{"gene":"NSD2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"MMSET (NSD2) was identified as a novel gene disrupted by the t(4;14)(p16.3;q32.3) translocation in multiple myeloma, resulting in IgH/MMSET hybrid transcripts and overexpression from endogenous promoters. The protein contains HMG box, hath region, PHD fingers, and a SET domain in the long form.","method":"Molecular cloning, hybrid transcript characterization, domain analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — original discovery paper replicated across subsequent studies, molecular characterization of gene structure and fusion transcripts","pmids":["9787135"],"is_preprint":false},{"year":2011,"finding":"Dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalytically active NSD2 is sufficient for gene activation and promotes oncogenic transformation in an H3K36me2-dependent manner.","method":"In vitro methyltransferase assay, genome-wide ChIP-seq, catalytic mutant rescue, xenograft tumor formation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay, genome-wide chromatin profiling, catalytic mutant validation, xenograft experiments, subsequently replicated by multiple labs","pmids":["22099308"],"is_preprint":false},{"year":2011,"finding":"MMSET/NSD2 is recruited to DNA double-strand breaks (DSBs) via interaction between the MDC1 BRCT domain and phosphorylated Ser102 of MMSET, and locally methylates H4K20 to facilitate 53BP1 recruitment to DSB sites.","method":"ChIP, immunofluorescence, co-immunoprecipitation, siRNA knockdown, DSB induction assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying MDC1-MMSET interaction, ChIP demonstrating local H4K20me2 increase, knockdown with specific phenotypic readout, published in high-impact journal","pmids":["21293379"],"is_preprint":false},{"year":2007,"finding":"MMSET possesses histone methyltransferase activity for H3K4 and H4K20 in vitro, but only for H4K20 in cells. MMSET forms a corepressor complex with HDAC1, HDAC2, mSin3a, and the histone demethylase LSD1, mediating transcriptional repression associated with increased H4K20 methylation and loss of histone acetylation.","method":"In vitro methyltransferase assay, co-immunoprecipitation, Gal4 transcriptional repression reporter assay, ChIP","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with substrate specificity determination, reciprocal Co-IP identifying corepressor complex, reporter assays with functional validation","pmids":["18156491"],"is_preprint":false},{"year":2014,"finding":"MMSET overexpression causes global increase in H3K36me2 and a concurrent global reduction in H3K27me3. Despite global H3K27me3 decrease, specific loci show enhanced EZH2 recruitment and become hypermethylated on H3K27. PHD domains are required for MMSET recruitment to chromatin.","method":"ChIP-seq, shRNA knockdown, EZH2 inhibitor sensitivity assays, domain deletion mutant analysis, xenograft model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, domain mutant analysis, multiple orthogonal methods in one study, in vivo tumor regression","pmids":["25188243"],"is_preprint":false},{"year":2008,"finding":"The RE-IIBP isoform of MMSET/NSD2 possesses H3K27 methyltransferase activity, with SET domain residues C483 and R477 being critical for catalytic activity. RE-IIBP represses transcription through HDAC recruitment mediated by H3K27 methylation.","method":"In vitro methyltransferase assay, point mutagenesis, ChIP, reporter gene assay, shRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay with active-site mutagenesis identifying critical residues, ChIP validation, multiple orthogonal methods","pmids":["18172012"],"is_preprint":false},{"year":2009,"finding":"NSD2 specifically interacts with the DNA-binding domain of the androgen receptor (AR) via its HMG domain. NSD2 is recruited to the PSA gene enhancer region by AR in a ligand-dependent manner and enhances AR-mediated transcription in a SET domain-dependent manner.","method":"Co-immunoprecipitation, ChIP, overexpression of wild-type vs. SET-deleted mutant, RT-PCR for PSA mRNA","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP demonstrating interaction, ChIP showing recruitment, single lab, domain deletion mutant analysis","pmids":["19481544"],"is_preprint":false},{"year":2012,"finding":"NSD2 acts as a coactivator of NF-κB by directly interacting with NF-κB and mediating H3K36me2 and H3K36me3 elevation at NF-κB target gene promoters. NSD2 is also required for cytokine-induced recruitment of p300 acetyltransferase and histone hyperacetylation at these loci.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, reporter assays, gene expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP of NSD2-NF-κB interaction, ChIP at target promoters, single lab study with multiple methods","pmids":["22645312"],"is_preprint":false},{"year":2012,"finding":"MMSET activates TWIST1 expression by binding to the TWIST1 locus and increasing H3K36me2, driving epithelial-mesenchymal transition (EMT) and invasive properties in prostate cancer cells.","method":"ChIP, shRNA knockdown, overexpression, invasion/migration assays, TWIST1 rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating NSD2 occupancy at TWIST1 locus with H3K36me2 increase, functional rescue experiments confirming TWIST1 as mediator","pmids":["22797064"],"is_preprint":false},{"year":2012,"finding":"MMSET promotes myeloma cell proliferation by stimulating c-MYC expression at the post-transcriptional level through repression of miR-126*. MMSET binds the miR-126* promoter with KAP1 corepressor and histone deacetylases, inducing heterochromatic marks (increased H3K9me3, decreased H3 acetylation) to repress miR-126*.","method":"ChIP, miRNA profiling, 3'UTR luciferase reporter assay, shRNA knockdown, cell proliferation assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating MMSET occupancy at miR-126* promoter, validated miRNA-mRNA target interaction, co-repressor complex identification","pmids":["22972034"],"is_preprint":false},{"year":2013,"finding":"WHSC1/NSD2 interacts with BRD4 and P-TEFb to facilitate transcriptional elongation, and also associates with the H3.3-specific histone chaperone HIRA independent of BRD4/P-TEFb, linking transcriptional elongation to H3.3 deposition at activated genes.","method":"Co-immunoprecipitation, ChIP, genetic knockout (Whsc1-/- cells), gene expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying BRD4, P-TEFb, and HIRA as binding partners, Whsc1 knockout cells demonstrating loss of H3.3 deposition and transcription, multiple orthogonal methods","pmids":["23921552"],"is_preprint":false},{"year":2013,"finding":"The PHD domains of NSD2 are important for recruiting it to oncogenic target gene loci, driving their transcriptional activation. NSD2 methyltransferase activity is crucial for myeloma cell clonogenicity, adherence, and proliferation.","method":"PHD domain mutant analysis, ChIP, shRNA knockdown, xenograft tumor model, colony formation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutants, ChIP demonstrating PHD-dependent recruitment, multiple functional readouts","pmids":["23980095"],"is_preprint":false},{"year":2016,"finding":"MMSET is required for efficient non-homologous end joining (NHEJ) and homologous recombination (HR). Loss of MMSET reduces expression and recruitment of DNA repair proteins to DSB sites and enhances sensitivity to DNA-damaging agents.","method":"NHEJ and HR reporter assays, ChIP, shRNA knockdown, xenograft chemosensitivity model, immunofluorescence for repair factor recruitment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative DNA repair pathway assays (NHEJ and HR reporters), repair protein recruitment ChIP, in vivo chemosensitivity validation, multiple orthogonal methods","pmids":["27109101"],"is_preprint":false},{"year":2017,"finding":"AKT phosphorylates WHSC1 at S172, preventing its degradation by the CRL4Cdt2 E3 ubiquitin ligase. Stabilized WHSC1 transcriptionally upregulates RICTOR (mTORC2 component) to further enhance AKT activity, creating a feedforward loop; WHSC1 also positively regulates Rac1 transcription.","method":"Mass spectrometry phospho-site identification, site-directed mutagenesis, co-immunoprecipitation, ubiquitination assays, ChIP, genetic mouse model (PTEN-null + WHSC1 overexpression), xenograft","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphorylation site identified by MS and validated by mutagenesis, E3 ligase identified by Co-IP, in vivo mouse model, multiple orthogonal methods","pmids":["28319045"],"is_preprint":false},{"year":2018,"finding":"MMSET methylates Aurora kinase A (AURKA), enhancing AURKA kinase activity and promoting p53 interaction with AURKA, which leads to proteasomal degradation of p53.","method":"Co-immunoprecipitation, in vitro methyltransferase assay, kinase activity assay, p53 degradation assay, shRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating MMSET-AURKA interaction, in vitro methylation assay, functional consequence (p53 degradation) shown with multiple methods, single lab","pmids":["30013191"],"is_preprint":false},{"year":2018,"finding":"The NSD2 E1099K activating mutation alters enzyme/substrate binding and enhances the rate of H3K36 methylation, particularly on H3.1-containing nucleosomes, resulting in increased H3K36me2 and decreased H3K27me3.","method":"In vitro methyltransferase assay, CRISPR-edited cell lines, histone mass spectrometry, gene expression profiling, xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinetics with mutant enzyme, CRISPR-edited isogenic lines, mass spectrometry of histone modifications, multiple orthogonal methods","pmids":["30171259"],"is_preprint":false},{"year":2019,"finding":"DNA DSBs promote NSD2-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA damage sites, governing efficient DSB repair partly through γH2AX dephosphorylation.","method":"Mass spectrometry, site-directed mutagenesis, Co-immunoprecipitation, in vitro methyltransferase assay, xenograft chemosensitivity experiments","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation assay, methylation site identified by MS and validated by mutagenesis, 53BP1 tudor domain reader shown by Co-IP, functional rescue experiments","pmids":["31217297"],"is_preprint":false},{"year":2019,"finding":"NSD2 overexpression drives clustered chromatin and transcriptional changes within specific insulated topological domains (TADs). H3K36me2 expansion is linked to alterations in H3K27ac and CTCF occupancy, with differentially expressed genes enriched within the same insulated domain as altered chromatin marks.","method":"ChIP-seq, Hi-C/TAD analysis, isogenic cell lines with high/low NSD2, logistic regression modeling of gene expression vs. chromatin changes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq and 3D chromatin organization in isogenic cell lines, multiple chromatin assays, rigorous statistical modeling","pmids":["31649247"],"is_preprint":false},{"year":2019,"finding":"MMSET/NSD2 is recruited to DNA damage sites by the endoribonuclease DICER, and catalyzes H4K20me2 at those sites, which facilitates recruitment of the NER factor XPA during global-genomic nucleotide excision repair (NER).","method":"ChIP, siRNA knockdown, immunofluorescence, NER assay, epistasis analysis of DICER-MMSET pathway","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating MMSET at UV-damage sites, functional NER assay, DICER-MMSET epistasis, single lab","pmids":["29233865"],"is_preprint":false},{"year":2019,"finding":"Whsc1 is required for pluripotency exit and mesendoderm specification in embryonic stem cells, functioning through binding to enhancers of mesendodermal regulators (Gata4, Brachyury/T, Gata6, Foxa2) together with Brd4, independently of its methyltransferase activity.","method":"Genetic knockout, rescue with methyltransferase-dead mutant, ChIP, RNA-seq, differentiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific developmental phenotype, methyltransferase-dead mutant rescue demonstrating activity-independent function, ChIP showing enhancer occupancy, multiple methods","pmids":["31235934"],"is_preprint":false},{"year":2020,"finding":"MMSET is degraded during S phase in a CRL4(Cdt2) E3 ligase- and proteasome-dependent manner. MMSET depletion causes defects in DNA replication and decreased association of pre-replication complex (pre-RC) factors with chromatin.","method":"Cell cycle synchronization, proteasome inhibitor treatment, chromatin fractionation, siRNA knockdown, DNA fiber assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRL4(Cdt2) dependence demonstrated by inhibitor and siRNA, chromatin fractionation of pre-RC factors, single lab","pmids":["26771714"],"is_preprint":false},{"year":2020,"finding":"NSD2 knockdown induces cellular senescence through RB-mediated downregulation of cell cycle genes. NSD2 is enriched at gene bodies of actively transcribed cell cycle genes and its loss decreases H3K36me3 at these loci.","method":"RNAi screen, ChIP-seq, transcriptome analysis, senescence assays (SA-β-gal, mitochondrial mass), knockdown in primary fibroblasts","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq showing NSD2 occupancy at cell cycle gene bodies, H3K36me3 loss after knockdown, RB-mediated mechanism supported by transcriptomics, single lab","pmids":["32573059"],"is_preprint":false},{"year":2020,"finding":"CD28 signaling induces NSD2 expression in T cells, and NSD2-mediated H3K36me2 is required for early Bcl6 expression and follicular helper T (Tfh) cell differentiation. ICOS signaling maintains sustained NSD2 expression. Ectopic Bcl6 rescues the Tfh defect in Nsd2-KO cells.","method":"Conditional knockout mouse model, flow cytometry, ChIP, retroviral rescue experiments, germinal center assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific immunological phenotype, genetic epistasis via Bcl6 rescue, ChIP demonstrating H3K36me2 at Bcl6 locus, multiple orthogonal methods","pmids":["31636135"],"is_preprint":false},{"year":2021,"finding":"NSD2 PWWP1 domain occupies the canonical H3K36me2-binding pocket. A chemical probe (UNC6934) antagonizing PWWP1-H3K36me2 interaction induces NSD2 accumulation in the nucleolus, phenocopying NSD2 isoform localization defects seen in t(4;14) MM.","method":"X-ray crystallography, surface plasmon resonance (SPR), cellular thermal shift assay, live cell imaging, chemical probe/control compound pair","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of PWWP1 domain, SPR binding quantification, chemical probe with matched negative control, multiple orthogonal methods including cellular imaging","pmids":["34782742"],"is_preprint":false},{"year":2021,"finding":"NSD2 promotes tumor angiogenesis by methylating STAT3 at K163, which activates STAT3 signaling and upregulates VEGFA expression. K163R mutation attenuates STAT3 activation and angiogenic function.","method":"Mass spectrometry for methylation site identification, site-directed mutagenesis, in vitro methyltransferase assay, angiogenesis assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro methyltransferase assay with mutagenesis identifying methylation site, functional consequence shown, single lab","pmids":["33742125"],"is_preprint":false},{"year":2021,"finding":"NSD2 interacts with SRC-3 to coordinate liquid-liquid phase separation of SRC-3, which enhances H3K36me2 modifications at anti-apoptotic gene promoters. Targeting the NSD2-SRC-3 interaction with SI-2 inhibitor sensitizes myeloma cells to bortezomib.","method":"Co-immunoprecipitation, phase separation assays, ChIP-seq, small molecule inhibitor (SI-2), in vitro and in vivo drug resistance models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying NSD2-SRC-3 interaction, phase separation assays, ChIP-seq at anti-apoptotic gene promoters, single lab","pmids":["33589584"],"is_preprint":false},{"year":2021,"finding":"NSD2 interacts with the SWI/SNF ATPase subunit SMARCA2 in a non-canonical, SWI/SNF complex-independent manner, forming a complex that localizes to the PTP4A3 promoter, increases H3K36me2, and drives transcriptional activation of PTP4A3.","method":"SILAC mass spectrometry, co-immunoprecipitation, RNA-seq, ChIP, pharmacological inhibition with BET inhibitor PFI-3, xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative mass spectrometry for interaction discovery, reciprocal Co-IP, ChIP at target promoter, functional validation by drug inhibition and xenograft, multiple orthogonal methods","pmids":["33602783"],"is_preprint":false},{"year":2021,"finding":"NSD2 E1099K mutation in ALL drives glucocorticoid resistance by promoting H3K27me3 accumulation at the NR3C1 (glucocorticoid receptor) promoter, suppressing GR expression and autoactivation. PRC2 inhibitors restore NR3C1 expression and glucocorticoid sensitivity.","method":"CRISPR correction of E1099K, drug screen, ChIP-seq, isogenic cell line comparison, patient-derived xenograft, PRC2 inhibitor treatment","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-corrected isogenic lines establishing causality, ChIP-seq demonstrating H3K27me3 at GR promoter, PDX model, multiple orthogonal methods","pmids":["34417224"],"is_preprint":false},{"year":2021,"finding":"NSD2 via H3K36me2 catalysis cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. The hyperactive NSD2-E1099K variant accelerates malignant tumor progression in KRAS-driven LUAD mouse models. Combined NSD2 depletion with MEK1/2 inhibition causes near-complete regression of LUAD tumors.","method":"In vivo mouse LUAD model, CRISPRi gene knockdown system, PDX models, MEK inhibitor combination treatment, RNA-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic models, CRISPRi loss-of-function, PDX models, genetic epistasis with KRAS, combination treatment validation","pmids":["34555356"],"is_preprint":false},{"year":2021,"finding":"IFN-γ/STAT1 signaling stimulates WHSC1 expression, and WHSC1 directly interacts with NLRC5 to promote MHC-I gene transcription, enabling antitumor immune responses in colorectal cancer cells.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, flow cytometry for MHC-I expression, syngeneic mouse tumor models, immune checkpoint blockade experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating WHSC1-NLRC5 interaction, ChIP at MHC-I gene loci, multiple in vivo models, mechanistic pathway well supported","pmids":["35230972"],"is_preprint":false},{"year":2022,"finding":"NSD2 loss-of-function missense variants reduce H3K36me2 methylation activity in vitro and fail to reconstitute H3K36me2 in NSD2 knockout cells, establishing a causal link between catalytic impairment and the developmental phenotype (Rauch-Steindl syndrome).","method":"In vitro methyltransferase assay with patient-derived missense variants, NSD2-knockout cell complementation, structural modeling","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay of multiple patient variants, NSD2 KO cell rescue experiments, structural modeling supporting mechanism","pmids":["33941880"],"is_preprint":false},{"year":2022,"finding":"NSD2 is required for H3K36me2 and H3K36me3 in spermatogenic cells. NSD2 interacts with PSMA8 to regulate acetylated histone degradation affecting H4K16ac, and NSD2 loss impairs EP300-induced H4K5/8ac recognized by BRDT, leading to defective histone eviction and retention of histones in spermatozoa.","method":"Conditional knockout mouse model, ChIP-seq, co-immunoprecipitation of NSD2-PSMA8 interaction, mass spectrometry of histone modifications, fertility assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined fertility phenotype, ChIP-seq, Co-IP identifying PSMA8 interaction, histone modification mass spectrometry, multiple orthogonal methods","pmids":["35736136"],"is_preprint":false},{"year":2022,"finding":"NSD2 upregulates CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the maternal-fetal interface decidua, required for maternal-fetal immune tolerance.","method":"Conditional knockout mouse model, ChIP, flow cytometry for Treg levels, CXCR4 expression analysis, fetal loss phenotype","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific immune phenotype, ChIP demonstrating H3K36me2 at CXCR4 locus, single lab","pmids":["35322173"],"is_preprint":false},{"year":2023,"finding":"NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in prostate cancer. NSD2 H3K36 dimethyltransferase activity is required for over 65% of tumor-specific AR cistrome. NSD2 inactivation disrupts AR transactivation and increases dependency on NSD1 paralog.","method":"ChIP-seq (AR, NSD2, H3K36me2), CRISPR-mediated NSD2 inactivation, PROTAC dual NSD1/2 degrader, patient sample analysis, prostate cancer cell models","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, CRISPR loss-of-function, PROTAC degrader tool, patient cohort validation, multiple orthogonal methods","pmids":["39251788"],"is_preprint":false},{"year":2024,"finding":"FBXO22 can be recruited to mediate NSD2 degradation via a molecular mechanism where a primary amine-containing compound (UNC8732) is metabolized to an aldehyde that engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex to NSD2.","method":"Targeted protein degradation assays, FBXO22 co-immunoprecipitation, chemical probe and genetic rescue experiments, cell proliferation and apoptosis assays in ALL cells","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic characterization of E3 ligase recruitment, Co-IP, chemical biology approach with matched controls, multiple orthogonal validation methods","pmids":["38965384"],"is_preprint":false},{"year":2020,"finding":"H3K36me2 by MMSET promotes classical (Ligase4-dependent) non-homologous end-joining at deprotected telomeres. MMSET catalytic activity (SET domain) is required for this effect, and H3K36me2 levels directly correlate with NHEJ efficiency at telomeres.","method":"Methyltransferase screen at telomeres, NHEJ reporter assay distinguishing classical vs. alternative NHEJ, ChIP for H3K36me2 at subtelomeric regions, MMSET catalytic mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NHEJ assay with pathway specificity (Ligase4 vs. Ligase3), catalytic mutant validation, ChIP, single lab","pmids":["32472076"],"is_preprint":false},{"year":2024,"finding":"In a systematic perturbation study, NSD2 predominantly deposits H3K36me2 at intergenic regions, with NSD1 being the primary intergenic H3K36me2 methyltransferase. Within genes, SETD2 deposits H3K36me3 while NSD2 contributes H3K36me2 independently of SETD2. A hierarchy of K36MT activities is defined as NSD1 > NSD2 > NSD3 > ASH1L.","method":"CRISPR KO of individual H3K36 methyltransferases, ChIP-seq, CUT&RUN, RNA-seq in mouse mesenchymal stem cells","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic perturbation with matched ChIP-seq across multiple methyltransferases, genome-wide resolution, rigorous comparison of enzyme activities","pmids":["39390582"],"is_preprint":false},{"year":2005,"finding":"MMSET I isoform (but not MMSET II or RE-IIBP) represses transcription and specifically recruits HDAC1 and mSin3b (but not HDAC2 or HDAC4) in co-immunoprecipitation assays, with this repression activity being partially reversed by the HDAC inhibitor TSA.","method":"Co-immunoprecipitation, transcriptional reporter assay (thymidine kinase promoter), HDAC inhibitor treatment, isoform-specific overexpression","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP demonstrating isoform-specific corepressor recruitment, reporter assay, single lab","pmids":["16197452"],"is_preprint":false},{"year":2012,"finding":"MMSET regulates class switch recombination (CSR) through its histone methyltransferase activity. MMSET knockdown impairs 53BP1 recruitment and germline transcription of immunoglobulin switch regions, resulting in defective CSR without affecting cell viability.","method":"shRNA knockdown, CSR assay, immunofluorescence for 53BP1 recruitment, RT-PCR for germline transcription, cell viability assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional CSR assay, 53BP1 recruitment assay, pathway epistasis with H4K20me2/53BP1 axis, single lab","pmids":["23241889"],"is_preprint":false},{"year":2021,"finding":"NSD2 interacts with RARα and protects it from degradation, and enhances nuclear condensation (phase separation) of RARα. NSD2 also modifies H3K36me2 at the CD38 promoter to increase CD38 expression in response to ATRA stimulation.","method":"Co-immunoprecipitation, confocal live imaging for nuclear condensation, ChIP, flow cytometry for CD38, shRNA knockdown","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating NSD2-RARα interaction, ChIP at CD38 promoter, live imaging for phase condensation, single lab","pmids":["36918219"],"is_preprint":false},{"year":2025,"finding":"NSD2-mediated H3K36me2 directly activates ULK1 transcription in triple-negative breast cancer cells, promoting autophagosome maturation and autophagic flux to drive TNBC metastasis.","method":"ChIP demonstrating H3K36me2 at ULK1 locus, shRNA knockdown, overexpression, autophagy flux assays, in vivo metastasis models, pharmacological NSD2 inhibition","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at ULK1 locus, functional autophagy assays, in vivo metastasis validation, single lab","pmids":["40097917"],"is_preprint":false}],"current_model":"NSD2 (MMSET/WHSC1) is a histone methyltransferase whose primary enzymatic activity is dimethylation of H3K36 (H3K36me2), a mark that broadly promotes active transcription; it also catalyzes H4K20me2 at DNA double-strand breaks to recruit 53BP1 and facilitate DNA repair, non-histone methylation of substrates including PTEN (K349) and STAT3 (K163), and methylation-independent functions including binding of PHD and PWWP domains to chromatin and acting as a coactivator/corepressor through interaction with partners such as HDAC1/2, mSin3, LSD1, BRD4, P-TEFb, HIRA, NF-κB, AR, NLRC5, SMARCA2, and SRC-3; in cancer, oncogenic t(4;14) translocation-driven NSD2 overexpression globally expands H3K36me2 domains, competes with H3K27me3, reprograms the transcriptional landscape, and confers resistance to DNA-damaging agents and promotes metastasis through multiple downstream gene regulatory axes."},"narrative":{"mechanistic_narrative":"NSD2 (MMSET/WHSC1) is a chromatin-modifying histone methyltransferase whose principal catalytic activity is dimethylation of histone H3 at lysine 36 (H3K36me2), a mark sufficient to drive gene activation and oncogenic transformation [PMID:22099308]. It was first identified as the gene disrupted by the recurrent t(4;14) translocation in multiple myeloma, which drives its overexpression from the IgH locus [PMID:9787135]. Catalytically, NSD2 deposits H3K36me2 predominantly at intergenic regions within a defined hierarchy of H3K36 methyltransferases, contributing intragenic H3K36me2 independently of SETD2 [PMID:39390582]; its overexpression globally expands H3K36me2 domains with a reciprocal global loss of H3K27me3, and reorganizes chromatin and transcription within insulated topological domains via coordinated changes in H3K27ac and CTCF occupancy [PMID:25188243, PMID:31649247]. The recurrent E1099K mutation enhances H3K36 methylation kinetics, especially on H3.1 nucleosomes, further elevating H3K36me2 and depleting H3K27me3 [PMID:30171259]. Recruitment to chromatin depends on its PHD fingers and on the PWWP1 domain, which reads H3K36me2 through a canonical aromatic pocket [PMID:23980095, PMID:34782742]. Beyond its core enzymatic role, NSD2 acts as a transcriptional coregulator: it activates targets in concert with NF-κB, BRD4/P-TEFb and the HIRA H3.3 chaperone, the AR/FOXA1 neo-enhanceosome, NLRC5, SMARCA2, and SRC-3, and it forms isoform-specific corepressor complexes with HDAC1/2, mSin3 and LSD1 [PMID:22645312, PMID:23921552, PMID:39251788, PMID:35230972, PMID:33602783, PMID:18156491]. In genome maintenance, NSD2 is recruited to DNA double-strand breaks and catalyzes H4K20me2 to promote 53BP1 loading, supporting non-homologous end-joining and homologous recombination [PMID:21293379, PMID:27109101]. It also methylates non-histone substrates, including PTEN at K349 to direct PTEN to damage sites for repair and STAT3 at K163 to drive VEGFA-dependent angiogenesis [PMID:31217297, PMID:33742125]. NSD2 stability is controlled by AKT phosphorylation and CRL4(Cdt2)- and FBXO22-dependent degradation [PMID:28319045, PMID:38965384]. Catalytic loss-of-function missense variants that fail to reconstitute H3K36me2 cause the developmental disorder Rauch-Steindl syndrome [PMID:33941880].","teleology":[{"year":1998,"claim":"Establishing NSD2's clinical relevance, it was identified as the gene disrupted by t(4;14) in multiple myeloma, framing it as a translocation-driven oncogene before its biochemical function was known.","evidence":"Molecular cloning and hybrid transcript characterization of the IgH/MMSET fusion, with domain analysis revealing HMG, PHD, and SET domains","pmids":["9787135"],"confidence":"High","gaps":["Did not define the enzymatic activity of the SET domain","Did not establish which substrates or marks drive the oncogenic phenotype"]},{"year":2007,"claim":"Early biochemistry assigned MMSET a methyltransferase activity and a corepressor role, the first mechanistic insight into how it alters chromatin.","evidence":"In vitro methyltransferase assays (H3K4/H4K20), Co-IP defining an HDAC1/2-mSin3a-LSD1 corepressor complex, and Gal4 reporter assays","pmids":["18156491","16197452"],"confidence":"High","gaps":["In vitro vs. in cell substrate discrepancy left the physiological mark unresolved","Did not reconcile a corepressor role with later activating functions"]},{"year":2008,"claim":"Isoform-specific assays showed distinct catalytic outputs, with the RE-IIBP isoform methylating H3K27 via defined SET residues, complicating the simple one-enzyme-one-mark view.","evidence":"In vitro methyltransferase assays with C483/R477 active-site mutagenesis, ChIP, and reporter assays","pmids":["18172012"],"confidence":"High","gaps":["Relationship between RE-IIBP H3K27 activity and full-length NSD2 H3K36 activity unresolved","In vivo significance of isoform-specific catalysis not established"]},{"year":2011,"claim":"The field converged on H3K36me2 as NSD2's principal, oncogenically relevant activity, defining the mark whose deposition is sufficient for gene activation and transformation.","evidence":"In vitro methyltransferase assay, genome-wide ChIP-seq, catalytic mutant rescue, and xenograft tumor formation; separately, recruitment to DSBs via MDC1-MMSET phospho-S102 interaction with local H4K20me2 driving 53BP1","pmids":["22099308","21293379"],"confidence":"High","gaps":["How H3K36me2 expansion is read into transcriptional output not yet defined","Genome-wide chromatin domain effects not yet mapped"]},{"year":2014,"claim":"NSD2 was shown to antagonize Polycomb chromatin, establishing the H3K36me2/H3K27me3 balance as a central axis of its oncogenic reprogramming.","evidence":"ChIP-seq, shRNA knockdown, EZH2 inhibitor sensitivity, PHD domain deletion mutants, and xenografts showing global H3K36me2 gain with global H3K27me3 loss but locus-specific EZH2 gain","pmids":["25188243"],"confidence":"High","gaps":["Mechanism of locus-selective EZH2 retargeting amid global H3K27me3 loss unclear","Direct PHD ligand at chromatin not defined"]},{"year":2013,"claim":"NSD2 was integrated into the transcriptional elongation machinery and chromatin recruitment logic, explaining how it activates target genes.","evidence":"Reciprocal Co-IP identifying BRD4, P-TEFb, and HIRA; Whsc1-knockout cells showing loss of H3.3 deposition; and PHD-mutant ChIP showing recruitment to oncogenic loci","pmids":["23921552","23980095"],"confidence":"High","gaps":["Whether elongation coupling is direct or downstream of H3K36me2 not resolved","Identity of PHD-recognized chromatin features unknown"]},{"year":2016,"claim":"NSD2 was established as a broad DNA-repair factor required for both NHEJ and HR, explaining how its overexpression confers resistance to DNA-damaging therapy.","evidence":"NHEJ/HR reporter assays, ChIP, shRNA knockdown, immunofluorescence for repair-factor recruitment, and in vivo chemosensitivity xenografts","pmids":["27109101"],"confidence":"High","gaps":["Whether repair defects are catalytic or scaffolding-dependent not fully separated","Which substrate (H4K20 vs. non-histone) is rate-limiting per pathway unclear"]},{"year":2018,"claim":"Structural-kinetic analysis of the recurrent E1099K mutation defined the molecular basis of NSD2 hyperactivity in cancer.","evidence":"In vitro methyltransferase kinetics with mutant enzyme, CRISPR-edited isogenic lines, and histone mass spectrometry showing enhanced H3K36me2 on H3.1 nucleosomes","pmids":["30171259"],"confidence":"High","gaps":["Nucleosome-context selectivity (H3.1 vs H3.3) mechanism not fully resolved","Therapeutic targetability of the mutant enzyme not addressed here"]},{"year":2017,"claim":"NSD2 protein abundance was linked to AKT signaling and a feedforward oncogenic loop, identifying how it is post-translationally stabilized.","evidence":"MS phospho-site identification (S172), mutagenesis, Co-IP of CRL4Cdt2, ubiquitination assays, and a PTEN-null + WHSC1 mouse model showing RICTOR/Rac1 upregulation","pmids":["28319045","26771714"],"confidence":"High","gaps":["Interplay between S172 stabilization and S-phase CRL4Cdt2 degradation timing not fully integrated","Generalizability of the AKT-NSD2-mTORC2 loop beyond PTEN-null contexts unclear"]},{"year":2019,"claim":"NSD2 was shown to methylate non-histone substrates and to act through methyltransferase-independent scaffolding, broadening its mechanistic repertoire beyond histone marks.","evidence":"MS/mutagenesis identifying PTEN K349 read by 53BP1 tudor at DSBs; Whsc1 KO with methyltransferase-dead rescue in ESC mesendoderm specification via Brd4-bound enhancers; Hi-C/ChIP-seq showing TAD-confined chromatin reprogramming","pmids":["31217297","31235934","31649247","29233865"],"confidence":"High","gaps":["Determinants of catalytic vs. non-catalytic mode selection unknown","Full set of non-histone substrates not enumerated"]},{"year":2021,"claim":"NSD2 was structurally defined as an H3K36me2 reader and embedded in diverse coactivator complexes and condensates, while its mutations were tied to therapy resistance, motivating targeted degraders.","evidence":"PWWP1 crystal structure and chemical probe (UNC6934); Co-IP/ChIP-seq of SRC-3 (phase separation), SMARCA2, NLRC5, and RARα; CRISPR-corrected E1099K showing H3K27me3 at NR3C1 driving glucocorticoid resistance","pmids":["34782742","33589584","33602783","35230972","36918219","34417224","33742125"],"confidence":"High","gaps":["How phase separation, reader function, and catalysis are mechanistically coupled is unresolved","Specificity of partner choice across cancer contexts not systematized"]},{"year":2022,"claim":"Patient-derived missense variants established NSD2 catalytic insufficiency as causal for a developmental disorder, extending its role from cancer to germline disease.","evidence":"In vitro methyltransferase assays of variants, NSD2-KO cell complementation, and structural modeling defining Rauch-Steindl syndrome","pmids":["33941880"],"confidence":"High","gaps":["Which developmental gene programs depend on H3K36me2 dosage not defined","Genotype-phenotype correlation across variants incomplete"]},{"year":2024,"claim":"Systematic perturbation placed NSD2 within the genome-wide hierarchy of H3K36 methyltransferases, and chemical degrader strategies provided a route to deplete it.","evidence":"CRISPR KO of individual K36 methyltransferases with ChIP-seq/CUT&RUN defining NSD1>NSD2>NSD3>ASH1L; FBXO22-recruiting molecular-glue degradation of NSD2 via aldehyde-engaged C326","pmids":["39390582","38965384"],"confidence":"High","gaps":["Functional consequences of intergenic vs. intragenic H3K36me2 deposition not fully separated","Selectivity of degraders against NSD1/NSD3 paralogs not established here"]},{"year":null,"claim":"How NSD2 selects between its histone catalytic, non-histone methylation, and scaffolding/condensate functions in a given cellular context, and how these are integrated to specify oncogenic versus developmental outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking catalytic and methyltransferase-independent functions","Context determinants of partner and substrate choice undefined","Comprehensive non-histone substrate map lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,5,15,36]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,24,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,8,33]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,23]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,12,17]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,10,33]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,15,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,12,16,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,27,28,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,29,38]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,30,31]}],"complexes":["NSD2-HDAC1/2-mSin3a-LSD1 corepressor complex","AR/FOXA1 neo-enhanceosome"],"partners":["MDC1","BRD4","HIRA","SMARCA2","NLRC5","SRC-3","PSMA8","FBXO22"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O96028","full_name":"Histone-lysine N-methyltransferase NSD2","aliases":["Multiple myeloma SET domain-containing protein","MMSET","Nuclear SET domain-containing protein 2","Protein trithorax-5","Wolf-Hirschhorn syndrome candidate 1 protein"],"length_aa":1365,"mass_kda":152.3,"function":"Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:19808676, PubMed:22099308, PubMed:27571355, PubMed:29728617, PubMed:33941880). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:22099308). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (PubMed:22099308). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (By similarity). By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes (PubMed:16115125, PubMed:22099308, PubMed:29728617). In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation (By similarity). During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes (By similarity). Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation (PubMed:29728617). During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation (By similarity). During B-cell development, required for the generation of the B1 lineage (By similarity). During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response (By similarity). Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation (By similarity). By regulating the methylation of histone H3 at 'Lys-36' and histone H4 at 'Lys-20' at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA (By similarity) Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:22099308). Methylation of histone H3 at 'Lys-27' is controversial (PubMed:18172012, PubMed:22099308). Mono-, di- or tri-methylates histone H3 at 'Lys-27' (H3K27me, H3K27me2 and H3K27me3) (PubMed:18172012). Does not methylate histone H3 at 'Lys-27' (PubMed:22099308). May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment (PubMed:11152655, PubMed:18172012)","subcellular_location":"Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/O96028/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NSD2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HMGN5","stoichiometry":4.0},{"gene":"NUCKS1","stoichiometry":4.0},{"gene":"EPN2","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN2","stoichiometry":0.2},{"gene":"MYO1E","stoichiometry":0.2},{"gene":"NCK1","stoichiometry":0.2},{"gene":"NECAP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NSD2","total_profiled":1310},"omim":[{"mim_id":"619695","title":"RAUCH-STEINDL SYNDROME; RAUST","url":"https://www.omim.org/entry/619695"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"607083","title":"NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 3; NSD3","url":"https://www.omim.org/entry/607083"},{"mim_id":"606681","title":"NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 1; NSD1","url":"https://www.omim.org/entry/606681"},{"mim_id":"602952","title":"NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 2; NSD2","url":"https://www.omim.org/entry/602952"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NSD2"},"hgnc":{"alias_symbol":["MMSET","KMT3G"],"prev_symbol":["WHSC1"]},"alphafold":{"accession":"O96028","domains":[{"cath_id":"2.30.30.140","chopping":"225-362","consensus_level":"high","plddt":82.5688,"start":225,"end":362},{"cath_id":"3.30.40.10","chopping":"670-715","consensus_level":"medium","plddt":89.0715,"start":670,"end":715},{"cath_id":"2.170.270.10","chopping":"988-1178","consensus_level":"high","plddt":91.6335,"start":988,"end":1178}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O96028","model_url":"https://alphafold.ebi.ac.uk/files/AF-O96028-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O96028-F1-predicted_aligned_error_v6.png","plddt_mean":65.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NSD2","jax_strain_url":"https://www.jax.org/strain/search?query=NSD2"},"sequence":{"accession":"O96028","fasta_url":"https://rest.uniprot.org/uniprotkb/O96028.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O96028/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O96028"}},"corpus_meta":[{"pmid":"9787135","id":"PMC_9787135","title":"The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9787135","citation_count":442,"is_preprint":false},{"pmid":"22099308","id":"PMC_22099308","title":"NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22099308","citation_count":369,"is_preprint":false},{"pmid":"21293379","id":"PMC_21293379","title":"MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21293379","citation_count":336,"is_preprint":false},{"pmid":"25188243","id":"PMC_25188243","title":"Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation.","date":"2014","source":"PLoS 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The protein contains HMG box, hath region, PHD fingers, and a SET domain in the long form.\",\n      \"method\": \"Molecular cloning, hybrid transcript characterization, domain analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original discovery paper replicated across subsequent studies, molecular characterization of gene structure and fusion transcripts\",\n      \"pmids\": [\"9787135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalytically active NSD2 is sufficient for gene activation and promotes oncogenic transformation in an H3K36me2-dependent manner.\",\n      \"method\": \"In vitro methyltransferase assay, genome-wide ChIP-seq, catalytic mutant rescue, xenograft tumor formation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay, genome-wide chromatin profiling, catalytic mutant validation, xenograft experiments, subsequently replicated by multiple labs\",\n      \"pmids\": [\"22099308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MMSET/NSD2 is recruited to DNA double-strand breaks (DSBs) via interaction between the MDC1 BRCT domain and phosphorylated Ser102 of MMSET, and locally methylates H4K20 to facilitate 53BP1 recruitment to DSB sites.\",\n      \"method\": \"ChIP, immunofluorescence, co-immunoprecipitation, siRNA knockdown, DSB induction assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying MDC1-MMSET interaction, ChIP demonstrating local H4K20me2 increase, knockdown with specific phenotypic readout, published in high-impact journal\",\n      \"pmids\": [\"21293379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MMSET possesses histone methyltransferase activity for H3K4 and H4K20 in vitro, but only for H4K20 in cells. MMSET forms a corepressor complex with HDAC1, HDAC2, mSin3a, and the histone demethylase LSD1, mediating transcriptional repression associated with increased H4K20 methylation and loss of histone acetylation.\",\n      \"method\": \"In vitro methyltransferase assay, co-immunoprecipitation, Gal4 transcriptional repression reporter assay, ChIP\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with substrate specificity determination, reciprocal Co-IP identifying corepressor complex, reporter assays with functional validation\",\n      \"pmids\": [\"18156491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMSET overexpression causes global increase in H3K36me2 and a concurrent global reduction in H3K27me3. Despite global H3K27me3 decrease, specific loci show enhanced EZH2 recruitment and become hypermethylated on H3K27. PHD domains are required for MMSET recruitment to chromatin.\",\n      \"method\": \"ChIP-seq, shRNA knockdown, EZH2 inhibitor sensitivity assays, domain deletion mutant analysis, xenograft model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, domain mutant analysis, multiple orthogonal methods in one study, in vivo tumor regression\",\n      \"pmids\": [\"25188243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The RE-IIBP isoform of MMSET/NSD2 possesses H3K27 methyltransferase activity, with SET domain residues C483 and R477 being critical for catalytic activity. RE-IIBP represses transcription through HDAC recruitment mediated by H3K27 methylation.\",\n      \"method\": \"In vitro methyltransferase assay, point mutagenesis, ChIP, reporter gene assay, shRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with active-site mutagenesis identifying critical residues, ChIP validation, multiple orthogonal methods\",\n      \"pmids\": [\"18172012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NSD2 specifically interacts with the DNA-binding domain of the androgen receptor (AR) via its HMG domain. NSD2 is recruited to the PSA gene enhancer region by AR in a ligand-dependent manner and enhances AR-mediated transcription in a SET domain-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, overexpression of wild-type vs. SET-deleted mutant, RT-PCR for PSA mRNA\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP demonstrating interaction, ChIP showing recruitment, single lab, domain deletion mutant analysis\",\n      \"pmids\": [\"19481544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NSD2 acts as a coactivator of NF-κB by directly interacting with NF-κB and mediating H3K36me2 and H3K36me3 elevation at NF-κB target gene promoters. NSD2 is also required for cytokine-induced recruitment of p300 acetyltransferase and histone hyperacetylation at these loci.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, reporter assays, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP of NSD2-NF-κB interaction, ChIP at target promoters, single lab study with multiple methods\",\n      \"pmids\": [\"22645312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMSET activates TWIST1 expression by binding to the TWIST1 locus and increasing H3K36me2, driving epithelial-mesenchymal transition (EMT) and invasive properties in prostate cancer cells.\",\n      \"method\": \"ChIP, shRNA knockdown, overexpression, invasion/migration assays, TWIST1 rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating NSD2 occupancy at TWIST1 locus with H3K36me2 increase, functional rescue experiments confirming TWIST1 as mediator\",\n      \"pmids\": [\"22797064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMSET promotes myeloma cell proliferation by stimulating c-MYC expression at the post-transcriptional level through repression of miR-126*. MMSET binds the miR-126* promoter with KAP1 corepressor and histone deacetylases, inducing heterochromatic marks (increased H3K9me3, decreased H3 acetylation) to repress miR-126*.\",\n      \"method\": \"ChIP, miRNA profiling, 3'UTR luciferase reporter assay, shRNA knockdown, cell proliferation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating MMSET occupancy at miR-126* promoter, validated miRNA-mRNA target interaction, co-repressor complex identification\",\n      \"pmids\": [\"22972034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WHSC1/NSD2 interacts with BRD4 and P-TEFb to facilitate transcriptional elongation, and also associates with the H3.3-specific histone chaperone HIRA independent of BRD4/P-TEFb, linking transcriptional elongation to H3.3 deposition at activated genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, genetic knockout (Whsc1-/- cells), gene expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying BRD4, P-TEFb, and HIRA as binding partners, Whsc1 knockout cells demonstrating loss of H3.3 deposition and transcription, multiple orthogonal methods\",\n      \"pmids\": [\"23921552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The PHD domains of NSD2 are important for recruiting it to oncogenic target gene loci, driving their transcriptional activation. NSD2 methyltransferase activity is crucial for myeloma cell clonogenicity, adherence, and proliferation.\",\n      \"method\": \"PHD domain mutant analysis, ChIP, shRNA knockdown, xenograft tumor model, colony formation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutants, ChIP demonstrating PHD-dependent recruitment, multiple functional readouts\",\n      \"pmids\": [\"23980095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMSET is required for efficient non-homologous end joining (NHEJ) and homologous recombination (HR). Loss of MMSET reduces expression and recruitment of DNA repair proteins to DSB sites and enhances sensitivity to DNA-damaging agents.\",\n      \"method\": \"NHEJ and HR reporter assays, ChIP, shRNA knockdown, xenograft chemosensitivity model, immunofluorescence for repair factor recruitment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative DNA repair pathway assays (NHEJ and HR reporters), repair protein recruitment ChIP, in vivo chemosensitivity validation, multiple orthogonal methods\",\n      \"pmids\": [\"27109101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AKT phosphorylates WHSC1 at S172, preventing its degradation by the CRL4Cdt2 E3 ubiquitin ligase. Stabilized WHSC1 transcriptionally upregulates RICTOR (mTORC2 component) to further enhance AKT activity, creating a feedforward loop; WHSC1 also positively regulates Rac1 transcription.\",\n      \"method\": \"Mass spectrometry phospho-site identification, site-directed mutagenesis, co-immunoprecipitation, ubiquitination assays, ChIP, genetic mouse model (PTEN-null + WHSC1 overexpression), xenograft\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphorylation site identified by MS and validated by mutagenesis, E3 ligase identified by Co-IP, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"28319045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMSET methylates Aurora kinase A (AURKA), enhancing AURKA kinase activity and promoting p53 interaction with AURKA, which leads to proteasomal degradation of p53.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methyltransferase assay, kinase activity assay, p53 degradation assay, shRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating MMSET-AURKA interaction, in vitro methylation assay, functional consequence (p53 degradation) shown with multiple methods, single lab\",\n      \"pmids\": [\"30013191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The NSD2 E1099K activating mutation alters enzyme/substrate binding and enhances the rate of H3K36 methylation, particularly on H3.1-containing nucleosomes, resulting in increased H3K36me2 and decreased H3K27me3.\",\n      \"method\": \"In vitro methyltransferase assay, CRISPR-edited cell lines, histone mass spectrometry, gene expression profiling, xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinetics with mutant enzyme, CRISPR-edited isogenic lines, mass spectrometry of histone modifications, multiple orthogonal methods\",\n      \"pmids\": [\"30171259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNA DSBs promote NSD2-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA damage sites, governing efficient DSB repair partly through γH2AX dephosphorylation.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis, Co-immunoprecipitation, in vitro methyltransferase assay, xenograft chemosensitivity experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation assay, methylation site identified by MS and validated by mutagenesis, 53BP1 tudor domain reader shown by Co-IP, functional rescue experiments\",\n      \"pmids\": [\"31217297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NSD2 overexpression drives clustered chromatin and transcriptional changes within specific insulated topological domains (TADs). H3K36me2 expansion is linked to alterations in H3K27ac and CTCF occupancy, with differentially expressed genes enriched within the same insulated domain as altered chromatin marks.\",\n      \"method\": \"ChIP-seq, Hi-C/TAD analysis, isogenic cell lines with high/low NSD2, logistic regression modeling of gene expression vs. chromatin changes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq and 3D chromatin organization in isogenic cell lines, multiple chromatin assays, rigorous statistical modeling\",\n      \"pmids\": [\"31649247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MMSET/NSD2 is recruited to DNA damage sites by the endoribonuclease DICER, and catalyzes H4K20me2 at those sites, which facilitates recruitment of the NER factor XPA during global-genomic nucleotide excision repair (NER).\",\n      \"method\": \"ChIP, siRNA knockdown, immunofluorescence, NER assay, epistasis analysis of DICER-MMSET pathway\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating MMSET at UV-damage sites, functional NER assay, DICER-MMSET epistasis, single lab\",\n      \"pmids\": [\"29233865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Whsc1 is required for pluripotency exit and mesendoderm specification in embryonic stem cells, functioning through binding to enhancers of mesendodermal regulators (Gata4, Brachyury/T, Gata6, Foxa2) together with Brd4, independently of its methyltransferase activity.\",\n      \"method\": \"Genetic knockout, rescue with methyltransferase-dead mutant, ChIP, RNA-seq, differentiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific developmental phenotype, methyltransferase-dead mutant rescue demonstrating activity-independent function, ChIP showing enhancer occupancy, multiple methods\",\n      \"pmids\": [\"31235934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MMSET is degraded during S phase in a CRL4(Cdt2) E3 ligase- and proteasome-dependent manner. MMSET depletion causes defects in DNA replication and decreased association of pre-replication complex (pre-RC) factors with chromatin.\",\n      \"method\": \"Cell cycle synchronization, proteasome inhibitor treatment, chromatin fractionation, siRNA knockdown, DNA fiber assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRL4(Cdt2) dependence demonstrated by inhibitor and siRNA, chromatin fractionation of pre-RC factors, single lab\",\n      \"pmids\": [\"26771714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NSD2 knockdown induces cellular senescence through RB-mediated downregulation of cell cycle genes. NSD2 is enriched at gene bodies of actively transcribed cell cycle genes and its loss decreases H3K36me3 at these loci.\",\n      \"method\": \"RNAi screen, ChIP-seq, transcriptome analysis, senescence assays (SA-β-gal, mitochondrial mass), knockdown in primary fibroblasts\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq showing NSD2 occupancy at cell cycle gene bodies, H3K36me3 loss after knockdown, RB-mediated mechanism supported by transcriptomics, single lab\",\n      \"pmids\": [\"32573059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD28 signaling induces NSD2 expression in T cells, and NSD2-mediated H3K36me2 is required for early Bcl6 expression and follicular helper T (Tfh) cell differentiation. ICOS signaling maintains sustained NSD2 expression. Ectopic Bcl6 rescues the Tfh defect in Nsd2-KO cells.\",\n      \"method\": \"Conditional knockout mouse model, flow cytometry, ChIP, retroviral rescue experiments, germinal center assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific immunological phenotype, genetic epistasis via Bcl6 rescue, ChIP demonstrating H3K36me2 at Bcl6 locus, multiple orthogonal methods\",\n      \"pmids\": [\"31636135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 PWWP1 domain occupies the canonical H3K36me2-binding pocket. A chemical probe (UNC6934) antagonizing PWWP1-H3K36me2 interaction induces NSD2 accumulation in the nucleolus, phenocopying NSD2 isoform localization defects seen in t(4;14) MM.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance (SPR), cellular thermal shift assay, live cell imaging, chemical probe/control compound pair\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of PWWP1 domain, SPR binding quantification, chemical probe with matched negative control, multiple orthogonal methods including cellular imaging\",\n      \"pmids\": [\"34782742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 promotes tumor angiogenesis by methylating STAT3 at K163, which activates STAT3 signaling and upregulates VEGFA expression. K163R mutation attenuates STAT3 activation and angiogenic function.\",\n      \"method\": \"Mass spectrometry for methylation site identification, site-directed mutagenesis, in vitro methyltransferase assay, angiogenesis assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro methyltransferase assay with mutagenesis identifying methylation site, functional consequence shown, single lab\",\n      \"pmids\": [\"33742125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 interacts with SRC-3 to coordinate liquid-liquid phase separation of SRC-3, which enhances H3K36me2 modifications at anti-apoptotic gene promoters. Targeting the NSD2-SRC-3 interaction with SI-2 inhibitor sensitizes myeloma cells to bortezomib.\",\n      \"method\": \"Co-immunoprecipitation, phase separation assays, ChIP-seq, small molecule inhibitor (SI-2), in vitro and in vivo drug resistance models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying NSD2-SRC-3 interaction, phase separation assays, ChIP-seq at anti-apoptotic gene promoters, single lab\",\n      \"pmids\": [\"33589584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 interacts with the SWI/SNF ATPase subunit SMARCA2 in a non-canonical, SWI/SNF complex-independent manner, forming a complex that localizes to the PTP4A3 promoter, increases H3K36me2, and drives transcriptional activation of PTP4A3.\",\n      \"method\": \"SILAC mass spectrometry, co-immunoprecipitation, RNA-seq, ChIP, pharmacological inhibition with BET inhibitor PFI-3, xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative mass spectrometry for interaction discovery, reciprocal Co-IP, ChIP at target promoter, functional validation by drug inhibition and xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"33602783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 E1099K mutation in ALL drives glucocorticoid resistance by promoting H3K27me3 accumulation at the NR3C1 (glucocorticoid receptor) promoter, suppressing GR expression and autoactivation. PRC2 inhibitors restore NR3C1 expression and glucocorticoid sensitivity.\",\n      \"method\": \"CRISPR correction of E1099K, drug screen, ChIP-seq, isogenic cell line comparison, patient-derived xenograft, PRC2 inhibitor treatment\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-corrected isogenic lines establishing causality, ChIP-seq demonstrating H3K27me3 at GR promoter, PDX model, multiple orthogonal methods\",\n      \"pmids\": [\"34417224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 via H3K36me2 catalysis cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. The hyperactive NSD2-E1099K variant accelerates malignant tumor progression in KRAS-driven LUAD mouse models. Combined NSD2 depletion with MEK1/2 inhibition causes near-complete regression of LUAD tumors.\",\n      \"method\": \"In vivo mouse LUAD model, CRISPRi gene knockdown system, PDX models, MEK inhibitor combination treatment, RNA-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetic models, CRISPRi loss-of-function, PDX models, genetic epistasis with KRAS, combination treatment validation\",\n      \"pmids\": [\"34555356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFN-γ/STAT1 signaling stimulates WHSC1 expression, and WHSC1 directly interacts with NLRC5 to promote MHC-I gene transcription, enabling antitumor immune responses in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, flow cytometry for MHC-I expression, syngeneic mouse tumor models, immune checkpoint blockade experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating WHSC1-NLRC5 interaction, ChIP at MHC-I gene loci, multiple in vivo models, mechanistic pathway well supported\",\n      \"pmids\": [\"35230972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSD2 loss-of-function missense variants reduce H3K36me2 methylation activity in vitro and fail to reconstitute H3K36me2 in NSD2 knockout cells, establishing a causal link between catalytic impairment and the developmental phenotype (Rauch-Steindl syndrome).\",\n      \"method\": \"In vitro methyltransferase assay with patient-derived missense variants, NSD2-knockout cell complementation, structural modeling\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay of multiple patient variants, NSD2 KO cell rescue experiments, structural modeling supporting mechanism\",\n      \"pmids\": [\"33941880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSD2 is required for H3K36me2 and H3K36me3 in spermatogenic cells. NSD2 interacts with PSMA8 to regulate acetylated histone degradation affecting H4K16ac, and NSD2 loss impairs EP300-induced H4K5/8ac recognized by BRDT, leading to defective histone eviction and retention of histones in spermatozoa.\",\n      \"method\": \"Conditional knockout mouse model, ChIP-seq, co-immunoprecipitation of NSD2-PSMA8 interaction, mass spectrometry of histone modifications, fertility assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined fertility phenotype, ChIP-seq, Co-IP identifying PSMA8 interaction, histone modification mass spectrometry, multiple orthogonal methods\",\n      \"pmids\": [\"35736136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSD2 upregulates CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the maternal-fetal interface decidua, required for maternal-fetal immune tolerance.\",\n      \"method\": \"Conditional knockout mouse model, ChIP, flow cytometry for Treg levels, CXCR4 expression analysis, fetal loss phenotype\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific immune phenotype, ChIP demonstrating H3K36me2 at CXCR4 locus, single lab\",\n      \"pmids\": [\"35322173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in prostate cancer. NSD2 H3K36 dimethyltransferase activity is required for over 65% of tumor-specific AR cistrome. NSD2 inactivation disrupts AR transactivation and increases dependency on NSD1 paralog.\",\n      \"method\": \"ChIP-seq (AR, NSD2, H3K36me2), CRISPR-mediated NSD2 inactivation, PROTAC dual NSD1/2 degrader, patient sample analysis, prostate cancer cell models\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, CRISPR loss-of-function, PROTAC degrader tool, patient cohort validation, multiple orthogonal methods\",\n      \"pmids\": [\"39251788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO22 can be recruited to mediate NSD2 degradation via a molecular mechanism where a primary amine-containing compound (UNC8732) is metabolized to an aldehyde that engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex to NSD2.\",\n      \"method\": \"Targeted protein degradation assays, FBXO22 co-immunoprecipitation, chemical probe and genetic rescue experiments, cell proliferation and apoptosis assays in ALL cells\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic characterization of E3 ligase recruitment, Co-IP, chemical biology approach with matched controls, multiple orthogonal validation methods\",\n      \"pmids\": [\"38965384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3K36me2 by MMSET promotes classical (Ligase4-dependent) non-homologous end-joining at deprotected telomeres. MMSET catalytic activity (SET domain) is required for this effect, and H3K36me2 levels directly correlate with NHEJ efficiency at telomeres.\",\n      \"method\": \"Methyltransferase screen at telomeres, NHEJ reporter assay distinguishing classical vs. alternative NHEJ, ChIP for H3K36me2 at subtelomeric regions, MMSET catalytic mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NHEJ assay with pathway specificity (Ligase4 vs. Ligase3), catalytic mutant validation, ChIP, single lab\",\n      \"pmids\": [\"32472076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a systematic perturbation study, NSD2 predominantly deposits H3K36me2 at intergenic regions, with NSD1 being the primary intergenic H3K36me2 methyltransferase. Within genes, SETD2 deposits H3K36me3 while NSD2 contributes H3K36me2 independently of SETD2. A hierarchy of K36MT activities is defined as NSD1 > NSD2 > NSD3 > ASH1L.\",\n      \"method\": \"CRISPR KO of individual H3K36 methyltransferases, ChIP-seq, CUT&RUN, RNA-seq in mouse mesenchymal stem cells\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic perturbation with matched ChIP-seq across multiple methyltransferases, genome-wide resolution, rigorous comparison of enzyme activities\",\n      \"pmids\": [\"39390582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MMSET I isoform (but not MMSET II or RE-IIBP) represses transcription and specifically recruits HDAC1 and mSin3b (but not HDAC2 or HDAC4) in co-immunoprecipitation assays, with this repression activity being partially reversed by the HDAC inhibitor TSA.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assay (thymidine kinase promoter), HDAC inhibitor treatment, isoform-specific overexpression\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP demonstrating isoform-specific corepressor recruitment, reporter assay, single lab\",\n      \"pmids\": [\"16197452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMSET regulates class switch recombination (CSR) through its histone methyltransferase activity. MMSET knockdown impairs 53BP1 recruitment and germline transcription of immunoglobulin switch regions, resulting in defective CSR without affecting cell viability.\",\n      \"method\": \"shRNA knockdown, CSR assay, immunofluorescence for 53BP1 recruitment, RT-PCR for germline transcription, cell viability assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional CSR assay, 53BP1 recruitment assay, pathway epistasis with H4K20me2/53BP1 axis, single lab\",\n      \"pmids\": [\"23241889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSD2 interacts with RARα and protects it from degradation, and enhances nuclear condensation (phase separation) of RARα. NSD2 also modifies H3K36me2 at the CD38 promoter to increase CD38 expression in response to ATRA stimulation.\",\n      \"method\": \"Co-immunoprecipitation, confocal live imaging for nuclear condensation, ChIP, flow cytometry for CD38, shRNA knockdown\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating NSD2-RARα interaction, ChIP at CD38 promoter, live imaging for phase condensation, single lab\",\n      \"pmids\": [\"36918219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NSD2-mediated H3K36me2 directly activates ULK1 transcription in triple-negative breast cancer cells, promoting autophagosome maturation and autophagic flux to drive TNBC metastasis.\",\n      \"method\": \"ChIP demonstrating H3K36me2 at ULK1 locus, shRNA knockdown, overexpression, autophagy flux assays, in vivo metastasis models, pharmacological NSD2 inhibition\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at ULK1 locus, functional autophagy assays, in vivo metastasis validation, single lab\",\n      \"pmids\": [\"40097917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NSD2 (MMSET/WHSC1) is a histone methyltransferase whose primary enzymatic activity is dimethylation of H3K36 (H3K36me2), a mark that broadly promotes active transcription; it also catalyzes H4K20me2 at DNA double-strand breaks to recruit 53BP1 and facilitate DNA repair, non-histone methylation of substrates including PTEN (K349) and STAT3 (K163), and methylation-independent functions including binding of PHD and PWWP domains to chromatin and acting as a coactivator/corepressor through interaction with partners such as HDAC1/2, mSin3, LSD1, BRD4, P-TEFb, HIRA, NF-κB, AR, NLRC5, SMARCA2, and SRC-3; in cancer, oncogenic t(4;14) translocation-driven NSD2 overexpression globally expands H3K36me2 domains, competes with H3K27me3, reprograms the transcriptional landscape, and confers resistance to DNA-damaging agents and promotes metastasis through multiple downstream gene regulatory axes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NSD2 (MMSET/WHSC1) is a chromatin-modifying histone methyltransferase whose principal catalytic activity is dimethylation of histone H3 at lysine 36 (H3K36me2), a mark sufficient to drive gene activation and oncogenic transformation [#1]. It was first identified as the gene disrupted by the recurrent t(4;14) translocation in multiple myeloma, which drives its overexpression from the IgH locus [#0]. Catalytically, NSD2 deposits H3K36me2 predominantly at intergenic regions within a defined hierarchy of H3K36 methyltransferases, contributing intragenic H3K36me2 independently of SETD2 [#36]; its overexpression globally expands H3K36me2 domains with a reciprocal global loss of H3K27me3, and reorganizes chromatin and transcription within insulated topological domains via coordinated changes in H3K27ac and CTCF occupancy [#4, #17]. The recurrent E1099K mutation enhances H3K36 methylation kinetics, especially on H3.1 nucleosomes, further elevating H3K36me2 and depleting H3K27me3 [#15]. Recruitment to chromatin depends on its PHD fingers and on the PWWP1 domain, which reads H3K36me2 through a canonical aromatic pocket [#11, #23]. Beyond its core enzymatic role, NSD2 acts as a transcriptional coregulator: it activates targets in concert with NF-\\u03baB, BRD4/P-TEFb and the HIRA H3.3 chaperone, the AR/FOXA1 neo-enhanceosome, NLRC5, SMARCA2, and SRC-3, and it forms isoform-specific corepressor complexes with HDAC1/2, mSin3 and LSD1 [#7, #10, #33, #29, #26, #3]. In genome maintenance, NSD2 is recruited to DNA double-strand breaks and catalyzes H4K20me2 to promote 53BP1 loading, supporting non-homologous end-joining and homologous recombination [#2, #12]. It also methylates non-histone substrates, including PTEN at K349 to direct PTEN to damage sites for repair and STAT3 at K163 to drive VEGFA-dependent angiogenesis [#16, #24]. NSD2 stability is controlled by AKT phosphorylation and CRL4(Cdt2)- and FBXO22-dependent degradation [#13, #34]. Catalytic loss-of-function missense variants that fail to reconstitute H3K36me2 cause the developmental disorder Rauch-Steindl syndrome [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing NSD2's clinical relevance, it was identified as the gene disrupted by t(4;14) in multiple myeloma, framing it as a translocation-driven oncogene before its biochemical function was known.\",\n      \"evidence\": \"Molecular cloning and hybrid transcript characterization of the IgH/MMSET fusion, with domain analysis revealing HMG, PHD, and SET domains\",\n      \"pmids\": [\"9787135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the enzymatic activity of the SET domain\", \"Did not establish which substrates or marks drive the oncogenic phenotype\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Early biochemistry assigned MMSET a methyltransferase activity and a corepressor role, the first mechanistic insight into how it alters chromatin.\",\n      \"evidence\": \"In vitro methyltransferase assays (H3K4/H4K20), Co-IP defining an HDAC1/2-mSin3a-LSD1 corepressor complex, and Gal4 reporter assays\",\n      \"pmids\": [\"18156491\", \"16197452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro vs. in cell substrate discrepancy left the physiological mark unresolved\", \"Did not reconcile a corepressor role with later activating functions\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Isoform-specific assays showed distinct catalytic outputs, with the RE-IIBP isoform methylating H3K27 via defined SET residues, complicating the simple one-enzyme-one-mark view.\",\n      \"evidence\": \"In vitro methyltransferase assays with C483/R477 active-site mutagenesis, ChIP, and reporter assays\",\n      \"pmids\": [\"18172012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between RE-IIBP H3K27 activity and full-length NSD2 H3K36 activity unresolved\", \"In vivo significance of isoform-specific catalysis not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The field converged on H3K36me2 as NSD2's principal, oncogenically relevant activity, defining the mark whose deposition is sufficient for gene activation and transformation.\",\n      \"evidence\": \"In vitro methyltransferase assay, genome-wide ChIP-seq, catalytic mutant rescue, and xenograft tumor formation; separately, recruitment to DSBs via MDC1-MMSET phospho-S102 interaction with local H4K20me2 driving 53BP1\",\n      \"pmids\": [\"22099308\", \"21293379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K36me2 expansion is read into transcriptional output not yet defined\", \"Genome-wide chromatin domain effects not yet mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"NSD2 was shown to antagonize Polycomb chromatin, establishing the H3K36me2/H3K27me3 balance as a central axis of its oncogenic reprogramming.\",\n      \"evidence\": \"ChIP-seq, shRNA knockdown, EZH2 inhibitor sensitivity, PHD domain deletion mutants, and xenografts showing global H3K36me2 gain with global H3K27me3 loss but locus-specific EZH2 gain\",\n      \"pmids\": [\"25188243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of locus-selective EZH2 retargeting amid global H3K27me3 loss unclear\", \"Direct PHD ligand at chromatin not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"NSD2 was integrated into the transcriptional elongation machinery and chromatin recruitment logic, explaining how it activates target genes.\",\n      \"evidence\": \"Reciprocal Co-IP identifying BRD4, P-TEFb, and HIRA; Whsc1-knockout cells showing loss of H3.3 deposition; and PHD-mutant ChIP showing recruitment to oncogenic loci\",\n      \"pmids\": [\"23921552\", \"23980095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether elongation coupling is direct or downstream of H3K36me2 not resolved\", \"Identity of PHD-recognized chromatin features unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"NSD2 was established as a broad DNA-repair factor required for both NHEJ and HR, explaining how its overexpression confers resistance to DNA-damaging therapy.\",\n      \"evidence\": \"NHEJ/HR reporter assays, ChIP, shRNA knockdown, immunofluorescence for repair-factor recruitment, and in vivo chemosensitivity xenografts\",\n      \"pmids\": [\"27109101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether repair defects are catalytic or scaffolding-dependent not fully separated\", \"Which substrate (H4K20 vs. non-histone) is rate-limiting per pathway unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural-kinetic analysis of the recurrent E1099K mutation defined the molecular basis of NSD2 hyperactivity in cancer.\",\n      \"evidence\": \"In vitro methyltransferase kinetics with mutant enzyme, CRISPR-edited isogenic lines, and histone mass spectrometry showing enhanced H3K36me2 on H3.1 nucleosomes\",\n      \"pmids\": [\"30171259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleosome-context selectivity (H3.1 vs H3.3) mechanism not fully resolved\", \"Therapeutic targetability of the mutant enzyme not addressed here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NSD2 protein abundance was linked to AKT signaling and a feedforward oncogenic loop, identifying how it is post-translationally stabilized.\",\n      \"evidence\": \"MS phospho-site identification (S172), mutagenesis, Co-IP of CRL4Cdt2, ubiquitination assays, and a PTEN-null + WHSC1 mouse model showing RICTOR/Rac1 upregulation\",\n      \"pmids\": [\"28319045\", \"26771714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between S172 stabilization and S-phase CRL4Cdt2 degradation timing not fully integrated\", \"Generalizability of the AKT-NSD2-mTORC2 loop beyond PTEN-null contexts unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NSD2 was shown to methylate non-histone substrates and to act through methyltransferase-independent scaffolding, broadening its mechanistic repertoire beyond histone marks.\",\n      \"evidence\": \"MS/mutagenesis identifying PTEN K349 read by 53BP1 tudor at DSBs; Whsc1 KO with methyltransferase-dead rescue in ESC mesendoderm specification via Brd4-bound enhancers; Hi-C/ChIP-seq showing TAD-confined chromatin reprogramming\",\n      \"pmids\": [\"31217297\", \"31235934\", \"31649247\", \"29233865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of catalytic vs. non-catalytic mode selection unknown\", \"Full set of non-histone substrates not enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NSD2 was structurally defined as an H3K36me2 reader and embedded in diverse coactivator complexes and condensates, while its mutations were tied to therapy resistance, motivating targeted degraders.\",\n      \"evidence\": \"PWWP1 crystal structure and chemical probe (UNC6934); Co-IP/ChIP-seq of SRC-3 (phase separation), SMARCA2, NLRC5, and RAR\\u03b1; CRISPR-corrected E1099K showing H3K27me3 at NR3C1 driving glucocorticoid resistance\",\n      \"pmids\": [\"34782742\", \"33589584\", \"33602783\", \"35230972\", \"36918219\", \"34417224\", \"33742125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phase separation, reader function, and catalysis are mechanistically coupled is unresolved\", \"Specificity of partner choice across cancer contexts not systematized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Patient-derived missense variants established NSD2 catalytic insufficiency as causal for a developmental disorder, extending its role from cancer to germline disease.\",\n      \"evidence\": \"In vitro methyltransferase assays of variants, NSD2-KO cell complementation, and structural modeling defining Rauch-Steindl syndrome\",\n      \"pmids\": [\"33941880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which developmental gene programs depend on H3K36me2 dosage not defined\", \"Genotype-phenotype correlation across variants incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Systematic perturbation placed NSD2 within the genome-wide hierarchy of H3K36 methyltransferases, and chemical degrader strategies provided a route to deplete it.\",\n      \"evidence\": \"CRISPR KO of individual K36 methyltransferases with ChIP-seq/CUT&RUN defining NSD1>NSD2>NSD3>ASH1L; FBXO22-recruiting molecular-glue degradation of NSD2 via aldehyde-engaged C326\",\n      \"pmids\": [\"39390582\", \"38965384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of intergenic vs. intragenic H3K36me2 deposition not fully separated\", \"Selectivity of degraders against NSD1/NSD3 paralogs not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NSD2 selects between its histone catalytic, non-histone methylation, and scaffolding/condensate functions in a given cellular context, and how these are integrated to specify oncogenic versus developmental outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model linking catalytic and methyltransferase-independent functions\", \"Context determinants of partner and substrate choice undefined\", \"Comprehensive non-histone substrate map lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 5, 15, 36]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 24, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 8, 33]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 23]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 10, 33]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 15, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 12, 16, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 27, 28, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 29, 38]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 30, 31]}\n    ],\n    \"complexes\": [\n      \"NSD2-HDAC1/2-mSin3a-LSD1 corepressor complex\",\n      \"AR/FOXA1 neo-enhanceosome\"\n    ],\n    \"partners\": [\n      \"MDC1\",\n      \"BRD4\",\n      \"HIRA\",\n      \"SMARCA2\",\n      \"NLRC5\",\n      \"SRC-3\",\n      \"PSMA8\",\n      \"FBXO22\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}