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Showing NSD2 — WHSC1 is a alias.

NSD2

Histone-lysine N-methyltransferase NSD2 · UniProt O96028

Length
1365 aa
Mass
152.3 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    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

    PMID:9787135

    Open questions at the time
    • Did not define the enzymatic activity of the SET domain
    • Did not establish which substrates or marks drive the oncogenic phenotype
  2. 2007 High

    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

    PMID:16197452 PMID:18156491

    Open questions at the time
    • In vitro vs. in cell substrate discrepancy left the physiological mark unresolved
    • Did not reconcile a corepressor role with later activating functions
  3. 2008 High

    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

    PMID:18172012

    Open questions at the time
    • Relationship between RE-IIBP H3K27 activity and full-length NSD2 H3K36 activity unresolved
    • In vivo significance of isoform-specific catalysis not established
  4. 2011 High

    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

    PMID:21293379 PMID:22099308

    Open questions at the time
    • How H3K36me2 expansion is read into transcriptional output not yet defined
    • Genome-wide chromatin domain effects not yet mapped
  5. 2014 High

    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

    PMID:25188243

    Open questions at the time
    • Mechanism of locus-selective EZH2 retargeting amid global H3K27me3 loss unclear
    • Direct PHD ligand at chromatin not defined
  6. 2013 High

    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

    PMID:23921552 PMID:23980095

    Open questions at the time
    • Whether elongation coupling is direct or downstream of H3K36me2 not resolved
    • Identity of PHD-recognized chromatin features unknown
  7. 2016 High

    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

    PMID:27109101

    Open questions at the time
    • Whether repair defects are catalytic or scaffolding-dependent not fully separated
    • Which substrate (H4K20 vs. non-histone) is rate-limiting per pathway unclear
  8. 2018 High

    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

    PMID:30171259

    Open questions at the time
    • Nucleosome-context selectivity (H3.1 vs H3.3) mechanism not fully resolved
    • Therapeutic targetability of the mutant enzyme not addressed here
  9. 2017 High

    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

    PMID:26771714 PMID:28319045

    Open questions at the time
    • 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
  10. 2019 High

    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

    PMID:29233865 PMID:31217297 PMID:31235934 PMID:31649247

    Open questions at the time
    • Determinants of catalytic vs. non-catalytic mode selection unknown
    • Full set of non-histone substrates not enumerated
  11. 2021 High

    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

    PMID:33589584 PMID:33602783 PMID:33742125 PMID:34417224 PMID:34782742 PMID:35230972 PMID:36918219

    Open questions at the time
    • How phase separation, reader function, and catalysis are mechanistically coupled is unresolved
    • Specificity of partner choice across cancer contexts not systematized
  12. 2022 High

    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

    PMID:33941880

    Open questions at the time
    • Which developmental gene programs depend on H3K36me2 dosage not defined
    • Genotype-phenotype correlation across variants incomplete
  13. 2024 High

    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

    PMID:38965384 PMID:39390582

    Open questions at the time
    • Functional consequences of intergenic vs. intragenic H3K36me2 deposition not fully separated
    • Selectivity of degraders against NSD1/NSD3 paralogs not established here

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 1 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3
Partners
BRD4FBXO22HIRAMDC1NLRC5PSMA8SMARCA2SRC-3
Complex memberships
AR/FOXA1 neo-enhanceosomeNSD2-HDAC1/2-mSin3a-LSD1 corepressor complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Molecular cloning, hybrid transcript characterization, domain analysis Blood High 9787135
2011 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. In vitro methyltransferase assay, genome-wide ChIP-seq, catalytic mutant rescue, xenograft tumor formation Molecular cell High 22099308
2011 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. ChIP, immunofluorescence, co-immunoprecipitation, siRNA knockdown, DSB induction assays Nature High 21293379
2007 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. In vitro methyltransferase assay, co-immunoprecipitation, Gal4 transcriptional repression reporter assay, ChIP Blood High 18156491
2014 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. ChIP-seq, shRNA knockdown, EZH2 inhibitor sensitivity assays, domain deletion mutant analysis, xenograft model PLoS genetics High 25188243
2008 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. In vitro methyltransferase assay, point mutagenesis, ChIP, reporter gene assay, shRNA knockdown Molecular and cellular biology High 18172012
2009 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. Co-immunoprecipitation, ChIP, overexpression of wild-type vs. SET-deleted mutant, RT-PCR for PSA mRNA FEBS letters Medium 19481544
2012 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. Co-immunoprecipitation, ChIP, shRNA knockdown, reporter assays, gene expression analysis Molecular and cellular biology Medium 22645312
2012 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. ChIP, shRNA knockdown, overexpression, invasion/migration assays, TWIST1 rescue experiments Oncogene Medium 22797064
2012 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*. ChIP, miRNA profiling, 3'UTR luciferase reporter assay, shRNA knockdown, cell proliferation assays Leukemia Medium 22972034
2013 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. Co-immunoprecipitation, ChIP, genetic knockout (Whsc1-/- cells), gene expression analysis The EMBO journal High 23921552
2013 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. PHD domain mutant analysis, ChIP, shRNA knockdown, xenograft tumor model, colony formation assays Cancer research Medium 23980095
2016 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. NHEJ and HR reporter assays, ChIP, shRNA knockdown, xenograft chemosensitivity model, immunofluorescence for repair factor recruitment Oncogene High 27109101
2017 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. Mass spectrometry phospho-site identification, site-directed mutagenesis, co-immunoprecipitation, ubiquitination assays, ChIP, genetic mouse model (PTEN-null + WHSC1 overexpression), xenograft The Journal of clinical investigation High 28319045
2018 MMSET methylates Aurora kinase A (AURKA), enhancing AURKA kinase activity and promoting p53 interaction with AURKA, which leads to proteasomal degradation of p53. Co-immunoprecipitation, in vitro methyltransferase assay, kinase activity assay, p53 degradation assay, shRNA knockdown Oncogene Medium 30013191
2018 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. In vitro methyltransferase assay, CRISPR-edited cell lines, histone mass spectrometry, gene expression profiling, xenograft Oncogene High 30171259
2019 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. Mass spectrometry, site-directed mutagenesis, Co-immunoprecipitation, in vitro methyltransferase assay, xenograft chemosensitivity experiments Cancer discovery High 31217297
2019 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. ChIP-seq, Hi-C/TAD analysis, isogenic cell lines with high/low NSD2, logistic regression modeling of gene expression vs. chromatin changes Nature communications High 31649247
2019 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). ChIP, siRNA knockdown, immunofluorescence, NER assay, epistasis analysis of DICER-MMSET pathway The Journal of cell biology Medium 29233865
2019 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. Genetic knockout, rescue with methyltransferase-dead mutant, ChIP, RNA-seq, differentiation assays Nature cell biology High 31235934
2020 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. Cell cycle synchronization, proteasome inhibitor treatment, chromatin fractionation, siRNA knockdown, DNA fiber assay Cell cycle (Georgetown, Tex.) Medium 26771714
2020 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. RNAi screen, ChIP-seq, transcriptome analysis, senescence assays (SA-β-gal, mitochondrial mass), knockdown in primary fibroblasts Aging cell Medium 32573059
2020 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. Conditional knockout mouse model, flow cytometry, ChIP, retroviral rescue experiments, germinal center assays The Journal of experimental medicine High 31636135
2021 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. X-ray crystallography, surface plasmon resonance (SPR), cellular thermal shift assay, live cell imaging, chemical probe/control compound pair Nature chemical biology High 34782742
2021 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. Mass spectrometry for methylation site identification, site-directed mutagenesis, in vitro methyltransferase assay, angiogenesis assays in vitro and in vivo Oncogene Medium 33742125
2021 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. Co-immunoprecipitation, phase separation assays, ChIP-seq, small molecule inhibitor (SI-2), in vitro and in vivo drug resistance models Nature communications Medium 33589584
2021 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. SILAC mass spectrometry, co-immunoprecipitation, RNA-seq, ChIP, pharmacological inhibition with BET inhibitor PFI-3, xenograft Cancer research High 33602783
2021 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. CRISPR correction of E1099K, drug screen, ChIP-seq, isogenic cell line comparison, patient-derived xenograft, PRC2 inhibitor treatment Cancer discovery High 34417224
2021 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. In vivo mouse LUAD model, CRISPRi gene knockdown system, PDX models, MEK inhibitor combination treatment, RNA-seq Molecular cell High 34555356
2021 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. Co-immunoprecipitation, ChIP, siRNA knockdown, flow cytometry for MHC-I expression, syngeneic mouse tumor models, immune checkpoint blockade experiments The Journal of clinical investigation High 35230972
2022 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). In vitro methyltransferase assay with patient-derived missense variants, NSD2-knockout cell complementation, structural modeling Genetics in medicine High 33941880
2022 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. Conditional knockout mouse model, ChIP-seq, co-immunoprecipitation of NSD2-PSMA8 interaction, mass spectrometry of histone modifications, fertility assays Nucleic acids research High 35736136
2022 NSD2 upregulates CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the maternal-fetal interface decidua, required for maternal-fetal immune tolerance. Conditional knockout mouse model, ChIP, flow cytometry for Treg levels, CXCR4 expression analysis, fetal loss phenotype Cellular & molecular immunology Medium 35322173
2023 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. ChIP-seq (AR, NSD2, H3K36me2), CRISPR-mediated NSD2 inactivation, PROTAC dual NSD1/2 degrader, patient sample analysis, prostate cancer cell models Nature genetics High 39251788
2024 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. Targeted protein degradation assays, FBXO22 co-immunoprecipitation, chemical probe and genetic rescue experiments, cell proliferation and apoptosis assays in ALL cells Nature chemical biology High 38965384
2020 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. Methyltransferase screen at telomeres, NHEJ reporter assay distinguishing classical vs. alternative NHEJ, ChIP for H3K36me2 at subtelomeric regions, MMSET catalytic mutant analysis Oncogene Medium 32472076
2024 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. CRISPR KO of individual H3K36 methyltransferases, ChIP-seq, CUT&RUN, RNA-seq in mouse mesenchymal stem cells Genome biology High 39390582
2005 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. Co-immunoprecipitation, transcriptional reporter assay (thymidine kinase promoter), HDAC inhibitor treatment, isoform-specific overexpression British journal of haematology Medium 16197452
2012 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. shRNA knockdown, CSR assay, immunofluorescence for 53BP1 recruitment, RT-PCR for germline transcription, cell viability assays Journal of immunology Medium 23241889
2021 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. Co-immunoprecipitation, confocal live imaging for nuclear condensation, ChIP, flow cytometry for CD38, shRNA knockdown Journal for immunotherapy of cancer Medium 36918219
2025 NSD2-mediated H3K36me2 directly activates ULK1 transcription in triple-negative breast cancer cells, promoting autophagosome maturation and autophagic flux to drive TNBC metastasis. ChIP demonstrating H3K36me2 at ULK1 locus, shRNA knockdown, overexpression, autophagy flux assays, in vivo metastasis models, pharmacological NSD2 inhibition Autophagy Medium 40097917

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 442 9787135
2011 NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Molecular cell 369 22099308
2011 MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 336 21293379
2014 Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation. PLoS genetics 198 25188243
2007 The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 160 18156491
2005 Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 148 15677557
2012 The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer. Oncogene 138 22797064
2007 The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 134 17942756
2012 Histone methyltransferase NSD2/MMSET mediates constitutive NF-κB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. Molecular and cellular biology 131 22645312
2011 The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 121 21385930
2017 AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis. The Journal of clinical investigation 108 28319045
2008 MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematologica 100 19059936
2014 WHSC1 promotes oncogenesis through regulation of NIMA-related kinase-7 in squamous cell carcinoma of the head and neck. Molecular cancer research : MCR 88 25280969
2019 NSD2 circular RNA promotes metastasis of colorectal cancer by targeting miR-199b-5p-mediated DDR1 and JAG1 signalling. The Journal of pathology 82 30666650
2008 Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Molecular and cellular biology 82 18172012
2020 CircRNA WHSC1 targets the miR-646/NPM1 pathway to promote the development of endometrial cancer. Journal of cellular and molecular medicine 79 32378344
2016 MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene 76 27109101
2021 NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. Molecular cell 75 34555356
2012 MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC. Leukemia 75 22972034
2021 A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization. Nature chemical biology 73 34782742
2019 PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage. Cancer discovery 72 31217297
2022 Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ-stimulated antitumor immunity. The Journal of clinical investigation 70 35230972
2019 NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nature communications 70 31649247
2013 NSD2 is recruited through its PHD domain to oncogenic gene loci to drive multiple myeloma. Cancer research 63 23980095
2008 MMSET is overexpressed in cancers: link with tumor aggressiveness. Biochemical and biophysical research communications 62 19121287
2021 Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma. Nature communications 60 33589584
2018 High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2. The Journal of biological chemistry 60 29945974
2013 WHSC1 links transcription elongation to HIRA-mediated histone H3.3 deposition. The EMBO journal 57 23921552
2009 The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS letters 56 19481544
2011 MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer research 55 21527557
2021 NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein. Oncogene 53 33742125
2021 Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. Journal of medicinal chemistry 52 33522809
2016 NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation. Scientific reports 50 27604143
2001 WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Genomics 50 11549311
2019 Histone methyltransferase NSD2 regulates apoptosis and chemosensitivity in osteosarcoma. Cell death & disease 49 30683853
2024 Recruitment of FBXO22 for targeted degradation of NSD2. Nature chemical biology 48 38965384
2022 Melatonin enhances osteoblastogenesis of senescent bone marrow stromal cells through NSD2-mediated chromatin remodelling. Clinical and translational medicine 46 35220680
2022 Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos. Journal of medicinal chemistry 46 35895319
2023 Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2. Journal of the American Chemical Society 45 36976643
2022 The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. Cellular and molecular life sciences : CMLS 45 35532818
2018 An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene 45 30171259
2023 The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM. Blood 42 35984902
2021 Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype. Genetics in medicine : official journal of the American College of Medical Genetics 42 33941880
2018 miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation. Oncotarget 42 29796186
2021 Identification of histone methyltransferase NSD2 as an important oncogenic gene in colorectal cancer. Cell death & disease 41 34671018
2018 Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2). American journal of medical genetics. Part A 38 30345613
2001 A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. American journal of respiratory cell and molecular biology 38 11152655
2020 The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling. Aging cell 37 32573059
2020 The Role of Methyltransferase NSD2 as a Potential Oncogene in Human Solid Tumors. OncoTargets and therapy 37 32764971
2019 Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling. Acta pharmacologica Sinica 37 30670815
2018 Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. Oncogene 37 30013191
2004 Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. British journal of haematology 37 15198734
2022 METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy. BMC nephrology 36 35354439
2017 MiR-2392 suppresses metastasis and epithelial-mesenchymal transition by targeting MAML3 and WHSC1 in gastric cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 28512191
2021 PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia. Cancer discovery 33 34417224
2012 The histone methyltransferase MMSET regulates class switch recombination. Journal of immunology (Baltimore, Md. : 1950) 33 23241889
2005 Evaluation of NSD2 and NSD3 in overgrowth syndromes. European journal of human genetics : EJHG 33 15483650
2018 De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features. Journal of human genetics 30 29760529
2024 NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. Nature genetics 27 39251788
2021 Exosomal-mediated transfer of APCDD1L-AS1 induces 5-fluorouracil resistance in oral squamous cell carcinoma via miR-1224-5p/nuclear receptor binding SET domain protein 2 (NSD2) axis. Bioengineered 27 34546854
2020 Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation. The Journal of experimental medicine 27 31636135
2013 Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma. Oncotarget 27 23900284
2022 H3K36me2 methyltransferase NSD2 orchestrates epigenetic reprogramming during spermatogenesis. Nucleic acids research 26 35736136
2015 MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib. Leukemia 26 26196464
2023 Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2). Journal of medicinal chemistry 25 37578463
2020 The NSD2 p.E1099K Mutation Is Enriched at Relapse and Confers Drug Resistance in a Cell Context-Dependent Manner in Pediatric Acute Lymphoblastic Leukemia. Molecular cancer research : MCR 25 32332049
2014 MMSET: role and therapeutic opportunities in multiple myeloma. BioMed research international 24 25093175
2012 Overexpression of MMSET in endometrial cancer: a clinicopathologic study. Journal of surgical oncology 24 22886632
2017 DICER- and MMSET-catalyzed H4K20me2 recruits the nucleotide excision repair factor XPA to DNA damage sites. The Journal of cell biology 23 29233865
2022 Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors. Journal of medicinal chemistry 22 35704853
2021 Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma. Oncogene 22 33420361
2021 Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2. Cell death discovery 22 33469000
2020 S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis. Chemico-biological interactions 22 32001260
2019 Whsc1 links pluripotency exit with mesendoderm specification. Nature cell biology 22 31235934
2005 Transcription repression activity is associated with the type I isoform of the MMSET gene involved in t(4;14) in multiple myeloma. British journal of haematology 22 16197452
2023 Recent advances in nuclear receptor-binding SET domain 2 (NSD2) inhibitors: An update and perspectives. European journal of medicinal chemistry 21 36863225
2023 All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma. Journal for immunotherapy of cancer 21 36918219
2021 CircRNA WHSC1 promotes non-small cell lung cancer progression via sponging microRNA-296-3p and up-regulating expression of AKT serine/threonine kinase 3. Journal of clinical laboratory analysis 21 34313353
2019 NSD2 inhibition suppresses metastasis in cervical cancer by promoting TGF-β/TGF-βRI/SMADs signaling. Biochemical and biophysical research communications 21 31526565
2021 SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma. Cancer research 20 33602783
2021 5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma. European journal of medicinal chemistry 20 34147909
2023 Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors. Journal of medicinal chemistry 19 36642961
2021 Circular RNA WHSC1 exerts oncogenic properties by regulating miR-7/TAB2 in lung cancer. Journal of cellular and molecular medicine 19 34551195
2020 H3K36 dimethylation by MMSET promotes classical non-homologous end-joining at unprotected telomeres. Oncogene 19 32472076
2019 NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy. Clinical science (London, England : 1979) 19 31040165
2015 Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis. Biochemical and biophysical research communications 19 25677622
2022 Histone methyltransferase Nsd2 ensures maternal-fetal immune tolerance by promoting regulatory T-cell recruitment. Cellular & molecular immunology 18 35322173
2020 WHSC1 Promotes Cell Proliferation, Migration, and Invasion in Hepatocellular Carcinoma by Activating mTORC1 Signaling. OncoTargets and therapy 18 32801739
2020 Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma. Molecular therapy. Nucleic acids 18 33552680
2024 Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader. Journal of medicinal chemistry 17 38687638
2020 WHSC1 promotes wnt/β-catenin signaling in a FoxM1-dependent manner facilitating proliferation, invasion and epithelial-mesenchymal transition in breast cancer. Journal of receptor and signal transduction research 17 32314642
2018 MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. Leukemia 17 30470837
2017 NSD2 promotes osteosarcoma cell proliferation and metastasis by inhibiting E-cadherin expression. European review for medical and pharmacological sciences 17 28338204
2016 MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. Cell cycle (Georgetown, Tex.) 17 26771714
2023 NSD2 promotes pressure overload-induced cardiac hypertrophy via activating circCmiss1/TfR1/ferroptosis signaling. Life sciences 16 37352916
2020 NSD2 Promotes Renal Cancer Progression Through Stimulating Akt/Erk Signaling. Cancer management and research 16 32021450
2019 Knockdown of NSD2 Suppresses Renal Cell Carcinoma Metastasis by Inhibiting Epithelial-Mesenchymal Transition. International journal of medical sciences 16 31692936
2025 H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy. Autophagy 15 40097917
2024 Systematic perturbations of SETD2, NSD1, NSD2, NSD3, and ASH1L reveal their distinct contributions to H3K36 methylation. Genome biology 15 39390582
2019 The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation. BMC cancer 15 31092221

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