{"gene":"HNRNPM","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1996,"finding":"hnRNPM proteins (72.5–74 kDa doublet) are components of hnRNP complexes and associate with the nuclear matrix during heat shock; monoclonal antibodies against synthetic hnRNPM peptides directly inhibit in vitro splicing, and heat-shocked nuclear extracts lacking hnRNPM lose splicing capacity, indicating hnRNPM is required for pre-mRNA splicing.","method":"Monoclonal antibody inhibition of in vitro splicing; heat-shock nuclear extract fractionation; cDNA cloning and sequencing; in situ hybridization (gene mapped to chromosome 19)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro splicing inhibition assay with antibodies, nuclear fractionation demonstrating loss of hnRNPM correlates with splicing arrest, two orthogonal methods in one study","pmids":["8692693"],"is_preprint":false},{"year":2010,"finding":"hnRNP-M directly interacts with spliceosome proteins CDC5L and PLRG1 in vivo; a central region of hnRNP-M is required for this interaction. This interaction is inhibited during heat-shock stress. An hnRNP-M mutant lacking the CDC5L/PLRG1 interaction domain cannot modulate alternative 5′ and 3′ splice site choices of an adeno-E1A mini-gene substrate.","method":"Co-immunoprecipitation (in vivo); domain deletion mutagenesis; mini-gene alternative splicing assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP identifying direct interaction, domain mutagenesis linking interaction domain to functional splicing outcome, two orthogonal methods","pmids":["20467437"],"is_preprint":false},{"year":2014,"finding":"hnRNPM promotes breast cancer metastasis by activating an alternative splicing switch during EMT, including switching CD44 from the epithelial (CD44v) to mesenchymal (CD44s) isoform. hnRNPM acts in a mesenchymal-specific manner by competing with the epithelial splicing regulator ESRP1 for the same GU-rich cis-regulatory RNA elements. Enforced CD44s expression overrides hnRNPM loss and restores EMT and metastasis.","method":"Genome-wide RNA-seq; shRNA knockdown and overexpression in cell lines and mouse metastasis models; epistasis (CD44s rescue experiment); ESRP1 competition assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (CD44s rescue), genome-wide sequencing, in vivo mouse metastasis model, competitive binding established; replicated by subsequent studies","pmids":["24840202"],"is_preprint":false},{"year":2015,"finding":"hnRNPM and p54nrb/NONO cooperate as components of protein complexes bound to both the FGF1 promoter and the FGF1 mRNA IRES to activate IRES-dependent translation during myoblast differentiation in a promoter-dependent manner. Knockdown of either protein blocks FGF1 induction and myotube formation.","method":"RNA immunoprecipitation; co-immunoprecipitation; knockdown/overexpression; mRNA transfection; promoter deletion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, promoter deletion, mRNA transfection) in a single lab establishing IRES-dependent translation role","pmids":["26332123"],"is_preprint":false},{"year":2017,"finding":"hnRNPM regulates an alternative splicing program in Ewing sarcoma cells downstream of PI3K/AKT/mTOR pathway inhibition; hnRNPM binding motifs are enriched in introns flanking BEZ235-regulated exons, and knockdown of hnRNPM abolishes a subset of BEZ235-induced splicing changes and enhances cytotoxicity.","method":"Splicing-sensitive arrays; bioinformatics motif enrichment; shRNA knockdown; clonogenicity assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing arrays plus knockdown establishing pathway position, motif enrichment linking binding to regulated exons, single lab","pmids":["29036465"],"is_preprint":false},{"year":2018,"finding":"hnRNPM and ESRP1 coregulate overlapping sets of cassette exon alternative splicing events in a largely discordant (antagonistic) manner; GU-rich motifs downstream of hnRNPM-repressed/ESRP1-enhanced exons support a model of competitive binding to these cis-elements during EMT.","method":"Genome-wide RNA-seq comparison of hnRNPM and ESRP1 splicing targets; motif enrichment analysis near coregulated exons","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide sequencing with motif analysis, single lab, mechanistic model supported computationally and by prior experimental work","pmids":["30042172"],"is_preprint":false},{"year":2018,"finding":"A cancer-associated MORC2 M276I mutation enhances binding of MORC2 to hnRNPM; this interaction promotes an hnRNPM-mediated CD44 splicing switch from CD44v to CD44s, driving EMT and lung metastasis. Knockdown of hnRNPM reduces mutant MORC2 binding to CD44 pre-mRNA and reverses the splicing switch.","method":"Co-immunoprecipitation; shRNA knockdown; splicing assays; cell migration/invasion assays; mouse lung metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, epistasis via hnRNPM knockdown reversing the phenotype, in vivo mouse model; single lab","pmids":["30093560"],"is_preprint":false},{"year":2019,"finding":"Under hypoxia, hnRNPM translocates from nucleus to cytoplasm where it binds target mRNA IRESs and promotes IRES-dependent translation initiation of a distinct set of genes involved in metabolic processes and cancer neoplasia.","method":"Proteomic/bioinformatic identification of hnRNPM as IRES-interacting factor; subcellular fractionation showing cytosolic translocation under hypoxia; transcriptomic and translatomic analyses; mouse carcinogenesis model","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple omics methods plus subcellular fractionation demonstrating localization change with functional consequence; single lab","pmids":["30852162"],"is_preprint":false},{"year":2019,"finding":"hnRNPM is a negative regulator of RLR-mediated innate antiviral signaling; viral infection causes translocation of hnRNPM from the nucleus to the cytoplasm, where it interacts with RIG-I and MDA5 and impairs their binding to viral RNA, thereby inhibiting innate antiviral responses.","method":"Overexpression and knockdown experiments; viral infection assays; Co-immunoprecipitation of hnRNPM with RIG-I and MDA5; RNA-binding competition assay; subcellular fractionation","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with RLRs, viral RNA binding competition, cytoplasmic translocation demonstrated; single lab, multiple orthogonal methods","pmids":["31433824"],"is_preprint":false},{"year":2020,"finding":"hnRNPM physically and functionally interacts with Matrin-3 (MATR3) in an RNA-dependent manner in mammalian cells; in Drosophila, rump (the hnRNPM homolog) modifies mutant MATR3 toxicity in vivo, and common RNA targets converge on biological processes important for neuronal health.","method":"Co-immunoprecipitation (RNA-dependent, mammalian cells); Drosophila genetic modifier screen; eCLIP dataset analysis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with RNA-dependence test, in vivo genetic modifier; single lab, two orthogonal systems","pmids":["32811564"],"is_preprint":false},{"year":2021,"finding":"HNRNPM binds to GU-rich elements in long flanking proximal introns of key homeostatic gene transcripts to prevent aberrant exon inclusion and backsplicing events (circular RNA formation), thereby maintaining transcriptome integrity and supporting prostate cancer cell growth.","method":"Pooled shRNA screens (in vitro and in vivo); eCLIP-seq; RNA-seq; splice-switching antisense oligonucleotides","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — eCLIP-seq defining binding sites at nucleotide resolution, in vivo shRNA screen, functional rescue with splice-switching oligonucleotides; multiple orthogonal methods","pmids":["34075878"],"is_preprint":false},{"year":2021,"finding":"hnRNPM directly interacts with CDR1as circular RNA in periodontal ligament stem cells (PDLSCs) and regulates its expression, thereby influencing PDLSC stemness through the CDR1as/miR-7/KLF4 axis.","method":"RNA immunoprecipitation; knockdown and overexpression experiments; stemness and differentiation assays","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/RIP identifying interaction, single lab, limited mechanistic follow-up on hnRNPM itself","pmids":["33837664"],"is_preprint":false},{"year":2021,"finding":"Knockdown of hnRNPM in the mouse CA1 hippocampal region impairs learning and memory, reduces pre- and post-synaptic protein levels (synaptophysin and PSD95), impairs dendritic spine morphology, and hnRNPM directly binds to the 3′UTR of synaptophysin and PSD95 mRNAs to stabilize them.","method":"In vivo shRNA knockdown in mouse CA1; behavioral memory tests; immunofluorescence/western blot; RNA immunoprecipitation (3′UTR binding)","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined phenotype, RIP demonstrating 3′UTR binding linked to mRNA stabilization; single lab","pmids":["33727124"],"is_preprint":false},{"year":2021,"finding":"circURI1 directly interacts with hnRNPM to modulate alternative splicing of genes involved in cell migration, thereby suppressing gastric cancer metastasis.","method":"RNA pulldown; RNA immunoprecipitation; alternative splicing analysis (RNA-seq); in vitro migration/invasion assays; in vivo metastasis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown and RIP establishing direct interaction, splicing outcome measured by RNA-seq, in vivo validation; single lab","pmids":["34385309"],"is_preprint":false},{"year":2022,"finding":"HNRNPM regulates alternative splicing of MBD2 pre-mRNA by binding to its flanking introns, generating isoforms with opposing roles; MBD2a promotes FZD3 expression and activates Wnt/β-catenin signaling, driving cancer stemness and immune evasion in hepatocellular carcinoma.","method":"RIP-seq; RNA-seq; chromatin immunoprecipitation; knockdown/antisense oligonucleotides; CD8+ T cell co-culture assays","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq defining intronic binding sites, splicing isoform functional characterization, in vivo tumor model; single lab","pmids":["35158098"],"is_preprint":false},{"year":2024,"finding":"hnRNPM preferentially binds to GU-rich elements at intronic LINE transposable elements in deep introns to repress pseudo splice site usage and suppress cryptic exon inclusion; loss of hnRNPM leads to cryptic exons that generate long dsRNAs (via base-pairing of inverted ALU elements among LINEs), triggering an interferon response.","method":"eCLIP-seq; RNA-seq; loss-of-function experiments; dsRNA detection; interferon pathway analysis; immune cell infiltration analysis in hnRNPM-deficient tumors","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — eCLIP-seq at nucleotide resolution linking binding to cryptic splicing suppression, functional dsRNA/IFN pathway consequence demonstrated, multiple orthogonal methods","pmids":["38815579"],"is_preprint":false},{"year":2024,"finding":"hnRNPM is a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS/STING and RIG-I/MAVS pathways; hnRNPM interacts with ELAVL1/HuR, TBK1, IKKε, IKKβ, and NF-κB p65, and confocal microscopy shows cytosolic/perinuclear co-localization of hnRNPM, ELAVL1, and TBK1.","method":"Interactome analysis by mass spectrometry; genome editing (knockouts); confocal microscopy; viral infection assays (HSV-1, Sendai virus); IRF3 phosphorylation assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome, CRISPR KO, direct confocal localization, IRF3 phosphorylation assay; single lab but multiple orthogonal methods","pmids":["39707025"],"is_preprint":false},{"year":2024,"finding":"FMRP interacts with hnRNPM to recognize splice sites and modulate exon-skipping splicing of SLC7A11 pre-mRNA, generating a specific SLC7A11-S splice variant that promotes ferroptosis resistance in breast cancer cells.","method":"Co-immunoprecipitation of FMRP and hnRNPM; splicing assays; overexpression/knockdown experiments; ferroptosis assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing protein interaction, functional splicing assay linking hnRNPM to isoform production and ferroptosis outcome; single lab","pmids":["39388855"],"is_preprint":false},{"year":2024,"finding":"PARP4 interacts with hnRNPM as a novel binding partner (identified by quantitative mass spectrometry interactomics); loss of PARP4 or hnRNPM results in overlapping intronic splicing perturbations and promotes lung adenocarcinoma tumorigenicity.","method":"Quantitative mass spectrometry interactomics; transcriptomic splicing analysis; in vitro and in vivo tumorigenicity assays","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactomics identifying interaction, convergent splicing phenotype on PARP4 and hnRNPM loss; single lab","pmids":["39034402"],"is_preprint":false},{"year":2025,"finding":"hnRNPM is SUMOylated at lysine 17; SENP1 is the de-SUMOylation enzyme (eraser). SUMOylated hnRNPM interacts with PFKFB3 and inhibits its phosphorylation and nuclear localization, thereby suppressing glycolysis. SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice.","method":"Global SUMOylated proteomic screening; site-specific mutagenesis (K17); Co-immunoprecipitation; SUMO-deficient mutant in vivo mouse model; lactate production and PFKFB3 phosphorylation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — proteomic identification of SUMOylation site, mutagenesis, Co-IP with PFKFB3, in vivo mouse model; single lab but multiple orthogonal methods","pmids":["39983892"],"is_preprint":false},{"year":2025,"finding":"hnRNPM interacts with PTBP1 to co-regulate alternative splicing during spermatogenesis; conditional knockout of hnRNPM in germ cells causes male infertility, sperm morphology defects, and 1617 alternative splicing changes including abnormal exon skipping in Cep152, Cyld, Inpp4b, and Cd59b.","method":"Conditional knockout mouse model; co-immunoprecipitation and mass spectrometry (identifying PTBP1 interaction); RNA-seq (alternative splicing analysis)","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined fertility phenotype, Co-IP/MS identifying PTBP1 interaction, genome-wide splicing analysis; single lab","pmids":["39780247"],"is_preprint":false},{"year":2025,"finding":"AURKB binds to HNRNPM and interferes with HNRNPM's interaction with PSAT1 mRNA, thereby suppressing HNRNPM-mediated PSAT1 mRNA degradation and increasing PSAT1 protein levels; this represents a kinase-independent oncogenic function of AURKB in colorectal cancer.","method":"Co-immunoprecipitation; proximity ligation assay; RNA immunoprecipitation-qPCR; mRNA stability assays; mass spectrometry","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PLA, RIP-qPCR, and mRNA stability assay together establishing mechanism; single lab, multiple orthogonal methods","pmids":["40784984"],"is_preprint":false},{"year":2025,"finding":"hnRNPM directly binds via its RRM2 domain to constitutive exon 9 of PLEKHB2 pre-mRNA, facilitating skipping of alternative exon 8 and generating the PLEKHB2-S isoform that promotes colorectal cancer cell proliferation.","method":"In vivo CLIP assay; minigene reporter splicing assay; RNA-seq; knockdown experiments in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — CLIP defining RRM2 binding to specific pre-mRNA sequence, minigene splicing assay; single lab, two orthogonal methods","pmids":["41109930"],"is_preprint":false},{"year":2025,"finding":"hnRNPM interacts with BCAS2 (a known splicing factor) in oocytes and modulates BCAS2 binding to pre-mRNA loci to control alternative splicing; conditional ablation of hnRNPM in oocytes causes cytoplasmic defects, meiotic arrest, and complete female infertility, with widespread alternative splicing disruption identified by SCAN-seq and LACE-seq.","method":"Genetic ablation (conditional knockout); SCAN-seq (novel isoform discovery); LACE-seq (single-nucleotide resolution binding sites); Co-immunoprecipitation of hnRNPM with BCAS2","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo KO with complete fertility phenotype, LACE-seq at single-nucleotide resolution, Co-IP with BCAS2, multiple orthogonal sequencing methods","pmids":["41680151"],"is_preprint":false},{"year":2025,"finding":"hnRNPM promotes apoptosis in pseudorabies virus (PRV)-infected cells by upregulating cleaved caspase-3, -6, -7, and Bax while downregulating Bcl-2; PRV infection induces nuclear translocation of hnRNPM, and hnRNPM co-localizes with caspase-6.","method":"Overexpression and knockdown in PK15/3D4/21 cells; viral replication assays; western blot for apoptosis markers; subcellular fractionation; co-localization (immunofluorescence)","journal":"Veterinary microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-localization without biochemical interaction proof, no mechanistic link beyond correlation of translocation and apoptosis markers","pmids":["40068468"],"is_preprint":false},{"year":2025,"finding":"KHSRP interacts with hnRNPM, which directly binds to GPX4 mRNA; hnRNPM overexpression rescues the decrease in GPX4 expression and ferroptosis induced by KHSRP knockdown, indicating that the KHSRP-hnRNPM complex regulates GPX4 mRNA stability post-transcriptionally.","method":"Co-immunoprecipitation; RNA immunoprecipitation; knockdown/overexpression rescue experiments; ferroptosis assays (lipid peroxidation, MDA, GSH)","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction, rescue experiment; single lab, limited mechanistic dissection of hnRNPM's direct role","pmids":["41176204"],"is_preprint":false}],"current_model":"HNRNPM is a nuclear RNA-binding protein that uses its RRM domains to bind GU-rich intronic elements on pre-mRNA, where it functions primarily as a splicing regulator—suppressing cryptic exon inclusion (including from LINE-embedded pseudo splice sites) and driving alternative splicing programs (e.g., the CD44v-to-CD44s switch during EMT by competing with ESRP1); it interacts directly with spliceosome components CDC5L/PLRG1 (requiring a central domain), PTBP1, and BCAS2 to modulate splice site choices across diverse biological contexts including cancer metastasis, spermatogenesis, and oocyte development; under stress (hypoxia or viral infection) hnRNPM translocates to the cytoplasm where it can promote IRES-dependent translation or engage with RIG-I/MDA5/TBK1 complexes to regulate innate immune signaling; additionally, SUMOylation of hnRNPM at K17 (with SENP1 as the eraser) redirects it to interact with PFKFB3 and suppress glycolysis, revealing a non-splicing metabolic function."},"narrative":{"mechanistic_narrative":"HNRNPM is a nuclear RNA-binding protein and core hnRNP complex component that functions principally as a pre-mRNA splicing regulator, recognizing GU-rich intronic cis-elements to direct splice site choice across development, cancer, and gametogenesis [PMID:8692693, PMID:24840202, PMID:34075878]. It executes splicing decisions by physically engaging spliceosome and accessory splicing factors—CDC5L/PLRG1 through a central interaction domain required for modulating 5′ and 3′ splice site selection [PMID:20467437], PTBP1 during spermatogenesis [PMID:39780247], and BCAS2 during oocyte maturation [PMID:41680151]—and by binding GU-rich elements through its RRM domains, including RRM2-mediated recognition of specific pre-mRNA exons [PMID:41109930]. A central activity is suppression of cryptic and aberrant splicing: HNRNPM binds GU-rich elements in long flanking introns and at intronic LINE elements to repress pseudo splice sites, prevent backsplicing, and block cryptic exon inclusion, thereby safeguarding transcriptome integrity; its loss generates cryptic exons that form long dsRNAs and trigger an interferon response [PMID:34075878, PMID:38815579]. In cancer it drives the mesenchymal CD44s splicing program during EMT by competing with the epithelial regulator ESRP1 for shared GU-rich elements, promoting metastasis [PMID:24840202, PMID:30042172, PMID:30093560]. Beyond splicing, HNRNPM acts post-transcriptionally to stabilize or degrade target mRNAs [PMID:33727124, PMID:40784984], and under stress it translocates to the cytoplasm to promote IRES-dependent translation and to modulate innate antiviral signaling through RIG-I/MDA5/TBK1 pathway components [PMID:30852162, PMID:31433824, PMID:39707025]. SUMOylation at K17, reversed by SENP1, redirects HNRNPM to interact with PFKFB3 and suppress glycolysis, defining a non-splicing metabolic role [PMID:39983892].","teleology":[{"year":1996,"claim":"Established that HNRNPM is not merely a structural hnRNP component but is functionally required for pre-mRNA splicing, linking it to the core splicing machinery.","evidence":"Monoclonal antibody inhibition of in vitro splicing and heat-shock nuclear extract fractionation","pmids":["8692693"],"confidence":"High","gaps":["Did not define RNA sequence specificity or which splicing steps HNRNPM acts on","No domain mapping of the splicing-relevant activity"]},{"year":2010,"claim":"Identified the molecular basis by which HNRNPM influences splice site choice—direct interaction with spliceosome proteins CDC5L/PLRG1 via a central domain whose deletion abolishes splicing modulation.","evidence":"Reciprocal Co-IP, domain deletion mutagenesis, and adeno-E1A minigene alternative splicing assay","pmids":["20467437"],"confidence":"High","gaps":["Did not map the RNA-binding determinants of splice site selection","Stress-induced loss of interaction not linked to specific transcripts"]},{"year":2014,"claim":"Defined a physiological splicing program for HNRNPM in cancer—driving the CD44v-to-CD44s switch during EMT by competing with ESRP1 for GU-rich elements, establishing it as a metastasis driver.","evidence":"Genome-wide RNA-seq, knockdown/overexpression, CD44s epistasis rescue, and mouse metastasis models","pmids":["24840202"],"confidence":"High","gaps":["Mechanism of mesenchymal-specific activity not fully resolved","Did not establish nucleotide-resolution binding sites"]},{"year":2015,"claim":"Revealed a non-splicing cytoplasmic function—HNRNPM cooperates with NONO on the FGF1 IRES to activate IRES-dependent translation during myoblast differentiation.","evidence":"RIP, Co-IP, promoter deletion, and mRNA transfection assays","pmids":["26332123"],"confidence":"Medium","gaps":["Mechanism of promoter-dependent IRES activation unclear","Did not address how nuclear HNRNPM accesses cytoplasmic IRESs"]},{"year":2017,"claim":"Placed HNRNPM-dependent splicing downstream of PI3K/AKT/mTOR signaling, connecting an oncogenic pathway to its alternative splicing output.","evidence":"Splicing-sensitive arrays, motif enrichment, and shRNA knockdown with clonogenicity assays in Ewing sarcoma","pmids":["29036465"],"confidence":"Medium","gaps":["How mTOR signaling regulates HNRNPM activity is unknown","Direct binding to regulated exons inferred from motifs, not measured"]},{"year":2018,"claim":"Consolidated the ESRP1-antagonism model genome-wide and identified MORC2 as a partner whose cancer mutation enhances HNRNPM-driven CD44 switching.","evidence":"Genome-wide RNA-seq comparison with motif analysis (idx 5); Co-IP, splicing/migration assays, and lung metastasis model (idx 6)","pmids":["30042172","30093560"],"confidence":"Medium","gaps":["Competition with ESRP1 supported computationally rather than by direct biochemical assay","How MORC2 mutation enhances HNRNPM recruitment to pre-mRNA not structurally defined"]},{"year":2019,"claim":"Demonstrated stress-induced nuclear-to-cytoplasmic relocalization as a switch between functions—promoting IRES translation under hypoxia and suppressing RIG-I/MDA5 antiviral signaling during infection.","evidence":"Subcellular fractionation, omics, Co-IP with RIG-I/MDA5, and viral RNA-binding competition assays","pmids":["30852162","31433824"],"confidence":"Medium","gaps":["Trigger and machinery controlling translocation undefined","Antiviral role here is negative, in tension with later positive regulation"]},{"year":2020,"claim":"Linked HNRNPM to neurodegeneration biology through an RNA-dependent interaction with MATR3 and modification of mutant MATR3 toxicity in vivo.","evidence":"RNA-dependent Co-IP in mammalian cells, Drosophila genetic modifier screen, and eCLIP analysis","pmids":["32811564"],"confidence":"Medium","gaps":["Shared target processing not mechanistically dissected","RNA-dependent nature leaves direct vs bridged interaction open"]},{"year":2021,"claim":"Defined HNRNPM as a transcriptome guardian—binding GU-rich elements in long flanking introns to prevent aberrant exon inclusion and circRNA backsplicing—and extended its roles to mRNA stability and circRNA binding.","evidence":"eCLIP-seq, in vivo shRNA screen, splice-switching oligos (idx 10); RIP/3'UTR binding in hippocampus (idx 12); circRNA RIP (idx 11, 13)","pmids":["34075878","33727124","34385309","33837664"],"confidence":"High","gaps":["How HNRNPM discriminates productive from aberrant splice sites unresolved","mRNA stabilization mechanism (3'UTR binding to half-life) not biochemically defined"]},{"year":2022,"claim":"Showed HNRNPM intronic binding generates functionally opposing splice isoforms (MBD2a/b) that control Wnt signaling and tumor immune evasion.","evidence":"RIP-seq, RNA-seq, ChIP, antisense oligos, and CD8+ T cell co-culture in HCC","pmids":["35158098"],"confidence":"Medium","gaps":["Determinants of isoform-specific outcome not generalized","Direct vs indirect control of FZD3/Wnt axis incompletely resolved"]},{"year":2024,"claim":"Provided the most mechanistic view of cryptic exon suppression—HNRNPM represses LINE-embedded pseudo splice sites; its loss generates dsRNA-forming cryptic exons that trigger interferon—and revealed positive antiviral and ferroptosis-regulating splicing roles plus PARP4 as a partner.","evidence":"eCLIP-seq and dsRNA/IFN analysis (idx 15); MS interactome, KO, and IRF3 phosphorylation (idx 16); FMRP Co-IP and SLC7A11 splicing (idx 17); MS interactomics with PARP4 (idx 18)","pmids":["38815579","39707025","39388855","39034402"],"confidence":"High","gaps":["Positive (idx 16) versus negative (idx 8) regulation of innate immunity not reconciled","How HNRNPM selectively targets LINE-proximal GU elements unknown"]},{"year":2025,"claim":"Established essential physiological splicing roles in gametogenesis via PTBP1 and BCAS2 partnerships, and uncovered a SUMOylation-controlled metabolic function and additional mRNA-fate partnerships (AURKB, KHSRP).","evidence":"Conditional KO with Co-IP/MS for PTBP1 (idx 20) and BCAS2 with LACE-seq (idx 23); SUMO proteomics, K17 mutagenesis, and PFKFB3 Co-IP (idx 19); Co-IP/PLA/RIP for AURKB-PSAT1 (idx 21); CLIP/minigene for PLEKHB2 (idx 22)","pmids":["39780247","41680151","39983892","40784984","41109930","41176204","40068468"],"confidence":"High","gaps":["Whether SUMOylation reciprocally gates splicing vs metabolic functions unknown","Coordination among the many partner-specific roles in a single cell unresolved"]},{"year":null,"claim":"It remains unknown how a single GU-rich RNA-binding protein partitions among its splicing, mRNA-stability, translational, antiviral, and metabolic roles, and what cellular signals select among its many distinct protein partners.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking SUMOylation, localization, and partner choice","Opposing antiviral roles across studies unreconciled","No high-resolution structure of HNRNPM bound to RNA or to spliceosome partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,10,15,22,23]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,10,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,8,16]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,10,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,14,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6,19]}],"complexes":["hnRNP complex","spliceosome"],"partners":["CDC5L","PLRG1","PTBP1","BCAS2","ESRP1","NONO","MATR3","PFKFB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52272","full_name":"Heterogeneous nuclear ribonucleoprotein M","aliases":[],"length_aa":730,"mass_kda":77.5,"function":"Pre-mRNA binding protein in vivo, binds avidly to poly(G) and poly(U) RNA homopolymers in vitro. Involved in splicing. Acts as a receptor for carcinoembryonic antigen in Kupffer cells, may initiate a series of signaling events leading to tyrosine phosphorylation of proteins and induction of IL-1 alpha, IL-6, IL-10 and tumor necrosis factor alpha cytokines","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P52272/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPM","classification":"Common Essential","n_dependent_lines":1102,"n_total_lines":1208,"dependency_fraction":0.9122516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":4.0},{"gene":"DDX21","stoichiometry":4.0},{"gene":"SSRP1","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPM","total_profiled":1310},"omim":[{"mim_id":"619395","title":"MYELIN EXPRESSION FACTOR 2; MYEF2","url":"https://www.omim.org/entry/619395"},{"mim_id":"160994","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN M; HNRNPM","url":"https://www.omim.org/entry/160994"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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This interaction is inhibited during heat-shock stress. An hnRNP-M mutant lacking the CDC5L/PLRG1 interaction domain cannot modulate alternative 5′ and 3′ splice site choices of an adeno-E1A mini-gene substrate.\",\n      \"method\": \"Co-immunoprecipitation (in vivo); domain deletion mutagenesis; mini-gene alternative splicing assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP identifying direct interaction, domain mutagenesis linking interaction domain to functional splicing outcome, two orthogonal methods\",\n      \"pmids\": [\"20467437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPM promotes breast cancer metastasis by activating an alternative splicing switch during EMT, including switching CD44 from the epithelial (CD44v) to mesenchymal (CD44s) isoform. hnRNPM acts in a mesenchymal-specific manner by competing with the epithelial splicing regulator ESRP1 for the same GU-rich cis-regulatory RNA elements. Enforced CD44s expression overrides hnRNPM loss and restores EMT and metastasis.\",\n      \"method\": \"Genome-wide RNA-seq; shRNA knockdown and overexpression in cell lines and mouse metastasis models; epistasis (CD44s rescue experiment); ESRP1 competition assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (CD44s rescue), genome-wide sequencing, in vivo mouse metastasis model, competitive binding established; replicated by subsequent studies\",\n      \"pmids\": [\"24840202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPM and p54nrb/NONO cooperate as components of protein complexes bound to both the FGF1 promoter and the FGF1 mRNA IRES to activate IRES-dependent translation during myoblast differentiation in a promoter-dependent manner. Knockdown of either protein blocks FGF1 induction and myotube formation.\",\n      \"method\": \"RNA immunoprecipitation; co-immunoprecipitation; knockdown/overexpression; mRNA transfection; promoter deletion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, Co-IP, promoter deletion, mRNA transfection) in a single lab establishing IRES-dependent translation role\",\n      \"pmids\": [\"26332123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPM regulates an alternative splicing program in Ewing sarcoma cells downstream of PI3K/AKT/mTOR pathway inhibition; hnRNPM binding motifs are enriched in introns flanking BEZ235-regulated exons, and knockdown of hnRNPM abolishes a subset of BEZ235-induced splicing changes and enhances cytotoxicity.\",\n      \"method\": \"Splicing-sensitive arrays; bioinformatics motif enrichment; shRNA knockdown; clonogenicity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing arrays plus knockdown establishing pathway position, motif enrichment linking binding to regulated exons, single lab\",\n      \"pmids\": [\"29036465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNPM and ESRP1 coregulate overlapping sets of cassette exon alternative splicing events in a largely discordant (antagonistic) manner; GU-rich motifs downstream of hnRNPM-repressed/ESRP1-enhanced exons support a model of competitive binding to these cis-elements during EMT.\",\n      \"method\": \"Genome-wide RNA-seq comparison of hnRNPM and ESRP1 splicing targets; motif enrichment analysis near coregulated exons\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide sequencing with motif analysis, single lab, mechanistic model supported computationally and by prior experimental work\",\n      \"pmids\": [\"30042172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A cancer-associated MORC2 M276I mutation enhances binding of MORC2 to hnRNPM; this interaction promotes an hnRNPM-mediated CD44 splicing switch from CD44v to CD44s, driving EMT and lung metastasis. Knockdown of hnRNPM reduces mutant MORC2 binding to CD44 pre-mRNA and reverses the splicing switch.\",\n      \"method\": \"Co-immunoprecipitation; shRNA knockdown; splicing assays; cell migration/invasion assays; mouse lung metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, epistasis via hnRNPM knockdown reversing the phenotype, in vivo mouse model; single lab\",\n      \"pmids\": [\"30093560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under hypoxia, hnRNPM translocates from nucleus to cytoplasm where it binds target mRNA IRESs and promotes IRES-dependent translation initiation of a distinct set of genes involved in metabolic processes and cancer neoplasia.\",\n      \"method\": \"Proteomic/bioinformatic identification of hnRNPM as IRES-interacting factor; subcellular fractionation showing cytosolic translocation under hypoxia; transcriptomic and translatomic analyses; mouse carcinogenesis model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple omics methods plus subcellular fractionation demonstrating localization change with functional consequence; single lab\",\n      \"pmids\": [\"30852162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPM is a negative regulator of RLR-mediated innate antiviral signaling; viral infection causes translocation of hnRNPM from the nucleus to the cytoplasm, where it interacts with RIG-I and MDA5 and impairs their binding to viral RNA, thereby inhibiting innate antiviral responses.\",\n      \"method\": \"Overexpression and knockdown experiments; viral infection assays; Co-immunoprecipitation of hnRNPM with RIG-I and MDA5; RNA-binding competition assay; subcellular fractionation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with RLRs, viral RNA binding competition, cytoplasmic translocation demonstrated; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31433824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPM physically and functionally interacts with Matrin-3 (MATR3) in an RNA-dependent manner in mammalian cells; in Drosophila, rump (the hnRNPM homolog) modifies mutant MATR3 toxicity in vivo, and common RNA targets converge on biological processes important for neuronal health.\",\n      \"method\": \"Co-immunoprecipitation (RNA-dependent, mammalian cells); Drosophila genetic modifier screen; eCLIP dataset analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with RNA-dependence test, in vivo genetic modifier; single lab, two orthogonal systems\",\n      \"pmids\": [\"32811564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HNRNPM binds to GU-rich elements in long flanking proximal introns of key homeostatic gene transcripts to prevent aberrant exon inclusion and backsplicing events (circular RNA formation), thereby maintaining transcriptome integrity and supporting prostate cancer cell growth.\",\n      \"method\": \"Pooled shRNA screens (in vitro and in vivo); eCLIP-seq; RNA-seq; splice-switching antisense oligonucleotides\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — eCLIP-seq defining binding sites at nucleotide resolution, in vivo shRNA screen, functional rescue with splice-switching oligonucleotides; multiple orthogonal methods\",\n      \"pmids\": [\"34075878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPM directly interacts with CDR1as circular RNA in periodontal ligament stem cells (PDLSCs) and regulates its expression, thereby influencing PDLSC stemness through the CDR1as/miR-7/KLF4 axis.\",\n      \"method\": \"RNA immunoprecipitation; knockdown and overexpression experiments; stemness and differentiation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/RIP identifying interaction, single lab, limited mechanistic follow-up on hnRNPM itself\",\n      \"pmids\": [\"33837664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of hnRNPM in the mouse CA1 hippocampal region impairs learning and memory, reduces pre- and post-synaptic protein levels (synaptophysin and PSD95), impairs dendritic spine morphology, and hnRNPM directly binds to the 3′UTR of synaptophysin and PSD95 mRNAs to stabilize them.\",\n      \"method\": \"In vivo shRNA knockdown in mouse CA1; behavioral memory tests; immunofluorescence/western blot; RNA immunoprecipitation (3′UTR binding)\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined phenotype, RIP demonstrating 3′UTR binding linked to mRNA stabilization; single lab\",\n      \"pmids\": [\"33727124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circURI1 directly interacts with hnRNPM to modulate alternative splicing of genes involved in cell migration, thereby suppressing gastric cancer metastasis.\",\n      \"method\": \"RNA pulldown; RNA immunoprecipitation; alternative splicing analysis (RNA-seq); in vitro migration/invasion assays; in vivo metastasis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown and RIP establishing direct interaction, splicing outcome measured by RNA-seq, in vivo validation; single lab\",\n      \"pmids\": [\"34385309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HNRNPM regulates alternative splicing of MBD2 pre-mRNA by binding to its flanking introns, generating isoforms with opposing roles; MBD2a promotes FZD3 expression and activates Wnt/β-catenin signaling, driving cancer stemness and immune evasion in hepatocellular carcinoma.\",\n      \"method\": \"RIP-seq; RNA-seq; chromatin immunoprecipitation; knockdown/antisense oligonucleotides; CD8+ T cell co-culture assays\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq defining intronic binding sites, splicing isoform functional characterization, in vivo tumor model; single lab\",\n      \"pmids\": [\"35158098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPM preferentially binds to GU-rich elements at intronic LINE transposable elements in deep introns to repress pseudo splice site usage and suppress cryptic exon inclusion; loss of hnRNPM leads to cryptic exons that generate long dsRNAs (via base-pairing of inverted ALU elements among LINEs), triggering an interferon response.\",\n      \"method\": \"eCLIP-seq; RNA-seq; loss-of-function experiments; dsRNA detection; interferon pathway analysis; immune cell infiltration analysis in hnRNPM-deficient tumors\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — eCLIP-seq at nucleotide resolution linking binding to cryptic splicing suppression, functional dsRNA/IFN pathway consequence demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"38815579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPM is a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS/STING and RIG-I/MAVS pathways; hnRNPM interacts with ELAVL1/HuR, TBK1, IKKε, IKKβ, and NF-κB p65, and confocal microscopy shows cytosolic/perinuclear co-localization of hnRNPM, ELAVL1, and TBK1.\",\n      \"method\": \"Interactome analysis by mass spectrometry; genome editing (knockouts); confocal microscopy; viral infection assays (HSV-1, Sendai virus); IRF3 phosphorylation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome, CRISPR KO, direct confocal localization, IRF3 phosphorylation assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39707025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FMRP interacts with hnRNPM to recognize splice sites and modulate exon-skipping splicing of SLC7A11 pre-mRNA, generating a specific SLC7A11-S splice variant that promotes ferroptosis resistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of FMRP and hnRNPM; splicing assays; overexpression/knockdown experiments; ferroptosis assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing protein interaction, functional splicing assay linking hnRNPM to isoform production and ferroptosis outcome; single lab\",\n      \"pmids\": [\"39388855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP4 interacts with hnRNPM as a novel binding partner (identified by quantitative mass spectrometry interactomics); loss of PARP4 or hnRNPM results in overlapping intronic splicing perturbations and promotes lung adenocarcinoma tumorigenicity.\",\n      \"method\": \"Quantitative mass spectrometry interactomics; transcriptomic splicing analysis; in vitro and in vivo tumorigenicity assays\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactomics identifying interaction, convergent splicing phenotype on PARP4 and hnRNPM loss; single lab\",\n      \"pmids\": [\"39034402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPM is SUMOylated at lysine 17; SENP1 is the de-SUMOylation enzyme (eraser). SUMOylated hnRNPM interacts with PFKFB3 and inhibits its phosphorylation and nuclear localization, thereby suppressing glycolysis. SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice.\",\n      \"method\": \"Global SUMOylated proteomic screening; site-specific mutagenesis (K17); Co-immunoprecipitation; SUMO-deficient mutant in vivo mouse model; lactate production and PFKFB3 phosphorylation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomic identification of SUMOylation site, mutagenesis, Co-IP with PFKFB3, in vivo mouse model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39983892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPM interacts with PTBP1 to co-regulate alternative splicing during spermatogenesis; conditional knockout of hnRNPM in germ cells causes male infertility, sperm morphology defects, and 1617 alternative splicing changes including abnormal exon skipping in Cep152, Cyld, Inpp4b, and Cd59b.\",\n      \"method\": \"Conditional knockout mouse model; co-immunoprecipitation and mass spectrometry (identifying PTBP1 interaction); RNA-seq (alternative splicing analysis)\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined fertility phenotype, Co-IP/MS identifying PTBP1 interaction, genome-wide splicing analysis; single lab\",\n      \"pmids\": [\"39780247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AURKB binds to HNRNPM and interferes with HNRNPM's interaction with PSAT1 mRNA, thereby suppressing HNRNPM-mediated PSAT1 mRNA degradation and increasing PSAT1 protein levels; this represents a kinase-independent oncogenic function of AURKB in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation; proximity ligation assay; RNA immunoprecipitation-qPCR; mRNA stability assays; mass spectrometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PLA, RIP-qPCR, and mRNA stability assay together establishing mechanism; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40784984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPM directly binds via its RRM2 domain to constitutive exon 9 of PLEKHB2 pre-mRNA, facilitating skipping of alternative exon 8 and generating the PLEKHB2-S isoform that promotes colorectal cancer cell proliferation.\",\n      \"method\": \"In vivo CLIP assay; minigene reporter splicing assay; RNA-seq; knockdown experiments in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CLIP defining RRM2 binding to specific pre-mRNA sequence, minigene splicing assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"41109930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPM interacts with BCAS2 (a known splicing factor) in oocytes and modulates BCAS2 binding to pre-mRNA loci to control alternative splicing; conditional ablation of hnRNPM in oocytes causes cytoplasmic defects, meiotic arrest, and complete female infertility, with widespread alternative splicing disruption identified by SCAN-seq and LACE-seq.\",\n      \"method\": \"Genetic ablation (conditional knockout); SCAN-seq (novel isoform discovery); LACE-seq (single-nucleotide resolution binding sites); Co-immunoprecipitation of hnRNPM with BCAS2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo KO with complete fertility phenotype, LACE-seq at single-nucleotide resolution, Co-IP with BCAS2, multiple orthogonal sequencing methods\",\n      \"pmids\": [\"41680151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPM promotes apoptosis in pseudorabies virus (PRV)-infected cells by upregulating cleaved caspase-3, -6, -7, and Bax while downregulating Bcl-2; PRV infection induces nuclear translocation of hnRNPM, and hnRNPM co-localizes with caspase-6.\",\n      \"method\": \"Overexpression and knockdown in PK15/3D4/21 cells; viral replication assays; western blot for apoptosis markers; subcellular fractionation; co-localization (immunofluorescence)\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-localization without biochemical interaction proof, no mechanistic link beyond correlation of translocation and apoptosis markers\",\n      \"pmids\": [\"40068468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KHSRP interacts with hnRNPM, which directly binds to GPX4 mRNA; hnRNPM overexpression rescues the decrease in GPX4 expression and ferroptosis induced by KHSRP knockdown, indicating that the KHSRP-hnRNPM complex regulates GPX4 mRNA stability post-transcriptionally.\",\n      \"method\": \"Co-immunoprecipitation; RNA immunoprecipitation; knockdown/overexpression rescue experiments; ferroptosis assays (lipid peroxidation, MDA, GSH)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction, rescue experiment; single lab, limited mechanistic dissection of hnRNPM's direct role\",\n      \"pmids\": [\"41176204\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPM is a nuclear RNA-binding protein that uses its RRM domains to bind GU-rich intronic elements on pre-mRNA, where it functions primarily as a splicing regulator—suppressing cryptic exon inclusion (including from LINE-embedded pseudo splice sites) and driving alternative splicing programs (e.g., the CD44v-to-CD44s switch during EMT by competing with ESRP1); it interacts directly with spliceosome components CDC5L/PLRG1 (requiring a central domain), PTBP1, and BCAS2 to modulate splice site choices across diverse biological contexts including cancer metastasis, spermatogenesis, and oocyte development; under stress (hypoxia or viral infection) hnRNPM translocates to the cytoplasm where it can promote IRES-dependent translation or engage with RIG-I/MDA5/TBK1 complexes to regulate innate immune signaling; additionally, SUMOylation of hnRNPM at K17 (with SENP1 as the eraser) redirects it to interact with PFKFB3 and suppress glycolysis, revealing a non-splicing metabolic function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPM is a nuclear RNA-binding protein and core hnRNP complex component that functions principally as a pre-mRNA splicing regulator, recognizing GU-rich intronic cis-elements to direct splice site choice across development, cancer, and gametogenesis [#0, #2, #10]. It executes splicing decisions by physically engaging spliceosome and accessory splicing factors—CDC5L/PLRG1 through a central interaction domain required for modulating 5′ and 3′ splice site selection [#1], PTBP1 during spermatogenesis [#20], and BCAS2 during oocyte maturation [#23]—and by binding GU-rich elements through its RRM domains, including RRM2-mediated recognition of specific pre-mRNA exons [#22]. A central activity is suppression of cryptic and aberrant splicing: HNRNPM binds GU-rich elements in long flanking introns and at intronic LINE elements to repress pseudo splice sites, prevent backsplicing, and block cryptic exon inclusion, thereby safeguarding transcriptome integrity; its loss generates cryptic exons that form long dsRNAs and trigger an interferon response [#10, #15]. In cancer it drives the mesenchymal CD44s splicing program during EMT by competing with the epithelial regulator ESRP1 for shared GU-rich elements, promoting metastasis [#2, #5, #6]. Beyond splicing, HNRNPM acts post-transcriptionally to stabilize or degrade target mRNAs [#12, #21], and under stress it translocates to the cytoplasm to promote IRES-dependent translation and to modulate innate antiviral signaling through RIG-I/MDA5/TBK1 pathway components [#7, #8, #16]. SUMOylation at K17, reversed by SENP1, redirects HNRNPM to interact with PFKFB3 and suppress glycolysis, defining a non-splicing metabolic role [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that HNRNPM is not merely a structural hnRNP component but is functionally required for pre-mRNA splicing, linking it to the core splicing machinery.\",\n      \"evidence\": \"Monoclonal antibody inhibition of in vitro splicing and heat-shock nuclear extract fractionation\",\n      \"pmids\": [\"8692693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define RNA sequence specificity or which splicing steps HNRNPM acts on\", \"No domain mapping of the splicing-relevant activity\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the molecular basis by which HNRNPM influences splice site choice—direct interaction with spliceosome proteins CDC5L/PLRG1 via a central domain whose deletion abolishes splicing modulation.\",\n      \"evidence\": \"Reciprocal Co-IP, domain deletion mutagenesis, and adeno-E1A minigene alternative splicing assay\",\n      \"pmids\": [\"20467437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the RNA-binding determinants of splice site selection\", \"Stress-induced loss of interaction not linked to specific transcripts\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a physiological splicing program for HNRNPM in cancer—driving the CD44v-to-CD44s switch during EMT by competing with ESRP1 for GU-rich elements, establishing it as a metastasis driver.\",\n      \"evidence\": \"Genome-wide RNA-seq, knockdown/overexpression, CD44s epistasis rescue, and mouse metastasis models\",\n      \"pmids\": [\"24840202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mesenchymal-specific activity not fully resolved\", \"Did not establish nucleotide-resolution binding sites\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-splicing cytoplasmic function—HNRNPM cooperates with NONO on the FGF1 IRES to activate IRES-dependent translation during myoblast differentiation.\",\n      \"evidence\": \"RIP, Co-IP, promoter deletion, and mRNA transfection assays\",\n      \"pmids\": [\"26332123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of promoter-dependent IRES activation unclear\", \"Did not address how nuclear HNRNPM accesses cytoplasmic IRESs\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed HNRNPM-dependent splicing downstream of PI3K/AKT/mTOR signaling, connecting an oncogenic pathway to its alternative splicing output.\",\n      \"evidence\": \"Splicing-sensitive arrays, motif enrichment, and shRNA knockdown with clonogenicity assays in Ewing sarcoma\",\n      \"pmids\": [\"29036465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mTOR signaling regulates HNRNPM activity is unknown\", \"Direct binding to regulated exons inferred from motifs, not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Consolidated the ESRP1-antagonism model genome-wide and identified MORC2 as a partner whose cancer mutation enhances HNRNPM-driven CD44 switching.\",\n      \"evidence\": \"Genome-wide RNA-seq comparison with motif analysis (idx 5); Co-IP, splicing/migration assays, and lung metastasis model (idx 6)\",\n      \"pmids\": [\"30042172\", \"30093560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition with ESRP1 supported computationally rather than by direct biochemical assay\", \"How MORC2 mutation enhances HNRNPM recruitment to pre-mRNA not structurally defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated stress-induced nuclear-to-cytoplasmic relocalization as a switch between functions—promoting IRES translation under hypoxia and suppressing RIG-I/MDA5 antiviral signaling during infection.\",\n      \"evidence\": \"Subcellular fractionation, omics, Co-IP with RIG-I/MDA5, and viral RNA-binding competition assays\",\n      \"pmids\": [\"30852162\", \"31433824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger and machinery controlling translocation undefined\", \"Antiviral role here is negative, in tension with later positive regulation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked HNRNPM to neurodegeneration biology through an RNA-dependent interaction with MATR3 and modification of mutant MATR3 toxicity in vivo.\",\n      \"evidence\": \"RNA-dependent Co-IP in mammalian cells, Drosophila genetic modifier screen, and eCLIP analysis\",\n      \"pmids\": [\"32811564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared target processing not mechanistically dissected\", \"RNA-dependent nature leaves direct vs bridged interaction open\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined HNRNPM as a transcriptome guardian—binding GU-rich elements in long flanking introns to prevent aberrant exon inclusion and circRNA backsplicing—and extended its roles to mRNA stability and circRNA binding.\",\n      \"evidence\": \"eCLIP-seq, in vivo shRNA screen, splice-switching oligos (idx 10); RIP/3'UTR binding in hippocampus (idx 12); circRNA RIP (idx 11, 13)\",\n      \"pmids\": [\"34075878\", \"33727124\", \"34385309\", \"33837664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HNRNPM discriminates productive from aberrant splice sites unresolved\", \"mRNA stabilization mechanism (3'UTR binding to half-life) not biochemically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed HNRNPM intronic binding generates functionally opposing splice isoforms (MBD2a/b) that control Wnt signaling and tumor immune evasion.\",\n      \"evidence\": \"RIP-seq, RNA-seq, ChIP, antisense oligos, and CD8+ T cell co-culture in HCC\",\n      \"pmids\": [\"35158098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of isoform-specific outcome not generalized\", \"Direct vs indirect control of FZD3/Wnt axis incompletely resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the most mechanistic view of cryptic exon suppression—HNRNPM represses LINE-embedded pseudo splice sites; its loss generates dsRNA-forming cryptic exons that trigger interferon—and revealed positive antiviral and ferroptosis-regulating splicing roles plus PARP4 as a partner.\",\n      \"evidence\": \"eCLIP-seq and dsRNA/IFN analysis (idx 15); MS interactome, KO, and IRF3 phosphorylation (idx 16); FMRP Co-IP and SLC7A11 splicing (idx 17); MS interactomics with PARP4 (idx 18)\",\n      \"pmids\": [\"38815579\", \"39707025\", \"39388855\", \"39034402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Positive (idx 16) versus negative (idx 8) regulation of innate immunity not reconciled\", \"How HNRNPM selectively targets LINE-proximal GU elements unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established essential physiological splicing roles in gametogenesis via PTBP1 and BCAS2 partnerships, and uncovered a SUMOylation-controlled metabolic function and additional mRNA-fate partnerships (AURKB, KHSRP).\",\n      \"evidence\": \"Conditional KO with Co-IP/MS for PTBP1 (idx 20) and BCAS2 with LACE-seq (idx 23); SUMO proteomics, K17 mutagenesis, and PFKFB3 Co-IP (idx 19); Co-IP/PLA/RIP for AURKB-PSAT1 (idx 21); CLIP/minigene for PLEKHB2 (idx 22)\",\n      \"pmids\": [\"39780247\", \"41680151\", \"39983892\", \"40784984\", \"41109930\", \"41176204\", \"40068468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUMOylation reciprocally gates splicing vs metabolic functions unknown\", \"Coordination among the many partner-specific roles in a single cell unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single GU-rich RNA-binding protein partitions among its splicing, mRNA-stability, translational, antiviral, and metabolic roles, and what cellular signals select among its many distinct protein partners.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking SUMOylation, localization, and partner choice\", \"Opposing antiviral roles across studies unreconciled\", \"No high-resolution structure of HNRNPM bound to RNA or to spliceosome partners\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 10, 15, 22, 23]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 10, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 8, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 10, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 14, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6, 19]}\n    ],\n    \"complexes\": [\"hnRNP complex\", \"spliceosome\"],\n    \"partners\": [\"CDC5L\", \"PLRG1\", \"PTBP1\", \"BCAS2\", \"ESRP1\", \"NONO\", \"MATR3\", \"PFKFB3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}