA receptor blockade, Kcc2 expression analysis in bv/bv mice","journal":"IBRO neuroscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, in situ hybridization with electrophysiology but limited mechanistic resolution; Kcc2 result is negative","pmids":["38229888"],"is_preprint":false},{"year":2025,"finding":"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.","method":"iPSC-derived neurons, multi-omics ALS/FTD patient data, TDP-43 depletion, RNA binding site analysis, stress granule functional assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint; iPSC-neuron and patient multi-omics; single lab, not yet peer-reviewed","pmids":["42146467"],"is_preprint":true},{"year":2026,"finding":"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.","method":"Nascent RNA sequencing in neuronal cells, 5' splice site mutagenesis, SRRM4-dependent microexon co-transcriptional splicing kinetics analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — nascent RNA sequencing plus mutagenesis of splice site establishes mechanism; preprint, single lab","pmids":["42146467"],"is_preprint":true},{"year":2024,"finding":"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.","method":"Massively parallel splicing assay (MPSA), computational modeling, comparison across vertebrate sequences","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — large-scale functional assay with mutagenesis; preprint, single lab","pmids":["bio_10.1101_2024.09.17.613571"],"is_preprint":true},{"year":2024,"finding":"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.","method":"PRPF40A and SRRM4 knockdown in mouse neuroblastoma cells, transcriptome-wide splicing analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint; knockdown splicing analysis defining SRRM4's relationship to the spliceosome; single lab","pmids":["bio_10.1101_2024.09.26.615222"],"is_preprint":true}],"current_model":"SRRM4/nSR100 is a vertebrate- and neural-specific RNA splicing factor that promotes inclusion of neural microexons (3–27 nt) and other alternative exons by binding UGC motifs in upstream polypyrimidine tracts and accelerating co-transcriptional removal of the flanking upstream intron, thereby enabling definition of the microexon's non-canonical downstream 5' splice site; its targets include REST (producing the truncated REST4 isoform that de-represses neuronal genes), protrudin, TAF1, LSD1+8a, Bif-1, and G3BP1, and its activity is critical for normal nervous system development, neuroendocrine cell identity, and—when aberrantly expressed—drives neuroendocrine transdifferentiation of prostate and lung cancers via a program that includes SOX2-dependent pluripotency gene induction."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2012,"claim":"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","pmids":["23055939"],"confidence":"High","gaps":["Did not define the molecular nature of the cis motif at nucleotide resolution","Mechanism of how SRRM4 promotes inclusion not addressed"]},{"year":2013,"claim":"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","pmids":["23928058"],"confidence":"Medium","gaps":["Single lab","Did not establish functional consequence of REST splicing on tumor phenotype"]},{"year":2015,"claim":"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","pmids":["25838543"],"confidence":"High","gaps":["Did not resolve the biochemical mechanism of microexon recognition","Direct RNA binding not mapped"]},{"year":2015,"claim":"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","pmids":["26071481"],"confidence":"Medium","gaps":["Correlative only; no direct SRRM4 manipulation","Causality not established in this study"]},{"year":2016,"claim":"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","pmids":["27180064"],"confidence":"High","gaps":["Full set of effector splicing targets beyond REST not enumerated","Mechanism of synergy with AR/TP53 not resolved"]},{"year":2017,"claim":"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","pmids":["28106138"],"confidence":"High","gaps":["Whether UGC recognition is direct binding not biochemically demonstrated","Generalizability of the UGC rule to all targets unaddressed"]},{"year":2018,"claim":"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","pmids":["30100395","29759485"],"confidence":"Medium","gaps":["Whether SOX2 induction is splicing-dependent unclear","Single lab for both findings"]},{"year":2019,"claim":"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","pmids":["31559909"],"confidence":"Medium","gaps":["Functional consequence of neuronal TFIID not characterized","Single lab"]},{"year":2020,"claim":"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","pmids":["32403054"],"confidence":"Medium","gaps":["Mechanism by which LSD1+8a redirects target specificity not resolved","Single lab"]},{"year":2021,"claim":"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","pmids":["33621242","34312180"],"confidence":"Medium","gaps":["Mechanistic basis of proliferation suppression unclear","Redundancy/division of labor between SRRM3 and SRRM4 incompletely mapped"]},{"year":2023,"claim":"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","pmids":["36650528"],"confidence":"Medium","gaps":["In vivo therapeutic efficacy not established","Single lab"]},{"year":2024,"claim":"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","pmids":["41958152"],"confidence":"Medium","gaps":["Single study cohort","Causal mechanism linking specific microexon changes to neurological phenotype not resolved"]},{"year":2024,"claim":"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)","pmids":["bio_10.1101_2024.09.17.613571"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Single lab"]},{"year":2026,"claim":"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)","pmids":["42146467"],"confidence":"Medium","gaps":["Preprint, single lab","Direct biochemical demonstration of SRRM4 binding to the spliceosome not shown"]},{"year":null,"claim":"How SRRM4 physically engages the spliceosome and its co-factors to accelerate upstream intron removal, and the structural basis of UGC recognition, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SRRM4 bound to RNA or spliceosome","Direct RNA-binding biochemistry not established","Full spliceosomal co-factor set incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5,6,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,12,13]}],"complexes":[],"partners":["PRPF40A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A7MD48","full_name":"Serine/arginine repetitive matrix protein 4","aliases":["Medulloblastoma antigen MU-MB-2.76","Neural-specific serine/arginine repetitive splicing factor of 100 kDa","Neural-specific SR-related protein of 100 kDa","nSR100"],"length_aa":611,"mass_kda":68.6,"function":"Splicing factor specifically required for neural cell differentiation. Acts in conjunction with nPTB/PTBP2 by binding directly to its regulated target transcripts and promotes neural-specific exon inclusion in many genes that function in neural cell differentiation. Required to promote the inclusion of neural-specific exon 10 in nPTB/PTBP2, leading to increased expression of neural-specific nPTB/PTBP2. Also promotes the inclusion of exon 16 in DAAM1 in neuron extracts (By similarity). Promotes alternative splicing of REST transcripts to produce REST isoform 3 (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells (PubMed:30684677). Plays an important role during embryonic development as well as in the proper functioning of the adult nervous system. Regulates alternative splicing events in genes with important neuronal functions (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/A7MD48/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRRM4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRRM4","total_profiled":1310},"omim":[{"mim_id":"621383","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 3; SRRM3","url":"https://www.omim.org/entry/621383"},{"mim_id":"613103","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 4; SRRM4","url":"https://www.omim.org/entry/613103"},{"mim_id":"606032","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 2; SRRM2","url":"https://www.omim.org/entry/606032"},{"mim_id":"600571","title":"RE1-SILENCING TRANSCRIPTION FACTOR; REST","url":"https://www.omim.org/entry/600571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":44.3},{"tissue":"retina","ntpm":27.0}],"url":"https://www.proteinatlas.org/search/SRRM4"},"hgnc":{"alias_symbol":["nSR100"],"prev_symbol":["KIAA1853"]},"alphafold":{"accession":"A7MD48","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A7MD48","model_url":"https://alphafold.ebi.ac.uk/files/AF-A7MD48-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A7MD48-F1-predicted_aligned_error_v6.png","plddt_mean":47.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRRM4","jax_strain_url":"https://www.jax.org/strain/search?query=SRRM4"},"sequence":{"accession":"A7MD48","fasta_url":"https://rest.uniprot.org/uniprotkb/A7MD48.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A7MD48/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A7MD48"}},"corpus_meta":[{"pmid":"27180064","id":"PMC_27180064","title":"SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition.","date":"2016","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/27180064","citation_count":150,"is_preprint":false},{"pmid":"26071481","id":"PMC_26071481","title":"SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/26071481","citation_count":148,"is_preprint":false},{"pmid":"25838543","id":"PMC_25838543","title":"Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development.","date":"2015","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25838543","citation_count":123,"is_preprint":false},{"pmid":"23055939","id":"PMC_23055939","title":"A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23055939","citation_count":80,"is_preprint":false},{"pmid":"30100395","id":"PMC_30100395","title":"A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network.","date":"2018","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30100395","citation_count":45,"is_preprint":false},{"pmid":"28106138","id":"PMC_28106138","title":"SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28106138","citation_count":39,"is_preprint":false},{"pmid":"34312180","id":"PMC_34312180","title":"RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer.","date":"2021","source":"Cancer 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the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer.","date":"2018","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/29759485","citation_count":19,"is_preprint":false},{"pmid":"36168302","id":"PMC_36168302","title":"CircRNA SRRM4 affects glucose metabolism by regulating PKM alternative splicing via SRSF3 deubiquitination in epilepsy.","date":"2022","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36168302","citation_count":19,"is_preprint":false},{"pmid":"33207694","id":"PMC_33207694","title":"SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33207694","citation_count":18,"is_preprint":false},{"pmid":"36650528","id":"PMC_36650528","title":"An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell 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Inclusion of a 6-nt nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons.\",\n      \"method\": \"Mouse knockout, whole-transcriptome splicing analysis, rescue experiment with Unc13b microexon in primary neurons\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — loss-of-function mouse model with defined cellular phenotypes, transcriptome-wide splicing analysis, and single-microexon rescue experiment providing orthogonal mechanistic validation\",\n      \"pmids\": [\"25838543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Positional cloning, transgenic rescue, transcriptome-wide splicing analysis, minigene assay with mutagenesis of cis motif\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — positional cloning, transgenic rescue, minigene assay, and mutagenesis in one study, replicated by the Bronx waltzer phenotype\",\n      \"pmids\": [\"23055939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq/bioinformatics (COMPAS), in vitro overexpression of SRRM4 in prostate cell lines, in vivo xenograft models, biochemical validation\",\n      \"journal\": \"European urology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo evidence across multiple models with specific mechanistic target (REST splicing), independently corroborated by other labs\",\n      \"pmids\": [\"27180064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"PCR-based REST splicing verification, whole-genome microarray analysis, IHC on patient-derived xenografts\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlative splicing PCR and arrays across multiple xenograft models, but no direct manipulation of SRRM4 in this study\",\n      \"pmids\": [\"26071481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, overexpression, RT-PCR splicing assay, pharmacological inhibitors (LY294002, U0126)\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown + overexpression with defined splicing readout, pharmacological pathway probing; single lab\",\n      \"pmids\": [\"23928058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"SRRM4 depletion and overexpression in neuronal cells, minigene assay, UGC motif deletion mutagenesis, neurite outgrowth assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro splicing assay with mutagenesis of cis element, loss-of-function and gain-of-function experiments, functional phenotype readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28106138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"SRRM4 knockdown and ectopic expression in neuronal cells, isoform-specific RNA probes and antibodies, UGC motif analysis\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdown/overexpression with defined splicing outcome and UGC motif characterization; single lab\",\n      \"pmids\": [\"31559909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Lentiviral SRRM4 overexpression, qPCR, immunoblotting, siRNA knockdown of SOX2, xenograft models, whole transcriptome analysis (AmpliSeq)\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SRRM4 overexpression with SOX2 knockdown epistasis, in vivo xenograft; single lab\",\n      \"pmids\": [\"30100395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Whole transcriptome comparison, SRRM4 overexpression cell models, functional apoptosis assays (camptothecin, UV irradiation), correlation in patient xenografts\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined splicing event, gain-of-function model, functional apoptosis readout; single lab\",\n      \"pmids\": [\"29759485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"SRRM4-overexpressing cell lines, RT-PCR splicing assay, gene expression analysis, patient-derived xenografts and metastatic biopsies\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function SRRM4 with defined splicing outcome and co-regulation readout; single lab, validated in clinical samples\",\n      \"pmids\": [\"32403054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SRRM4 overexpression in cancer cell lines (dose-response), mouse xenograft tumor growth assay, transcriptome analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in vitro and in vivo with dose-response; single lab with pan-cancer transcriptomic support\",\n      \"pmids\": [\"33621242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SRRM3 expression in cell lines, patient-derived xenografts, mCRPC specimens; SRRM3-induced REST splicing assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defines functional distinction between SRRM3 and SRRM4 via cell-line splicing assays and multi-model validation; relevant to SRRM4 mechanism by comparison\",\n      \"pmids\": [\"34312180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Gapmer ASO knockdown, RT-PCR splicing assay, FLAG-REST reconstitution, splice-switching oligonucleotide, cell viability assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ASO knockdown and splice-switching rescue with defined mechanistic readout; single lab\",\n      \"pmids\": [\"36650528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Exome/genome sequencing, short-read and long-read RNA-seq in patient fibroblasts with CRISPR-induced SRRM4 expression, transcriptomic analysis of downstream microexon splicing\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived functional genomics with defined splicing outcomes in SRRM4-expressing cells; single study\",\n      \"pmids\": [\"41958152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In situ hybridization for Srrm4 in cortex, electrophysiology, pharmacological GABAA receptor blockade, Kcc2 expression analysis in bv/bv mice\",\n      \"journal\": \"IBRO neuroscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, in situ hybridization with electrophysiology but limited mechanistic resolution; Kcc2 result is negative\",\n      \"pmids\": [\"38229888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"iPSC-derived neurons, multi-omics ALS/FTD patient data, TDP-43 depletion, RNA binding site analysis, stress granule functional assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint; iPSC-neuron and patient multi-omics; single lab, not yet peer-reviewed\",\n      \"pmids\": [\"42146467\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Nascent RNA sequencing in neuronal cells, 5' splice site mutagenesis, SRRM4-dependent microexon co-transcriptional splicing kinetics analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — nascent RNA sequencing plus mutagenesis of splice site establishes mechanism; preprint, single lab\",\n      \"pmids\": [\"42146467\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Massively parallel splicing assay (MPSA), computational modeling, comparison across vertebrate sequences\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — large-scale functional assay with mutagenesis; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.17.613571\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"PRPF40A and SRRM4 knockdown in mouse neuroblastoma cells, transcriptome-wide splicing analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint; knockdown splicing analysis defining SRRM4's relationship to the spliceosome; single lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.26.615222\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRRM4/nSR100 is a vertebrate- and neural-specific RNA splicing factor that promotes inclusion of neural microexons (3–27 nt) and other alternative exons by binding UGC motifs in upstream polypyrimidine tracts and accelerating co-transcriptional removal of the flanking upstream intron, thereby enabling definition of the microexon's non-canonical downstream 5' splice site; its targets include REST (producing the truncated REST4 isoform that de-represses neuronal genes), protrudin, TAF1, LSD1+8a, Bif-1, and G3BP1, and its activity is critical for normal nervous system development, neuroendocrine cell identity, and—when aberrantly expressed—drives neuroendocrine transdifferentiation of prostate and lung cancers via a program that includes SOX2-dependent pluripotency gene induction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. Mechanistically, SRRM4 recognizes UGC motifs in the polypyrimidine tract immediately upstream of a regulated microexon [#5, #6], 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 [#16]. 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 [#1]. Validated targets span protrudin (exon L, enhancing neurite outgrowth) [#5], a neuronal TAF1 microexon generating a neuron-specific TFIID complex [#6], and the REST gene, where SRRM4 generates a truncated REST4/sREST isoform lacking the transcriptional repressor domain to de-repress neuronal genes [#2, #4]. Aberrant SRRM4 activity drives neuroendocrine transdifferentiation of prostate cancer through REST splicing—potentiated by androgen receptor inhibition and TP53 loss [#2]—and through an additional program including SOX2-dependent pluripotency gene induction [#7], anti-apoptotic Bif-1 isoform switching [#8], and an NEPC-specific LSD1+8a isoform [#9]; ASO knockdown of SRRM4 or REST splice-switching oligonucleotides reduce cancer cell viability, establishing REST splicing as a key survival mechanism [#12]. 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 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Positional cloning, transgenic rescue, and minigene mutagenesis in Bronx waltzer mice with sensory hair cell transcriptome analysis\",\n      \"pmids\": [\"23055939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular nature of the cis motif at nucleotide resolution\", \"Mechanism of how SRRM4 promotes inclusion not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown and overexpression with RT-PCR splicing readout and pharmacological pathway inhibitors in SCLC cells\",\n      \"pmids\": [\"23928058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not establish functional consequence of REST splicing on tumor phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined SRRM4 as the master regulator of neural microexons whose loss causes specific neurodevelopmental defects, with single-microexon rescue proving microexons are functionally causal.\",\n      \"evidence\": \"Mouse knockout, transcriptome-wide splicing analysis, and Unc13b microexon rescue in primary neurons\",\n      \"pmids\": [\"25838543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the biochemical mechanism of microexon recognition\", \"Direct RNA binding not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SRRM4-driven REST4 splicing to the neuroendocrine phenotype of castration-resistant prostate cancer in patient-derived models.\",\n      \"evidence\": \"REST splicing PCR, whole-genome microarray, and IHC across LuCaP xenografts\",\n      \"pmids\": [\"26071481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative only; no direct SRRM4 manipulation\", \"Causality not established in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated causally that SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma via REST splicing, contextualized by AR inhibition and TP53 loss.\",\n      \"evidence\": \"SRRM4 overexpression in prostate cell lines, xenograft models, and biochemical validation\",\n      \"pmids\": [\"27180064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of effector splicing targets beyond REST not enumerated\", \"Mechanism of synergy with AR/TP53 not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the first nucleotide-level mechanism showing SRRM4 recognizes an upstream UGC motif to promote a functional protrudin microexon controlling neurite outgrowth.\",\n      \"evidence\": \"Depletion/overexpression, minigene assay with UGC deletion, and neurite outgrowth assays in Neuro2A and ES cells\",\n      \"pmids\": [\"28106138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UGC recognition is direct binding not biochemically demonstrated\", \"Generalizability of the UGC rule to all targets unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the oncogenic SRRM4 program beyond REST to SOX2-dependent pluripotency induction and anti-apoptotic Bif-1 isoform switching.\",\n      \"evidence\": \"Lentiviral SRRM4 overexpression with SOX2 knockdown epistasis and apoptosis assays in NEPC models and xenografts\",\n      \"pmids\": [\"30100395\", \"29759485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SOX2 induction is splicing-dependent unclear\", \"Single lab for both findings\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the UGC-polypyrimidine-tract recognition mechanism to TAF1, showing SRRM4 builds a neuron-specific TFIID complex via microexon inclusion.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression with isoform-specific probes and UGC motif analysis in neuronal cells\",\n      \"pmids\": [\"31559909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of neuronal TFIID not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"SRRM4-overexpressing cell lines, RT-PCR splicing assays, and clinical xenograft/biopsy validation\",\n      \"pmids\": [\"32403054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LSD1+8a redirects target specificity not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Dose-response SRRM4 overexpression with xenograft growth and pan-cancer transcriptomics; SRRM3 splicing assays in CRPC models\",\n      \"pmids\": [\"33621242\", \"34312180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of proliferation suppression unclear\", \"Redundancy/division of labor between SRRM3 and SRRM4 incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated REST splicing as a therapeutically actionable downstream node by showing SRRM4 ASO knockdown and REST splice-switching oligonucleotides reduce cancer cell viability.\",\n      \"evidence\": \"Gapmer ASO knockdown, splice-switching oligonucleotide, FLAG-REST reconstitution, and viability assays in SCLC and prostate cancer cells\",\n      \"pmids\": [\"36650528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo therapeutic efficacy not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a Mendelian disease link, showing de novo SRRM4 splice-donor variants disrupt downstream microexon splicing and cause a neurodevelopmental movement disorder.\",\n      \"evidence\": \"Exome/genome sequencing with short- and long-read RNA-seq in patient fibroblasts with CRISPR-induced SRRM4 expression\",\n      \"pmids\": [\"41958152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study cohort\", \"Causal mechanism linking specific microexon changes to neurological phenotype not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed microexon sensitivity to SRRM4 is determined largely by core splice-site architecture conserved across vertebrates, not by SRRM4 binding alone.\",\n      \"evidence\": \"Massively parallel splicing assay of 28,535 variants with computational modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.17.613571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Nascent RNA sequencing and 5' splice site mutagenesis in neuronal cells (preprint)\",\n      \"pmids\": [\"42146467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct biochemical demonstration of SRRM4 binding to the spliceosome not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRRM4 physically engages the spliceosome and its co-factors to accelerate upstream intron removal, and the structural basis of UGC recognition, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SRRM4 bound to RNA or spliceosome\", \"Direct RNA-binding biochemistry not established\", \"Full spliceosomal co-factor set incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5, 6, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PRPF40A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}