{"gene":"MATR3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2014,"finding":"The small RNA pY RNA1-s2 selectively binds to the nuclear matrix protein Matrin 3 (Matr3). This binding is highly dependent on the RNA sequence and requires both RRM domains of Matr3. Elements outside the RRM region also contribute to binding specificity, and phosphorylation of Matr3 enhances the pY RNA1-s2/Matr3 interaction.","method":"Mass spectrometric analysis of pY RNA1-s2-bound proteins from retina, Western blot, RRM domain-binding assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical binding assay with domain-mapping and phosphorylation follow-up, single lab","pmids":["24558381"],"is_preprint":false},{"year":2015,"finding":"Disruption of the MATR3 3' UTR (affecting polyadenylation and altering Matrin 3 protein expression) in a mouse gene-trap allele (Matr3 Gt-ex13) causes incompletely penetrant bicuspid aortic valve, coarctation of the aorta, patent ductus arteriosus, ventricular septal defect, and double-outlet right ventricle in heterozygotes, establishing that subtle perturbations in Matrin 3 expression cause left ventricular outflow tract defects.","method":"Mouse gene-trap model (Matr3 Gt-ex13), heterozygote phenotyping, RT-PCR/transcript analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with specific cardiovascular phenotype, single lab, corroborated by human translocation data","pmids":["25574029"],"is_preprint":false},{"year":2019,"finding":"Matrin-3 interacts with pri/pre-miR-138-2 (mapped to the loop region) and exerts an inhibitory function on nuclear pri-miR-138-2 processing, thereby suppressing mature miR-138 biogenesis in neurons.","method":"Biochemical pull-down assay identifying Matrin-3 as pri/pre-miR-138 interacting protein, loss-of-function experiments in HEK293 cells and primary neurons, protein localization studies","journal":"Neurobiology of learning and memory","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical interaction plus loss-of-function with specific miRNA processing phenotype, single lab","pmids":["30790622"],"is_preprint":false},{"year":2018,"finding":"MATR3 directly binds lncRNA SNHG1 in neuroblastoma cells. The direct binding was validated by Western blot after RNA protein pull-down and confirmed by RNA immunoprecipitation. MATR3 and SNHG1 co-regulate biological functions including RNA splicing.","method":"RNA-protein pull-down assay coupled with LC-MS/MS, Western blot, RNA immunoprecipitation (RIP)","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal RIP and pull-down validating direct interaction, single lab","pmids":["30516047"],"is_preprint":false},{"year":2020,"finding":"MATR3 S85C knock-in mice (generated by CRISPR/Cas9 at the endogenous Matr3 locus) recapitulate early-stage ALS features including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration, and neuroinflammation. The S85C mutation causes loss of MATR3 protein in cell bodies of Purkinje cells and motor neurons, indicating that loss of MATR3 function contributes to neuronal defects.","method":"CRISPR/Cas9 knock-in mouse model, behavioral assays, neuropathological histology, immunostaining","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous knock-in model with multiple orthogonal readouts (behavioral, histological, molecular), replicated across neuronal subtypes in the same study","pmids":["33082323"],"is_preprint":false},{"year":2020,"finding":"Expression of wild-type or mutant MATR3 in Drosophila motor neurons reduces climbing ability and lifespan, while expression in indirect flight muscles causes abnormal wing positioning and muscle degeneration. Mutant MATR3 confers more severe phenotypes than wild-type. A candidate screen identified axonal transport genes as enhancers of the MATR3 abnormal wing phenotype; knockdown of these genes increased protein levels and insolubility of mutant MATR3, implicating axonal transport dysfunction in MATR3-related disease pathogenesis.","method":"Transgenic Drosophila expressing human MATR3 (WT and mutant), behavioral assays, candidate modifier screen, protein solubility assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila model with multiple mutants and phenotypic readouts, single lab","pmids":["32515490"],"is_preprint":false},{"year":2020,"finding":"MATR3, identified via RNA antisense purification combined with mass spectrometry, binds to sequences within the alternatively spliced intron-1 of the muscle-restricted lncRNA pCharme and forms nuclear aggregates together with PTBP1. This interaction is required for pCharme's chromatin-associated activities during myogenesis.","method":"RNA antisense purification (RAP) with mass spectrometry, loss-of-function analysis, CRISPR-Cas9 intron deletion","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RAP-MS identification plus CRISPR functional validation, single lab","pmids":["33357424"],"is_preprint":false},{"year":2021,"finding":"MATR3 loss-of-function in human iPSCs alters the pluripotency circuitry by multiple mechanisms: (1) MATR3 binds to the OCT4 and YTHDF1 promoters to favor their transcription; (2) MATR3 is recruited on ribosomes and controls translation of specific transcripts including NANOG and LIN28A by direct binding; (3) MATR3 downregulation affects the m6A epitranscriptomic regulation of OCT4 mRNA via YTHDF1.","method":"MATR3 knockdown in hiPSCs, chromatin immunoprecipitation (promoter binding), ribosome fractionation, RNA binding and stability assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in one study (ChIP, ribosome fractionation, RBP binding), single lab","pmids":["33733063"],"is_preprint":false},{"year":2022,"finding":"MATR3 interacts with the Mettl3-Mettl14 m6A methyltransferase complex in macrophages and inhibits pro-inflammatory MAPK signaling by promoting m6A-mediated mRNA decay. Under oxLDL stimulation, MATR3 expression decreases, leading to disruption of the Mettl3-Mettl14 complex and increased inflammatory signaling.","method":"Co-immunoprecipitation, overexpression and knockdown in macrophages, in vivo atherosclerosis model, signaling pathway analysis","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex interaction plus in vivo functional validation, single lab","pmids":["36368640"],"is_preprint":false},{"year":2022,"finding":"MATR3 S85C KI mice exhibit selective loss of MATR3 staining in α-motor neurons (but not γ-motor neurons) in cervical, thoracic, and lumbar spinal cord, in parvalbumin-positive interneurons, in subsets of upper motor neurons, and in hippocampal CA1 neurons, demonstrating cell-type-selective vulnerability.","method":"Histological analysis of MATR3 S85C knock-in mice, immunostaining with cell-type markers","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunohistological localization in endogenous knock-in model with cell-type markers, single lab","pmids":["35205163"],"is_preprint":false},{"year":2023,"finding":"MATR3, a nuclear matrix protein, interacts with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect each other's nuclear localization. MATR3 depletion redistributes H3K27me3-modified chromatin and decreases intra-TAD interactions in TADs that highly transcribe MATR3-associated AS L1 RNAs. ALS-associated MATR3 mutants alter biophysical features of this meshwork and cause abnormal H3K27me3 staining.","method":"MATR3 depletion, Hi-C/TAD analysis, ATAC-seq, phase separation assays, immunostaining, ALS mutant comparison","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal chromatin methods (Hi-C, ATAC-seq) plus phase separation assay and ALS mutant characterization, single lab","pmids":["37381832"],"is_preprint":false},{"year":2023,"finding":"MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression in FSHD muscle cells, rescuing cell viability and myogenic differentiation. A shorter MATR3 fragment is necessary and sufficient to block DUX4-induced toxicity to the same extent as full-length MATR3.","method":"Co-immunoprecipitation, pull-down assays, gene expression assays, cell viability and differentiation assays in FSHD muscle cells, domain deletion analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction validated plus functional domain mapping with rescue experiments, single lab","pmids":["37703175"],"is_preprint":false},{"year":2023,"finding":"MATR3 promotes A-to-I RNA editing of CTSB mRNA by recruiting ADAR1 to this target. Mechanistically, S-nitrosylation of CTSB promotes dephosphorylation and nuclear translocation of ADD1, which then recruits MATR3 and ADAR1 to CTSB mRNA, enabling HuR binding and mRNA stabilization.","method":"Co-immunoprecipitation, RNA immunoprecipitation, RNA editing assays, nuclear translocation imaging, loss-of-function experiments","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP experiments and RIP validation establishing the ADD1/MATR3/ADAR1 complex, single lab","pmids":["37156877"],"is_preprint":false},{"year":2023,"finding":"lncRNA15691 directly binds to and stabilizes MATR3 by inhibiting its nuclear degradation mediated by PKA. MATR3 in turn upregulates CCR9 expression, promoting T-ALL cell invasion and bone marrow infiltration.","method":"RNA protein pull-down assay with LC-MS/MS, RNA immunoprecipitation (RIP) validation, loss-of-function experiments, in vivo xenograft model","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pull-down and RIP validation of interaction, functional consequence established with in vivo data, single lab","pmids":["36822174"],"is_preprint":false},{"year":2023,"finding":"MATR3 interacts with the WTAP/METTL3/METTL14 m6A methyltransferase complex (co-immunoprecipitation validated). Loss of MATR3 in pterygium tissue is associated with loss of WTAP-MATR3 interaction and reduced binding of WTAP and MATR3 to 3' UTR regions of target RNA molecules.","method":"Co-immunoprecipitation with mass spectrometry, methylated RNA immunoprecipitation (MeRIP)","journal":"Acta histochemica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/MeRIP experiment from tissue samples, single lab, no functional reconstitution","pmids":["37913560"],"is_preprint":false},{"year":2024,"finding":"Loss of MATR3 leads to cryptic exon inclusion in many transcripts, establishing a role for MATR3 in cryptic splicing repression. The ALS-linked S85C variant reduces MATR3 solubility but does not impair RNA binding. A novel neurodevelopmental disease-associated M548T variant (in the RRM2 domain) reduces protein solubility and impairs both RNA binding and cryptic splicing repression.","method":"MATR3 loss-of-function RNA-seq, protein solubility assays, RNA binding assays, analysis of S85C and M548T variants","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq-based cryptic splicing discovery combined with biochemical solubility and RNA binding assays on multiple variants, single lab","pmids":["38320753"],"is_preprint":false},{"year":2024,"finding":"MATR3 binds to DHX58 mRNA through its RRM structural domain and recruits YTHDF2 (an m6A reader), leading to degradation of DHX58 mRNA and suppression of the type I IFN signaling pathway in liver cancer cells.","method":"RNA-seq, RNA immunoprecipitation, Co-immunoprecipitation, MATR3 RRM domain mutation analysis, MATR3 knockout experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level RIP mapping and co-IP of MATR3-YTHDF2 complex plus knockout functional validation, single lab","pmids":["39276912"],"is_preprint":false},{"year":2025,"finding":"EZH2-mediated methylation of DDX1 at K234 disrupts DDX1's interaction with splicing factors and RNA targets, promoting exon 14 skipping in MATR3. This truncated MATR3 isoform disrupts nuclear architecture, increases chromatin accessibility, and activates Wnt signaling leading to nucleus pulposus cell senescence and apoptosis. Delivery of full-length MATR3 mRNA reduces NP cell degeneration and alleviates disc degeneration in vivo.","method":"In vitro splicing assays, AAV/mRNA delivery in vivo, chromatin accessibility (ATAC-seq), signaling pathway analysis, mass spectrometry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue with full-length MATR3, single lab","pmids":["40610464"],"is_preprint":false},{"year":2025,"finding":"IFN-I signaling drives phospho-regulation of MATR3's RNA-binding activity, as experimentally confirmed using RNA interactome capture (RIC) comparing phosphorylation states of RNA-bound proteomes after IFN-I treatment.","method":"RNA interactome capture (RIC) with phosphorylation state profiling, knockdown screen","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — single lab preprint, RIC method is rigorous but this specific finding on MATR3 is one of many in a large screen","pmids":[],"is_preprint":true},{"year":2024,"finding":"MATR3, along with FUS and hnRNPA1, binds to and downregulates REST mRNA, thereby promoting UNC13A transcription. Loss of MATR3 leads to REST upregulation in cultured cells, and REST upregulation was detected in motor neurons of ALS patients.","method":"RNA binding assays, REST mRNA quantification after RBP knockdown, motor neuron analysis from ALS patient tissue","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic detail on MATR3-REST binding not extensively validated with orthogonal methods","pmids":[],"is_preprint":true},{"year":2025,"finding":"MATR3 interacts with METTL3 by co-immunoprecipitation and stabilizes METTL3 protein by inhibiting its proteasomal degradation. METTL3 in turn mediates m6A modification of MSI2 mRNA to enhance its stability, activating the Wnt/β-Catenin pathway and promoting myocardial fibrosis.","method":"Co-immunoprecipitation, methylated RNA immunoprecipitation (MeRIP-qPCR), MATR3 knockdown in human atrial fibroblasts and in vivo mouse model, Western blot, proteasome inhibition assay","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with proteasome inhibition establishing MATR3-METTL3 stabilization mechanism, plus in vivo validation, single lab","pmids":["41849072"],"is_preprint":false},{"year":2021,"finding":"MATR3 F115C knock-in mice generated by CRISPR/Cas9 did not exhibit motor deficits, neuropathology, MATR3 pathology, or TDP-43 pathology up to 2 years of age, indicating that the F115C mutation in MATR3 alone does not confer pathogenicity in mice.","method":"CRISPR/Cas9 knock-in mouse model, behavioral testing, neuropathological examination, immunostaining","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous knock-in with multiple readouts yielding a clear negative result, single lab","pmids":["34182213"],"is_preprint":false}],"current_model":"MATR3 (Matrin-3) is a nuclear matrix RNA/DNA-binding protein (containing two RRM domains) that functions as a cryptic splicing repressor, regulates miRNA biogenesis (inhibiting pri-miR-138-2 processing), modulates chromatin organization through phase-separated meshworks with antisense LINE1 RNAs, controls m6A methyltransferase complex assembly and target mRNA stability (by recruiting METTL3-METTL14, YTHDF2, or ADAR1 to specific mRNAs), directly binds and blocks the transcription factor DUX4, promotes UNC13A expression by suppressing REST mRNA, and whose disease-linked S85C mutation reduces protein solubility and causes selective loss of MATR3 in specific neuronal subtypes leading to ALS-like neurodegeneration in knock-in mice."},"narrative":{"mechanistic_narrative":"MATR3 (Matrin-3) is a nuclear matrix RNA/DNA-binding protein that acts at multiple steps of gene expression — splicing, RNA editing, m6A-dependent mRNA fate, miRNA processing, and chromatin organization [PMID:38320753, PMID:37381832, PMID:37156877]. Its RRM domains mediate sequence-specific RNA recognition, including binding of structured RNAs such as pY RNA1-s2, where binding requires both RRMs and is enhanced by phosphorylation [PMID:24558381]. MATR3 represses cryptic exon inclusion across many transcripts, and disease-linked variants that reduce its solubility (S85C, M548T) cause loss of function; the RRM2 M548T variant additionally impairs RNA binding and cryptic splicing repression [PMID:38320753]. In chromatin, MATR3 partners with antisense LINE1 RNAs to form a phase-separated meshwork that organizes H3K27me3-marked chromatin and intra-TAD interactions, and ALS-associated mutants disrupt this meshwork's biophysical properties [PMID:37381832]. MATR3 functions as a scaffold for m6A machinery, interacting with the METTL3–METTL14/WTAP methyltransferase complex and m6A readers (YTHDF2) to direct target mRNA stability and decay, as shown for inflammatory signaling in macrophages and for DHX58 in liver cancer [PMID:36368640, PMID:37913560, PMID:39276912, PMID:41849072]. It also recruits ADAR1 to drive A-to-I editing and stabilization of CTSB mRNA within an ADD1-dependent complex [PMID:37156877]. The endogenous S85C knock-in mouse recapitulates early ALS-like features — motor impairment, NMJ defects, Purkinje and motor neuron degeneration — accompanied by cell-type-selective loss of MATR3 protein in vulnerable neuronal populations, establishing loss of MATR3 function as a contributor to neurodegeneration [PMID:33082323, PMID:35205163]. MATR3 additionally blocks DUX4-mediated toxicity in FSHD muscle through direct binding to the DUX4 DNA-binding domain [PMID:37703175].","teleology":[{"year":2014,"claim":"Established that MATR3 is a sequence-specific RNA-binding protein whose recognition requires both RRM domains and is tunable by phosphorylation, defining the biochemical basis of its RNA engagement.","evidence":"Mass spectrometry of pY RNA1-s2-bound proteins from retina with RRM domain-binding and phosphorylation assays","pmids":["24558381"],"confidence":"Medium","gaps":["Physiological RNA targets in this context not defined","Kinase responsible for the phosphorylation not identified"]},{"year":2015,"claim":"Demonstrated in vivo that subtle changes in MATR3 dosage cause developmental cardiovascular defects, showing organismal sensitivity to MATR3 expression level.","evidence":"Mouse gene-trap allele (Matr3 Gt-ex13) with 3'UTR disruption, heterozygote phenotyping","pmids":["25574029"],"confidence":"Medium","gaps":["Molecular pathway linking MATR3 dosage to outflow tract development unknown","Incomplete penetrance unexplained"]},{"year":2018,"claim":"Broadened MATR3's regulatory repertoire to lncRNA partnership, showing it directly binds SNHG1 and co-regulates RNA splicing.","evidence":"RNA-protein pull-down with LC-MS/MS and reciprocal RIP in neuroblastoma cells","pmids":["30516047"],"confidence":"Medium","gaps":["Specific splicing targets co-regulated not enumerated","Functional consequence beyond cell line not tested"]},{"year":2019,"claim":"Showed MATR3 acts in miRNA biogenesis by binding pri/pre-miR-138-2 and inhibiting its processing, extending its function to small-RNA regulation in neurons.","evidence":"Biochemical pull-down and loss-of-function in HEK293 and primary neurons","pmids":["30790622"],"confidence":"Medium","gaps":["Mechanism of processing inhibition not resolved","Whether other pri-miRNAs are regulated unknown"]},{"year":2020,"claim":"Provided the strongest genetic evidence that the ALS-linked S85C mutation drives selective neurodegeneration through loss of MATR3 protein in vulnerable neurons.","evidence":"Endogenous CRISPR/Cas9 S85C knock-in mice with behavioral, histological and molecular readouts","pmids":["33082323"],"confidence":"High","gaps":["Molecular cause of cell-body MATR3 loss not established","Downstream RNA-processing changes in vivo not mapped"]},{"year":2020,"claim":"Implicated axonal transport in MATR3 proteostasis, showing transport-gene knockdown raises mutant MATR3 levels and insolubility.","evidence":"Transgenic Drosophila expressing human MATR3 with modifier screen and solubility assays","pmids":["32515490"],"confidence":"Medium","gaps":["Direct biochemical link between transport machinery and MATR3 solubility unclear","Relevance to mammalian neurons untested in this study"]},{"year":2020,"claim":"Connected MATR3 to muscle-specific lncRNA function and nuclear aggregation, showing it binds pCharme intron-1 with PTBP1 to support chromatin-associated activity in myogenesis.","evidence":"RAP-MS, loss-of-function, and CRISPR intron deletion","pmids":["33357424"],"confidence":"Medium","gaps":["Composition and dynamics of the nuclear aggregates not fully defined","Direct chromatin targets not mapped"]},{"year":2021,"claim":"Defined a multi-layered role for MATR3 in the pluripotency circuit — promoter binding, ribosome-associated translation control, and m6A/YTHDF1-mediated regulation of OCT4.","evidence":"MATR3 knockdown in hiPSCs with ChIP, ribosome fractionation, and RNA binding/stability assays","pmids":["33733063"],"confidence":"Medium","gaps":["Whether MATR3 acts as a bona fide transcriptional regulator versus indirect effect unresolved","Generality of ribosome association across cell types unknown"]},{"year":2021,"claim":"Showed that not all disease-linked MATR3 mutations are pathogenic in vivo, as F115C knock-in mice lacked phenotype, distinguishing variant-specific consequences.","evidence":"CRISPR/Cas9 F115C knock-in mice with behavioral and neuropathological examination","pmids":["34182213"],"confidence":"Medium","gaps":["Reason for genotype-phenotype discordance versus S85C not established","Possible species or modifier dependence untested"]},{"year":2022,"claim":"Established MATR3 as a scaffold for the METTL3-METTL14 m6A methyltransferase complex that restrains inflammatory signaling via m6A-mediated mRNA decay.","evidence":"Co-IP, knockdown/overexpression in macrophages, and in vivo atherosclerosis model","pmids":["36368640"],"confidence":"Medium","gaps":["Direct mRNA targets of the decay not fully defined","Whether MATR3 directly contacts the methyltransferase or via RNA unclear"]},{"year":2022,"claim":"Refined cell-type-selective vulnerability by mapping which neuronal subtypes lose MATR3 in S85C mice (α- but not γ-motor neurons, parvalbumin interneurons, CA1).","evidence":"Immunohistology with cell-type markers in S85C knock-in mice","pmids":["35205163"],"confidence":"Medium","gaps":["Basis of selective vulnerability not explained","Functional consequence per cell type not assessed"]},{"year":2023,"claim":"Revealed a structural genome-organizing function: MATR3 forms a phase-separated meshwork with antisense LINE1 RNAs that controls H3K27me3 distribution and TAD interactions, disrupted by ALS mutants.","evidence":"MATR3 depletion with Hi-C, ATAC-seq, phase separation assays, and ALS mutant comparison","pmids":["37381832"],"confidence":"Medium","gaps":["Causal link between meshwork disruption and neurodegeneration not established","Determinants of AS L1 RNA selectivity unknown"]},{"year":2023,"claim":"Identified MATR3 as a direct DUX4 antagonist, binding the DUX4 DNA-binding domain to block its toxicity and rescue FSHD muscle cells, with a minimal sufficient fragment.","evidence":"Co-IP, pull-down, domain deletion, and viability/differentiation rescue in FSHD muscle cells","pmids":["37703175"],"confidence":"Medium","gaps":["Structural basis of the MATR3-DUX4 interaction not solved","Endogenous relevance in patient muscle not confirmed"]},{"year":2023,"claim":"Showed MATR3 directs A-to-I RNA editing by recruiting ADAR1 to CTSB mRNA within an S-nitrosylation/ADD1-driven complex enabling HuR-mediated stabilization.","evidence":"Co-IP, RIP, RNA editing assays, and nuclear translocation imaging","pmids":["37156877"],"confidence":"Medium","gaps":["Generality beyond CTSB unknown","Order of complex assembly not fully resolved"]},{"year":2023,"claim":"Demonstrated MATR3 protein levels are controlled by lncRNA-mediated protection from PKA-dependent nuclear degradation, with downstream effects on T-ALL invasion.","evidence":"RNA-protein pull-down with LC-MS/MS, RIP, loss-of-function, and xenograft model","pmids":["36822174"],"confidence":"Medium","gaps":["Mechanism of PKA-driven MATR3 degradation not detailed","Direct versus indirect CCR9 regulation unclear"]},{"year":2023,"claim":"Linked MATR3 to the WTAP/METTL3/METTL14 complex and 3'UTR target binding, supporting its role in m6A deposition on specific transcripts.","evidence":"Co-IP with mass spectrometry and MeRIP in pterygium tissue","pmids":["37913560"],"confidence":"Low","gaps":["Single co-IP/MeRIP from tissue without functional reconstitution","Direct target mRNAs not validated"]},{"year":2024,"claim":"Defined cryptic splicing repression as a core MATR3 function and distinguished variant mechanisms: S85C reduces solubility without impairing RNA binding, whereas RRM2 M548T impairs both binding and repression.","evidence":"Loss-of-function RNA-seq, protein solubility assays, and RNA binding assays on S85C/M548T variants","pmids":["38320753"],"confidence":"Medium","gaps":["Specific pathogenic cryptic targets not prioritized","How solubility loss translates to functional loss in vivo unclear"]},{"year":2024,"claim":"Showed MATR3 uses its RRM domain to bind DHX58 mRNA and recruit YTHDF2 for m6A-dependent decay, suppressing type I IFN signaling in liver cancer.","evidence":"RNA-seq, RIP, co-IP, RRM mutation analysis, and MATR3 knockout","pmids":["39276912"],"confidence":"Medium","gaps":["Whether this decay route generalizes to other IFN regulators unknown","Direct MATR3-YTHDF2 contact versus RNA bridging not resolved"]},{"year":2024,"claim":"Implicated MATR3 in ALS-relevant UNC13A regulation by binding and downregulating REST mRNA alongside FUS and hnRNPA1.","evidence":"RNA binding assays, REST quantification after RBP knockdown, and ALS patient motor neuron analysis (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint; MATR3-REST binding not validated with orthogonal methods","Direct versus indirect REST regulation unclear"]},{"year":2025,"claim":"Showed MATR3 stabilizes METTL3 by blocking its proteasomal degradation, linking MATR3 to METTL3-dependent m6A modification of MSI2 and Wnt-driven myocardial fibrosis.","evidence":"Co-IP, MeRIP-qPCR, proteasome inhibition, knockdown in fibroblasts, and in vivo mouse model","pmids":["41849072"],"confidence":"Medium","gaps":["Mechanism by which MATR3 protects METTL3 from degradation not defined","Whether stabilization is direct unclear"]},{"year":2025,"claim":"Established that an aberrant exon-14-skipped MATR3 isoform disrupts nuclear architecture and drives disc degeneration, with full-length MATR3 mRNA delivery providing in vivo rescue.","evidence":"In vitro splicing assays, ATAC-seq, mass spectrometry, and AAV/mRNA delivery in vivo","pmids":["40610464"],"confidence":"Medium","gaps":["How the truncated isoform alters chromatin mechanistically not fully resolved","Translatability of mRNA delivery beyond disc not assessed"]},{"year":2025,"claim":"Indicated IFN-I signaling phospho-regulates MATR3's RNA-binding activity, linking immune signaling to its function.","evidence":"RNA interactome capture with phosphorylation-state profiling and knockdown screen (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint; one finding within a large screen, not independently validated","Phosphosites and functional consequences for MATR3 not defined"]},{"year":null,"claim":"How MATR3's diverse molecular activities (cryptic splicing repression, m6A scaffolding, RNA editing, chromatin meshwork formation) integrate to produce cell-type-selective neurodegeneration remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism connecting MATR3 loss of solubility to selective neuronal vulnerability","Structural model of RNA/DNA and protein partner engagement lacking","In vivo target spectrum of MATR3's m6A and editing functions not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,6,15,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,12,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,12,14,16,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10,2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,8,12,15,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,9,15]}],"complexes":["METTL3-METTL14/WTAP m6A methyltransferase complex","ADD1/MATR3/ADAR1 RNA-editing complex"],"partners":["METTL3","METTL14","WTAP","YTHDF2","ADAR1","PTBP1","DUX4","ADD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43243","full_name":"Matrin-3","aliases":[],"length_aa":847,"mass_kda":94.6,"function":"May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. In association with the SFPQ-NONO heteromer may play a role in nuclear retention of defective RNAs. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs (PubMed:32245947). May bind to specific miRNA hairpins (PubMed:28431233)","subcellular_location":"Nucleus matrix","url":"https://www.uniprot.org/uniprotkb/P43243/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MATR3","classification":"Not Classified","n_dependent_lines":213,"n_total_lines":1208,"dependency_fraction":0.1763245033112583},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"EMC8","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"FTH1","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MATR3","total_profiled":1310},"omim":[{"mim_id":"614349","title":"ZINC FINGER PROTEIN 638; ZNF638","url":"https://www.omim.org/entry/614349"},{"mim_id":"611420","title":"CDKN1A-INTERACTING ZINC FINGER PROTEIN 1; CIZ1","url":"https://www.omim.org/entry/611420"},{"mim_id":"606070","title":"AMYOTROPHIC LATERAL SCLEROSIS 21; ALS21","url":"https://www.omim.org/entry/606070"},{"mim_id":"603790","title":"SOLUTE CARRIER FAMILY 23 (NUCLEOBASE TRANSPORTER), MEMBER 1; SLC23A1","url":"https://www.omim.org/entry/603790"},{"mim_id":"314670","title":"X INACTIVATION-SPECIFIC TRANSCRIPT; XIST","url":"https://www.omim.org/entry/314670"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MATR3"},"hgnc":{"alias_symbol":["KIAA0723","MGC9105","VCPDM"],"prev_symbol":["MPD2"]},"alphafold":{"accession":"P43243","domains":[{"cath_id":"-","chopping":"274-324","consensus_level":"high","plddt":83.4061,"start":274,"end":324},{"cath_id":"3.30.70.330","chopping":"398-469","consensus_level":"high","plddt":83.8999,"start":398,"end":469},{"cath_id":"3.30.70.330","chopping":"496-581","consensus_level":"high","plddt":81.1102,"start":496,"end":581},{"cath_id":"3.30.160","chopping":"782-843","consensus_level":"high","plddt":84.9674,"start":782,"end":843}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43243","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43243-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43243-F1-predicted_aligned_error_v6.png","plddt_mean":57.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MATR3","jax_strain_url":"https://www.jax.org/strain/search?query=MATR3"},"sequence":{"accession":"P43243","fasta_url":"https://rest.uniprot.org/uniprotkb/P43243.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43243/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43243"}},"corpus_meta":[{"pmid":"25574029","id":"PMC_25574029","title":"MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25574029","citation_count":84,"is_preprint":false},{"pmid":"26493020","id":"PMC_26493020","title":"Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis.","date":"2015","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/26493020","citation_count":57,"is_preprint":false},{"pmid":"25771394","id":"PMC_25771394","title":"Mutational analysis of MATR3 in Taiwanese patients with amyotrophic lateral sclerosis.","date":"2015","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/25771394","citation_count":54,"is_preprint":false},{"pmid":"36368640","id":"PMC_36368640","title":"Matr3 reshapes m6A modification complex to alleviate macrophage inflammation during atherosclerosis.","date":"2022","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/36368640","citation_count":40,"is_preprint":false},{"pmid":"33082323","id":"PMC_33082323","title":"Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33082323","citation_count":37,"is_preprint":false},{"pmid":"33357424","id":"PMC_33357424","title":"Intronic Determinants Coordinate Charme lncRNA Nuclear Activity through the Interaction with MATR3 and PTBP1.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33357424","citation_count":33,"is_preprint":false},{"pmid":"30516047","id":"PMC_30516047","title":"RNA-Binding Proteomics Reveals MATR3 Interacting with lncRNA SNHG1 To Enhance Neuroblastoma Progression.","date":"2018","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/30516047","citation_count":31,"is_preprint":false},{"pmid":"26708275","id":"PMC_26708275","title":"MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis.","date":"2015","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/26708275","citation_count":28,"is_preprint":false},{"pmid":"30563574","id":"PMC_30563574","title":"Analysis of spinal and muscle pathology in transgenic mice overexpressing wild-type and ALS-linked mutant MATR3.","date":"2018","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/30563574","citation_count":22,"is_preprint":false},{"pmid":"31056746","id":"PMC_31056746","title":"A mutant MATR3 mouse model to explain multisystem proteinopathy.","date":"2019","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31056746","citation_count":21,"is_preprint":false},{"pmid":"33733063","id":"PMC_33733063","title":"Multilayer and MATR3-dependent regulation of mRNAs maintains pluripotency in human induced pluripotent stem cells.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/33733063","citation_count":18,"is_preprint":false},{"pmid":"37381832","id":"PMC_37381832","title":"MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37381832","citation_count":17,"is_preprint":false},{"pmid":"24558381","id":"PMC_24558381","title":"pY RNA1-s2: a highly retina-enriched small RNA that selectively binds to Matrin 3 (Matr3).","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24558381","citation_count":16,"is_preprint":false},{"pmid":"30790622","id":"PMC_30790622","title":"The nuclear matrix protein Matr3 regulates processing of the synaptic microRNA-138-5p.","date":"2019","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/30790622","citation_count":15,"is_preprint":false},{"pmid":"25523636","id":"PMC_25523636","title":"Mutation analysis of MATR3 in Australian familial amyotrophic lateral sclerosis.","date":"2014","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/25523636","citation_count":15,"is_preprint":false},{"pmid":"37156877","id":"PMC_37156877","title":"Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37156877","citation_count":14,"is_preprint":false},{"pmid":"25677933","id":"PMC_25677933","title":"Impairment of respiratory function in late-onset distal myopathy due to MATR3 Mutation.","date":"2015","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/25677933","citation_count":12,"is_preprint":false},{"pmid":"38320753","id":"PMC_38320753","title":"MATR3 pathogenic variants differentially impair its cryptic splicing repression function.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/38320753","citation_count":11,"is_preprint":false},{"pmid":"21683594","id":"PMC_21683594","title":"A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients.","date":"2011","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/21683594","citation_count":11,"is_preprint":false},{"pmid":"40610464","id":"PMC_40610464","title":"DDX1 methylation mediated MATR3 splicing regulates intervertebral disc degeneration by initiating chromatin reprogramming.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40610464","citation_count":9,"is_preprint":false},{"pmid":"35205163","id":"PMC_35205163","title":"Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35205163","citation_count":9,"is_preprint":false},{"pmid":"34182213","id":"PMC_34182213","title":"MATR3 F115C knock-in mice do not exhibit motor defects or neuropathological features of ALS.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34182213","citation_count":9,"is_preprint":false},{"pmid":"32515490","id":"PMC_32515490","title":"Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.","date":"2020","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/32515490","citation_count":9,"is_preprint":false},{"pmid":"32731393","id":"PMC_32731393","title":"The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32731393","citation_count":8,"is_preprint":false},{"pmid":"39276912","id":"PMC_39276912","title":"MATR3 promotes liver cancer progression by suppressing DHX58-mediated type I interferon response.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39276912","citation_count":7,"is_preprint":false},{"pmid":"37703175","id":"PMC_37703175","title":"MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37703175","citation_count":7,"is_preprint":false},{"pmid":"38891112","id":"PMC_38891112","title":"MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38891112","citation_count":6,"is_preprint":false},{"pmid":"34659085","id":"PMC_34659085","title":"First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease.","date":"2021","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34659085","citation_count":6,"is_preprint":false},{"pmid":"36140262","id":"PMC_36140262","title":"Matrin3 (MATR3) Expression Is Associated with Hemophagocytosis.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36140262","citation_count":4,"is_preprint":false},{"pmid":"16674563","id":"PMC_16674563","title":"Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM).","date":"2006","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16674563","citation_count":4,"is_preprint":false},{"pmid":"36689813","id":"PMC_36689813","title":"MATR3 P154S knock-in mice do not exhibit motor, muscle or neuropathologic features of ALS.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36689813","citation_count":3,"is_preprint":false},{"pmid":"36822174","id":"PMC_36822174","title":"LncRNA15691 promotes T-ALL infiltration by upregulating CCR9 via increased MATR3 stability.","date":"2023","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/36822174","citation_count":3,"is_preprint":false},{"pmid":"37913560","id":"PMC_37913560","title":"The effect on m6A methylation writer complex by the reduced MATR3 in pterygium.","date":"2023","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/37913560","citation_count":3,"is_preprint":false},{"pmid":"35812165","id":"PMC_35812165","title":"Expanding the Phenotypic Spectrum of Vocal Cord and Pharyngeal Weakness With Distal Myopathy due to the p.S85C MATR3 Mutation.","date":"2022","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35812165","citation_count":2,"is_preprint":false},{"pmid":"30366341","id":"PMC_30366341","title":"Generation and characterization of a human iPSC line from an ALS patient carrying the Q66K-MATR3 mutation.","date":"2018","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30366341","citation_count":2,"is_preprint":false},{"pmid":"39919500","id":"PMC_39919500","title":"ASFV p30 interacts with CCAR2 and MATR3 to promote ASFV replication.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39919500","citation_count":1,"is_preprint":false},{"pmid":"40790242","id":"PMC_40790242","title":"Sex-dependent epigenetic disruption of YY1 binding by prenatal BPA exposure downregulates Matr3 and alters Agap1 splicing in the offspring hippocampus.","date":"2025","source":"Biology of sex differences","url":"https://pubmed.ncbi.nlm.nih.gov/40790242","citation_count":1,"is_preprint":false},{"pmid":"39323783","id":"PMC_39323783","title":"Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39323783","citation_count":1,"is_preprint":false},{"pmid":"33388707","id":"PMC_33388707","title":"Generation of two induced pluripotent stem cell (iPSC) lines from an ALS patient with simultaneous mutations in KIF5A and MATR3 genes.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33388707","citation_count":1,"is_preprint":false},{"pmid":"39192891","id":"PMC_39192891","title":"Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39192891","citation_count":0,"is_preprint":false},{"pmid":"40447473","id":"PMC_40447473","title":"Autosomal dominant distal myopathy due to p.Ser85Cys mutation in the MATR3 gene: Novel case series and literature review.","date":"2025","source":"Revue neurologique","url":"https://pubmed.ncbi.nlm.nih.gov/40447473","citation_count":0,"is_preprint":false},{"pmid":"41849072","id":"PMC_41849072","title":"MATR3 regulates METTL3-Mediated m6A modification of MSI2 mRNA to activate the Wnt/β-Catenin pathway, exacerbating myocardial fibrosis and atrial fibrillation.","date":"2026","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/41849072","citation_count":0,"is_preprint":false},{"pmid":"28649522","id":"PMC_28649522","title":"Obstetric risk in patients with myopathy due to MATR3 mutations.","date":"2014","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/28649522","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.22.619761","title":"ALS-associated RNA binding proteins converge on  <i>UNC13A</i>  transcription through regulation of REST","date":"2024-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.22.619761","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.30.656608","title":"RNA binding regulation is a new dimension in the type I IFN response","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.656608","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.06.652480","title":"A role for the spinal cord cholinergic neuron circadian clock in RNA metabolism and mediating ALS disease phenotypes","date":"2025-05-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.652480","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21806,"output_tokens":5496,"usd":0.073929,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13916,"output_tokens":6311,"usd":0.113678,"stage2_stop_reason":"end_turn"},"total_usd":0.187607,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"The small RNA pY RNA1-s2 selectively binds to the nuclear matrix protein Matrin 3 (Matr3). This binding is highly dependent on the RNA sequence and requires both RRM domains of Matr3. Elements outside the RRM region also contribute to binding specificity, and phosphorylation of Matr3 enhances the pY RNA1-s2/Matr3 interaction.\",\n      \"method\": \"Mass spectrometric analysis of pY RNA1-s2-bound proteins from retina, Western blot, RRM domain-binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical binding assay with domain-mapping and phosphorylation follow-up, single lab\",\n      \"pmids\": [\"24558381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disruption of the MATR3 3' UTR (affecting polyadenylation and altering Matrin 3 protein expression) in a mouse gene-trap allele (Matr3 Gt-ex13) causes incompletely penetrant bicuspid aortic valve, coarctation of the aorta, patent ductus arteriosus, ventricular septal defect, and double-outlet right ventricle in heterozygotes, establishing that subtle perturbations in Matrin 3 expression cause left ventricular outflow tract defects.\",\n      \"method\": \"Mouse gene-trap model (Matr3 Gt-ex13), heterozygote phenotyping, RT-PCR/transcript analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with specific cardiovascular phenotype, single lab, corroborated by human translocation data\",\n      \"pmids\": [\"25574029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Matrin-3 interacts with pri/pre-miR-138-2 (mapped to the loop region) and exerts an inhibitory function on nuclear pri-miR-138-2 processing, thereby suppressing mature miR-138 biogenesis in neurons.\",\n      \"method\": \"Biochemical pull-down assay identifying Matrin-3 as pri/pre-miR-138 interacting protein, loss-of-function experiments in HEK293 cells and primary neurons, protein localization studies\",\n      \"journal\": \"Neurobiology of learning and memory\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical interaction plus loss-of-function with specific miRNA processing phenotype, single lab\",\n      \"pmids\": [\"30790622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MATR3 directly binds lncRNA SNHG1 in neuroblastoma cells. The direct binding was validated by Western blot after RNA protein pull-down and confirmed by RNA immunoprecipitation. MATR3 and SNHG1 co-regulate biological functions including RNA splicing.\",\n      \"method\": \"RNA-protein pull-down assay coupled with LC-MS/MS, Western blot, RNA immunoprecipitation (RIP)\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal RIP and pull-down validating direct interaction, single lab\",\n      \"pmids\": [\"30516047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MATR3 S85C knock-in mice (generated by CRISPR/Cas9 at the endogenous Matr3 locus) recapitulate early-stage ALS features including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration, and neuroinflammation. The S85C mutation causes loss of MATR3 protein in cell bodies of Purkinje cells and motor neurons, indicating that loss of MATR3 function contributes to neuronal defects.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model, behavioral assays, neuropathological histology, immunostaining\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous knock-in model with multiple orthogonal readouts (behavioral, histological, molecular), replicated across neuronal subtypes in the same study\",\n      \"pmids\": [\"33082323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Expression of wild-type or mutant MATR3 in Drosophila motor neurons reduces climbing ability and lifespan, while expression in indirect flight muscles causes abnormal wing positioning and muscle degeneration. Mutant MATR3 confers more severe phenotypes than wild-type. A candidate screen identified axonal transport genes as enhancers of the MATR3 abnormal wing phenotype; knockdown of these genes increased protein levels and insolubility of mutant MATR3, implicating axonal transport dysfunction in MATR3-related disease pathogenesis.\",\n      \"method\": \"Transgenic Drosophila expressing human MATR3 (WT and mutant), behavioral assays, candidate modifier screen, protein solubility assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila model with multiple mutants and phenotypic readouts, single lab\",\n      \"pmids\": [\"32515490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MATR3, identified via RNA antisense purification combined with mass spectrometry, binds to sequences within the alternatively spliced intron-1 of the muscle-restricted lncRNA pCharme and forms nuclear aggregates together with PTBP1. This interaction is required for pCharme's chromatin-associated activities during myogenesis.\",\n      \"method\": \"RNA antisense purification (RAP) with mass spectrometry, loss-of-function analysis, CRISPR-Cas9 intron deletion\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RAP-MS identification plus CRISPR functional validation, single lab\",\n      \"pmids\": [\"33357424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MATR3 loss-of-function in human iPSCs alters the pluripotency circuitry by multiple mechanisms: (1) MATR3 binds to the OCT4 and YTHDF1 promoters to favor their transcription; (2) MATR3 is recruited on ribosomes and controls translation of specific transcripts including NANOG and LIN28A by direct binding; (3) MATR3 downregulation affects the m6A epitranscriptomic regulation of OCT4 mRNA via YTHDF1.\",\n      \"method\": \"MATR3 knockdown in hiPSCs, chromatin immunoprecipitation (promoter binding), ribosome fractionation, RNA binding and stability assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in one study (ChIP, ribosome fractionation, RBP binding), single lab\",\n      \"pmids\": [\"33733063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MATR3 interacts with the Mettl3-Mettl14 m6A methyltransferase complex in macrophages and inhibits pro-inflammatory MAPK signaling by promoting m6A-mediated mRNA decay. Under oxLDL stimulation, MATR3 expression decreases, leading to disruption of the Mettl3-Mettl14 complex and increased inflammatory signaling.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in macrophages, in vivo atherosclerosis model, signaling pathway analysis\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex interaction plus in vivo functional validation, single lab\",\n      \"pmids\": [\"36368640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MATR3 S85C KI mice exhibit selective loss of MATR3 staining in α-motor neurons (but not γ-motor neurons) in cervical, thoracic, and lumbar spinal cord, in parvalbumin-positive interneurons, in subsets of upper motor neurons, and in hippocampal CA1 neurons, demonstrating cell-type-selective vulnerability.\",\n      \"method\": \"Histological analysis of MATR3 S85C knock-in mice, immunostaining with cell-type markers\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunohistological localization in endogenous knock-in model with cell-type markers, single lab\",\n      \"pmids\": [\"35205163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MATR3, a nuclear matrix protein, interacts with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect each other's nuclear localization. MATR3 depletion redistributes H3K27me3-modified chromatin and decreases intra-TAD interactions in TADs that highly transcribe MATR3-associated AS L1 RNAs. ALS-associated MATR3 mutants alter biophysical features of this meshwork and cause abnormal H3K27me3 staining.\",\n      \"method\": \"MATR3 depletion, Hi-C/TAD analysis, ATAC-seq, phase separation assays, immunostaining, ALS mutant comparison\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal chromatin methods (Hi-C, ATAC-seq) plus phase separation assay and ALS mutant characterization, single lab\",\n      \"pmids\": [\"37381832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression in FSHD muscle cells, rescuing cell viability and myogenic differentiation. A shorter MATR3 fragment is necessary and sufficient to block DUX4-induced toxicity to the same extent as full-length MATR3.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, gene expression assays, cell viability and differentiation assays in FSHD muscle cells, domain deletion analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction validated plus functional domain mapping with rescue experiments, single lab\",\n      \"pmids\": [\"37703175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MATR3 promotes A-to-I RNA editing of CTSB mRNA by recruiting ADAR1 to this target. Mechanistically, S-nitrosylation of CTSB promotes dephosphorylation and nuclear translocation of ADD1, which then recruits MATR3 and ADAR1 to CTSB mRNA, enabling HuR binding and mRNA stabilization.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, RNA editing assays, nuclear translocation imaging, loss-of-function experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP experiments and RIP validation establishing the ADD1/MATR3/ADAR1 complex, single lab\",\n      \"pmids\": [\"37156877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"lncRNA15691 directly binds to and stabilizes MATR3 by inhibiting its nuclear degradation mediated by PKA. MATR3 in turn upregulates CCR9 expression, promoting T-ALL cell invasion and bone marrow infiltration.\",\n      \"method\": \"RNA protein pull-down assay with LC-MS/MS, RNA immunoprecipitation (RIP) validation, loss-of-function experiments, in vivo xenograft model\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pull-down and RIP validation of interaction, functional consequence established with in vivo data, single lab\",\n      \"pmids\": [\"36822174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MATR3 interacts with the WTAP/METTL3/METTL14 m6A methyltransferase complex (co-immunoprecipitation validated). Loss of MATR3 in pterygium tissue is associated with loss of WTAP-MATR3 interaction and reduced binding of WTAP and MATR3 to 3' UTR regions of target RNA molecules.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, methylated RNA immunoprecipitation (MeRIP)\",\n      \"journal\": \"Acta histochemica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/MeRIP experiment from tissue samples, single lab, no functional reconstitution\",\n      \"pmids\": [\"37913560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of MATR3 leads to cryptic exon inclusion in many transcripts, establishing a role for MATR3 in cryptic splicing repression. The ALS-linked S85C variant reduces MATR3 solubility but does not impair RNA binding. A novel neurodevelopmental disease-associated M548T variant (in the RRM2 domain) reduces protein solubility and impairs both RNA binding and cryptic splicing repression.\",\n      \"method\": \"MATR3 loss-of-function RNA-seq, protein solubility assays, RNA binding assays, analysis of S85C and M548T variants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq-based cryptic splicing discovery combined with biochemical solubility and RNA binding assays on multiple variants, single lab\",\n      \"pmids\": [\"38320753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MATR3 binds to DHX58 mRNA through its RRM structural domain and recruits YTHDF2 (an m6A reader), leading to degradation of DHX58 mRNA and suppression of the type I IFN signaling pathway in liver cancer cells.\",\n      \"method\": \"RNA-seq, RNA immunoprecipitation, Co-immunoprecipitation, MATR3 RRM domain mutation analysis, MATR3 knockout experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level RIP mapping and co-IP of MATR3-YTHDF2 complex plus knockout functional validation, single lab\",\n      \"pmids\": [\"39276912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EZH2-mediated methylation of DDX1 at K234 disrupts DDX1's interaction with splicing factors and RNA targets, promoting exon 14 skipping in MATR3. This truncated MATR3 isoform disrupts nuclear architecture, increases chromatin accessibility, and activates Wnt signaling leading to nucleus pulposus cell senescence and apoptosis. Delivery of full-length MATR3 mRNA reduces NP cell degeneration and alleviates disc degeneration in vivo.\",\n      \"method\": \"In vitro splicing assays, AAV/mRNA delivery in vivo, chromatin accessibility (ATAC-seq), signaling pathway analysis, mass spectrometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue with full-length MATR3, single lab\",\n      \"pmids\": [\"40610464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFN-I signaling drives phospho-regulation of MATR3's RNA-binding activity, as experimentally confirmed using RNA interactome capture (RIC) comparing phosphorylation states of RNA-bound proteomes after IFN-I treatment.\",\n      \"method\": \"RNA interactome capture (RIC) with phosphorylation state profiling, knockdown screen\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab preprint, RIC method is rigorous but this specific finding on MATR3 is one of many in a large screen\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MATR3, along with FUS and hnRNPA1, binds to and downregulates REST mRNA, thereby promoting UNC13A transcription. Loss of MATR3 leads to REST upregulation in cultured cells, and REST upregulation was detected in motor neurons of ALS patients.\",\n      \"method\": \"RNA binding assays, REST mRNA quantification after RBP knockdown, motor neuron analysis from ALS patient tissue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic detail on MATR3-REST binding not extensively validated with orthogonal methods\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MATR3 interacts with METTL3 by co-immunoprecipitation and stabilizes METTL3 protein by inhibiting its proteasomal degradation. METTL3 in turn mediates m6A modification of MSI2 mRNA to enhance its stability, activating the Wnt/β-Catenin pathway and promoting myocardial fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, methylated RNA immunoprecipitation (MeRIP-qPCR), MATR3 knockdown in human atrial fibroblasts and in vivo mouse model, Western blot, proteasome inhibition assay\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with proteasome inhibition establishing MATR3-METTL3 stabilization mechanism, plus in vivo validation, single lab\",\n      \"pmids\": [\"41849072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MATR3 F115C knock-in mice generated by CRISPR/Cas9 did not exhibit motor deficits, neuropathology, MATR3 pathology, or TDP-43 pathology up to 2 years of age, indicating that the F115C mutation in MATR3 alone does not confer pathogenicity in mice.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model, behavioral testing, neuropathological examination, immunostaining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous knock-in with multiple readouts yielding a clear negative result, single lab\",\n      \"pmids\": [\"34182213\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MATR3 (Matrin-3) is a nuclear matrix RNA/DNA-binding protein (containing two RRM domains) that functions as a cryptic splicing repressor, regulates miRNA biogenesis (inhibiting pri-miR-138-2 processing), modulates chromatin organization through phase-separated meshworks with antisense LINE1 RNAs, controls m6A methyltransferase complex assembly and target mRNA stability (by recruiting METTL3-METTL14, YTHDF2, or ADAR1 to specific mRNAs), directly binds and blocks the transcription factor DUX4, promotes UNC13A expression by suppressing REST mRNA, and whose disease-linked S85C mutation reduces protein solubility and causes selective loss of MATR3 in specific neuronal subtypes leading to ALS-like neurodegeneration in knock-in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MATR3 (Matrin-3) is a nuclear matrix RNA/DNA-binding protein that acts at multiple steps of gene expression — splicing, RNA editing, m6A-dependent mRNA fate, miRNA processing, and chromatin organization [#15, #10, #12]. Its RRM domains mediate sequence-specific RNA recognition, including binding of structured RNAs such as pY RNA1-s2, where binding requires both RRMs and is enhanced by phosphorylation [#0]. MATR3 represses cryptic exon inclusion across many transcripts, and disease-linked variants that reduce its solubility (S85C, M548T) cause loss of function; the RRM2 M548T variant additionally impairs RNA binding and cryptic splicing repression [#15]. In chromatin, MATR3 partners with antisense LINE1 RNAs to form a phase-separated meshwork that organizes H3K27me3-marked chromatin and intra-TAD interactions, and ALS-associated mutants disrupt this meshwork's biophysical properties [#10]. MATR3 functions as a scaffold for m6A machinery, interacting with the METTL3–METTL14/WTAP methyltransferase complex and m6A readers (YTHDF2) to direct target mRNA stability and decay, as shown for inflammatory signaling in macrophages and for DHX58 in liver cancer [#8, #14, #16, #20]. It also recruits ADAR1 to drive A-to-I editing and stabilization of CTSB mRNA within an ADD1-dependent complex [#12]. The endogenous S85C knock-in mouse recapitulates early ALS-like features — motor impairment, NMJ defects, Purkinje and motor neuron degeneration — accompanied by cell-type-selective loss of MATR3 protein in vulnerable neuronal populations, establishing loss of MATR3 function as a contributor to neurodegeneration [#4, #9]. MATR3 additionally blocks DUX4-mediated toxicity in FSHD muscle through direct binding to the DUX4 DNA-binding domain [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that MATR3 is a sequence-specific RNA-binding protein whose recognition requires both RRM domains and is tunable by phosphorylation, defining the biochemical basis of its RNA engagement.\",\n      \"evidence\": \"Mass spectrometry of pY RNA1-s2-bound proteins from retina with RRM domain-binding and phosphorylation assays\",\n      \"pmids\": [\"24558381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological RNA targets in this context not defined\", \"Kinase responsible for the phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that subtle changes in MATR3 dosage cause developmental cardiovascular defects, showing organismal sensitivity to MATR3 expression level.\",\n      \"evidence\": \"Mouse gene-trap allele (Matr3 Gt-ex13) with 3'UTR disruption, heterozygote phenotyping\",\n      \"pmids\": [\"25574029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking MATR3 dosage to outflow tract development unknown\", \"Incomplete penetrance unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened MATR3's regulatory repertoire to lncRNA partnership, showing it directly binds SNHG1 and co-regulates RNA splicing.\",\n      \"evidence\": \"RNA-protein pull-down with LC-MS/MS and reciprocal RIP in neuroblastoma cells\",\n      \"pmids\": [\"30516047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific splicing targets co-regulated not enumerated\", \"Functional consequence beyond cell line not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed MATR3 acts in miRNA biogenesis by binding pri/pre-miR-138-2 and inhibiting its processing, extending its function to small-RNA regulation in neurons.\",\n      \"evidence\": \"Biochemical pull-down and loss-of-function in HEK293 and primary neurons\",\n      \"pmids\": [\"30790622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of processing inhibition not resolved\", \"Whether other pri-miRNAs are regulated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the strongest genetic evidence that the ALS-linked S85C mutation drives selective neurodegeneration through loss of MATR3 protein in vulnerable neurons.\",\n      \"evidence\": \"Endogenous CRISPR/Cas9 S85C knock-in mice with behavioral, histological and molecular readouts\",\n      \"pmids\": [\"33082323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of cell-body MATR3 loss not established\", \"Downstream RNA-processing changes in vivo not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated axonal transport in MATR3 proteostasis, showing transport-gene knockdown raises mutant MATR3 levels and insolubility.\",\n      \"evidence\": \"Transgenic Drosophila expressing human MATR3 with modifier screen and solubility assays\",\n      \"pmids\": [\"32515490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between transport machinery and MATR3 solubility unclear\", \"Relevance to mammalian neurons untested in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected MATR3 to muscle-specific lncRNA function and nuclear aggregation, showing it binds pCharme intron-1 with PTBP1 to support chromatin-associated activity in myogenesis.\",\n      \"evidence\": \"RAP-MS, loss-of-function, and CRISPR intron deletion\",\n      \"pmids\": [\"33357424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Composition and dynamics of the nuclear aggregates not fully defined\", \"Direct chromatin targets not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a multi-layered role for MATR3 in the pluripotency circuit — promoter binding, ribosome-associated translation control, and m6A/YTHDF1-mediated regulation of OCT4.\",\n      \"evidence\": \"MATR3 knockdown in hiPSCs with ChIP, ribosome fractionation, and RNA binding/stability assays\",\n      \"pmids\": [\"33733063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MATR3 acts as a bona fide transcriptional regulator versus indirect effect unresolved\", \"Generality of ribosome association across cell types unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that not all disease-linked MATR3 mutations are pathogenic in vivo, as F115C knock-in mice lacked phenotype, distinguishing variant-specific consequences.\",\n      \"evidence\": \"CRISPR/Cas9 F115C knock-in mice with behavioral and neuropathological examination\",\n      \"pmids\": [\"34182213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reason for genotype-phenotype discordance versus S85C not established\", \"Possible species or modifier dependence untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established MATR3 as a scaffold for the METTL3-METTL14 m6A methyltransferase complex that restrains inflammatory signaling via m6A-mediated mRNA decay.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression in macrophages, and in vivo atherosclerosis model\",\n      \"pmids\": [\"36368640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mRNA targets of the decay not fully defined\", \"Whether MATR3 directly contacts the methyltransferase or via RNA unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined cell-type-selective vulnerability by mapping which neuronal subtypes lose MATR3 in S85C mice (α- but not γ-motor neurons, parvalbumin interneurons, CA1).\",\n      \"evidence\": \"Immunohistology with cell-type markers in S85C knock-in mice\",\n      \"pmids\": [\"35205163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of selective vulnerability not explained\", \"Functional consequence per cell type not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a structural genome-organizing function: MATR3 forms a phase-separated meshwork with antisense LINE1 RNAs that controls H3K27me3 distribution and TAD interactions, disrupted by ALS mutants.\",\n      \"evidence\": \"MATR3 depletion with Hi-C, ATAC-seq, phase separation assays, and ALS mutant comparison\",\n      \"pmids\": [\"37381832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between meshwork disruption and neurodegeneration not established\", \"Determinants of AS L1 RNA selectivity unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MATR3 as a direct DUX4 antagonist, binding the DUX4 DNA-binding domain to block its toxicity and rescue FSHD muscle cells, with a minimal sufficient fragment.\",\n      \"evidence\": \"Co-IP, pull-down, domain deletion, and viability/differentiation rescue in FSHD muscle cells\",\n      \"pmids\": [\"37703175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the MATR3-DUX4 interaction not solved\", \"Endogenous relevance in patient muscle not confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed MATR3 directs A-to-I RNA editing by recruiting ADAR1 to CTSB mRNA within an S-nitrosylation/ADD1-driven complex enabling HuR-mediated stabilization.\",\n      \"evidence\": \"Co-IP, RIP, RNA editing assays, and nuclear translocation imaging\",\n      \"pmids\": [\"37156877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond CTSB unknown\", \"Order of complex assembly not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated MATR3 protein levels are controlled by lncRNA-mediated protection from PKA-dependent nuclear degradation, with downstream effects on T-ALL invasion.\",\n      \"evidence\": \"RNA-protein pull-down with LC-MS/MS, RIP, loss-of-function, and xenograft model\",\n      \"pmids\": [\"36822174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PKA-driven MATR3 degradation not detailed\", \"Direct versus indirect CCR9 regulation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked MATR3 to the WTAP/METTL3/METTL14 complex and 3'UTR target binding, supporting its role in m6A deposition on specific transcripts.\",\n      \"evidence\": \"Co-IP with mass spectrometry and MeRIP in pterygium tissue\",\n      \"pmids\": [\"37913560\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP/MeRIP from tissue without functional reconstitution\", \"Direct target mRNAs not validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined cryptic splicing repression as a core MATR3 function and distinguished variant mechanisms: S85C reduces solubility without impairing RNA binding, whereas RRM2 M548T impairs both binding and repression.\",\n      \"evidence\": \"Loss-of-function RNA-seq, protein solubility assays, and RNA binding assays on S85C/M548T variants\",\n      \"pmids\": [\"38320753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific pathogenic cryptic targets not prioritized\", \"How solubility loss translates to functional loss in vivo unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MATR3 uses its RRM domain to bind DHX58 mRNA and recruit YTHDF2 for m6A-dependent decay, suppressing type I IFN signaling in liver cancer.\",\n      \"evidence\": \"RNA-seq, RIP, co-IP, RRM mutation analysis, and MATR3 knockout\",\n      \"pmids\": [\"39276912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this decay route generalizes to other IFN regulators unknown\", \"Direct MATR3-YTHDF2 contact versus RNA bridging not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated MATR3 in ALS-relevant UNC13A regulation by binding and downregulating REST mRNA alongside FUS and hnRNPA1.\",\n      \"evidence\": \"RNA binding assays, REST quantification after RBP knockdown, and ALS patient motor neuron analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; MATR3-REST binding not validated with orthogonal methods\", \"Direct versus indirect REST regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MATR3 stabilizes METTL3 by blocking its proteasomal degradation, linking MATR3 to METTL3-dependent m6A modification of MSI2 and Wnt-driven myocardial fibrosis.\",\n      \"evidence\": \"Co-IP, MeRIP-qPCR, proteasome inhibition, knockdown in fibroblasts, and in vivo mouse model\",\n      \"pmids\": [\"41849072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MATR3 protects METTL3 from degradation not defined\", \"Whether stabilization is direct unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that an aberrant exon-14-skipped MATR3 isoform disrupts nuclear architecture and drives disc degeneration, with full-length MATR3 mRNA delivery providing in vivo rescue.\",\n      \"evidence\": \"In vitro splicing assays, ATAC-seq, mass spectrometry, and AAV/mRNA delivery in vivo\",\n      \"pmids\": [\"40610464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the truncated isoform alters chromatin mechanistically not fully resolved\", \"Translatability of mRNA delivery beyond disc not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Indicated IFN-I signaling phospho-regulates MATR3's RNA-binding activity, linking immune signaling to its function.\",\n      \"evidence\": \"RNA interactome capture with phosphorylation-state profiling and knockdown screen (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; one finding within a large screen, not independently validated\", \"Phosphosites and functional consequences for MATR3 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MATR3's diverse molecular activities (cryptic splicing repression, m6A scaffolding, RNA editing, chromatin meshwork formation) integrate to produce cell-type-selective neurodegeneration remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism connecting MATR3 loss of solubility to selective neuronal vulnerability\", \"Structural model of RNA/DNA and protein partner engagement lacking\", \"In vivo target spectrum of MATR3's m6A and editing functions not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 6, 15, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 12, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 12, 14, 16, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10, 2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 8, 12, 15, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9, 15]}\n    ],\n    \"complexes\": [\n      \"METTL3-METTL14/WTAP m6A methyltransferase complex\",\n      \"ADD1/MATR3/ADAR1 RNA-editing complex\"\n    ],\n    \"partners\": [\n      \"METTL3\",\n      \"METTL14\",\n      \"WTAP\",\n      \"YTHDF2\",\n      \"ADAR1\",\n      \"PTBP1\",\n      \"DUX4\",\n      \"ADD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}