Affinage

NSD1

Histone-lysine N-methyltransferase, H3 lysine-36 specific · UniProt Q96L73

Length
2696 aa
Mass
296.7 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NSD1 is a chromatin-modifying enzyme that functions as the predominant depositor of broad intergenic and enhancer-associated histone H3K36 mono- and di-methylation, organizing the epigenomic landscape during development and differentiation (PMID:32929285, PMID:39390582). Its SET domain carries intrinsic H3K36 methyltransferase activity gated by a regulatory autoinhibitory loop that occludes the substrate channel in the resting state and opens upon nucleosome engagement, explaining its preference for nucleosomal substrate and its dimethyl product specificity (PMID:21196496, PMID:32868895); this enzymatic activity is essential for early post-implantation development (PMID:12805229). The H3K36me2 NSD1 deposits acts as a node that recruits DNMT3A to pattern (including non-CG) DNA methylation and antagonizes PRC2/EZH2-dependent H3K27me3 deposition, in cooperation with SWI/SNF remodelers (PMID:32929285, PMID:37098340, PMID:35537449). Beyond catalysis, NSD1 reads chromatin and protein partners through dedicated modules: a tandem quadruple PHD-PWWP module recognizes p300-catalyzed H3K18ac to localize NSD1 to enhancers and promote RNA Pol II pause release—a coactivator function that operates partly independent of catalytic activity (PMID:37402365), while its PHD fingers bind methylated H3K4/H3K9 and its cysteine-rich C5HCH domain docks the corepressor Nizp1 via a C2HR zinc-finger motif (PMID:21972110, PMID:15169884). NSD1 also serves as a bifunctional nuclear-receptor intermediary, contacting both unliganded and liganded receptor LBDs through distinct NR-box motifs and acting as an androgen receptor coregulator (PMID:9628876, PMID:11509567). These activities translate into tissue-specific roles in spermatogenesis and imprinting, skeletal progenitor differentiation, and the establishment of cortical neuron identity (PMID:32929285, PMID:34099628, PMID:37995181). NSD1 is recurrently disrupted in cancer: it is fused to NUP98 in childhood AML, where the chimera maintains Hox-A locus activation in a SET-domain-dependent manner (PMID:11493482, PMID:17589499), and Sotos-syndrome-associated SET- and PHD-domain mutations abrogate catalytic activity and methyl-histone/Nizp1 reading, respectively (PMID:24412544, PMID:21972110).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1998 High

    Established NSD1 as a bifunctional nuclear-receptor intermediary, answering whether it acts as activator or repressor by showing it does both depending on ligand state.

    Evidence Yeast two-hybrid, GST pulldown, and reporter assays with NID-L and NID+L domains against RAR/TR/RXR/ER LBDs

    PMID:9628876

    Open questions at the time
    • Did not establish enzymatic activity
    • No endogenous target genes identified
    • In vivo relevance of NR interactions untested
  2. 2001 Medium

    Implicated NSD1 in human malignancy by identifying its in-frame fusion to NUP98 in childhood AML.

    Evidence 3'-RACE, RT-PCR, and FISH on patient AML material

    PMID:11493482

    Open questions at the time
    • No functional assay of the fusion in this study
    • Mechanism of transformation unknown
  3. 2001 Medium

    Defined NSD1 (ARA267-alpha) as an androgen receptor coregulator, extending its nuclear-receptor role to prostate cancer signaling.

    Evidence Yeast two-hybrid, GST pulldown, and reporter assays in PC-3 and H1299 cells

    PMID:11509567

    Open questions at the time
    • Endogenous AR target genes not mapped
    • Link between AR coregulation and enzymatic activity unresolved
  4. 2003 High

    Identified NSD1 as a histone methyltransferase and demonstrated its essentiality, answering what its catalytic function is and whether it is required for life.

    Evidence In vitro methyltransferase assay with recombinant SET domain plus NSD1-null knockout mice

    PMID:12805229

    Open questions at the time
    • H3K36 vs H4K20 specificity later refined
    • Mechanism of developmental requirement not defined
    • Genomic targets unknown
  5. 2004 High

    Mapped the structural basis of NSD1's corepressor interaction by showing Nizp1 docks to the C5HCH domain via a novel C2HR zinc finger required for repression.

    Evidence Co-IP, GST pulldown, zinc-dependence and mutagenesis with transcriptional repression reporters

    PMID:15169884

    Open questions at the time
    • Genome-wide Nizp1/NSD1 co-target genes not identified
    • Relationship to methyltransferase activity unclear
  6. 2007 High

    Established the oncogenic mechanism of NUP98-NSD1, showing it drives AML through SET-domain-dependent Hox-A activation and EZH2 antagonism.

    Evidence Murine bone marrow transplant AML model, colony assays, ChIP, SET-domain and FG-repeat mutagenesis

    PMID:17589499

    Open questions at the time
    • Direct chromatin recruitment mechanism of the fusion not fully resolved
    • Cooperating mutations not addressed
  7. 2009 Medium

    Probed whether NSD1 acts as a tumor suppressor by showing promoter hypermethylation silences it in neuroblastoma/glioma, reducing H3K36/H4K20 methylation and growth.

    Evidence Bisulfite sequencing, ChIP, re-expression and colony formation assays in cell lines

    PMID:20018718

    Open questions at the time
    • Context-dependent tumor-suppressor vs oncogenic role unreconciled
    • MEIS1 regulation mechanism limited to ChIP
  8. 2009 Medium

    Extended NSD1 substrate scope beyond histones by reporting methylation of NF-kB p65 at K218/K221 to activate NF-kB signaling.

    Evidence Overexpression/knockdown, MS site identification, reporter and MEF gene-expression assays

    PMID:20080798

    Open questions at the time
    • p65 methylation not reproduced in a later systematic substrate assay (#11)
    • Single-lab finding
  9. 2010 Medium

    Linked NSD1-dependent H3K36 methylation to transcriptional elongation by showing it controls RNA Pol II CTD phospho-state at target promoters.

    Evidence ChIP-seq, ChIP-qPCR, siRNA, and Western blot for RNAP II Ser5/Ser2 phospho-forms

    PMID:20837538

    Open questions at the time
    • Direct vs indirect effect on Pol II phosphorylation unresolved
    • Limited number of target genes examined
  10. 2010 High

    Provided the structural explanation for NSD1's substrate gating, revealing an autoinhibitory loop that occludes the H3K36 channel and is relieved by the nucleosome.

    Evidence 1.7 A crystal structure of the catalytic domain plus molecular dynamics and docking

    PMID:21196496

    Open questions at the time
    • Active-state conformation inferred computationally, not crystallized with nucleosome
    • Mechanism of loop opening on chromatin not directly observed
  11. 2011 Medium

    Defined the molecular consequences of Sotos-syndrome PHD mutations, showing they disrupt methyl-H3 reading and Nizp1 recruitment.

    Evidence Histone peptide pulldowns, PHD mutagenesis, and Nizp1 co-IP

    PMID:21972110

    Open questions at the time
    • In vivo consequence of disrupted reading not tested
    • Functional readout of each PHD finger incomplete
  12. 2014 High

    Systematically resolved NSD1 substrate specificity, identifying preferred sequence context and ruling out H4K20 and p65 as substrates under these conditions.

    Evidence SPOT peptide arrays, in vitro methyltransferase assays, and SET-domain mutagenesis

    PMID:24412544

    Open questions at the time
    • In vivo relevance of non-histone substrates (H1.5 K168, H4K44) untested
    • Conflict with earlier p65/H4K20 reports unresolved
  13. 2013 Low

    Suggested an inflammasome-regulatory role by showing NSD1 dampens caspase-1 activation and pyroptosis in macrophages.

    Evidence siRNA knockdown with caspase-1 activity, cytokine ELISA, and cell death assays

    PMID:24058709

    Open questions at the time
    • Single knockdown approach without rescue
    • No direct biochemical mechanism for inflammasome modulation
    • Not independently confirmed
  14. 2020 High

    Established the H3K36me2-DNMT3A axis in vivo, showing germline NSD1 deposits broad H3K36me2 required for de novo DNA methylation and imprinting.

    Evidence Conditional KO mice with whole-genome bisulfite sequencing, ChIP-seq, RNA-seq in prospermatogonia and oocytes

    PMID:32929285

    Open questions at the time
    • Sex-specific division of labor with SETD2 mechanism not fully resolved
    • Direct DNMT3A recruitment biochemistry not shown here
  15. 2020 High

    Demonstrated druggability of the NSD1 SET domain, with a covalent inhibitor that opens the autoinhibitory loop and downregulates NUP98-NSD1 target genes.

    Evidence Fragment screening, X-ray crystallography of BT5 complex, cell-based H3K36me2 and colony assays in patient AML cells

    PMID:32868895

    Open questions at the time
    • Selectivity over other NSD family members not detailed here
    • In vivo efficacy untested in this study
  16. 2021 High

    Defined a skeletal developmental role, showing NSD1 in mesenchymal progenitors regulates Sox9 and HIF1a via H3K36 methylation to drive chondrogenesis.

    Evidence Prx1-Cre and Col2-Cre conditional KO mice, RNA-seq, ChIP-seq, in vitro differentiation

    PMID:34099628

    Open questions at the time
    • Direct vs indirect HIF1a activation mechanism unresolved
    • Relevance to Sotos overgrowth phenotype not directly linked
  17. 2022 High

    Mechanistically connected NSD1/H3K36me2 to PRC2 antagonism and SWI/SNF cooperation, explaining EZH2-inhibitor resistance in NSD1-null tumors.

    Evidence CRISPR screen and KO, KDM2A inhibitor rescue, ChIP-seq in SMARCB1-mutant rhabdoid cells

    PMID:35537449

    Open questions at the time
    • Precise biochemical link between H3K36me2 and PRC2 exclusion not fully reconstituted
    • Generalizability beyond SWI/SNF-deficient context unclear
  18. 2022 Medium

    Characterized NUP98-NSD1 condensate biology, identifying SMARCA5/BPTF as core interactors required for transformation.

    Evidence AP-MS, FRAP, proximity ligation, inducible knockdown, and SMARCA5 inhibition with colony assays

    PMID:35073946

    Open questions at the time
    • Causal role of condensate formation vs SMARCA5 activity disentangled only partially
    • Single-lab interactome
  19. 2023 High

    Separated NSD1's catalytic and coactivator functions, revealing a qPHD-PWWP module that reads H3K18ac to drive enhancer activity and Pol II pause release independent of methyltransferase activity.

    Evidence Auxin-inducible degron, ChIP-seq/ATAC-seq/GRO-seq, domain binding assays, catalytic-dead rescue, ESC differentiation

    PMID:37402365

    Open questions at the time
    • Mechanism by which non-catalytic NSD1 promotes pause release undefined
    • Relative contribution of catalytic vs non-catalytic functions context-dependent
  20. 2023 High

    Established the H3K36me2-DNMT3A-non-CG methylation pathway in neurons, linking NSD1 loss to DNMT3A-disorder-convergent gene dysregulation.

    Evidence Brain-specific conditional KO, ChIP-seq, whole-genome bisulfite sequencing, RNA-seq

    PMID:37098340

    Open questions at the time
    • Behavioral/disease phenotype consequences not addressed here
    • Direct DNMT3A recruitment biochemistry not shown
  21. 2023 High

    Showed NSD1-deposited H3K36me2 establishes and maintains cortical neuron areal and laminar identity, defining a postmitotic developmental function.

    Evidence Conditional KO mice, RNA-seq, ChIP-seq, DNA methylation profiling, electrophysiology, axonal tracing

    PMID:37995181

    Open questions at the time
    • Causal chain from H3K36me2 loss to wiring defects incompletely mapped
    • Reversibility not tested
  22. 2023 Medium

    Linked NSD1 loss to tumor immune evasion, showing reduced H3K36me2/elevated H3K27me3 silences T-cell chemokines CXCL9/10 in HNSCC.

    Evidence NSD1-mutant HNSCC models, ChIP-seq, KDM2A inhibition, syngeneic tumor models, flow cytometry

    PMID:37311054

    Open questions at the time
    • Direct chromatin mechanism at chemokine loci vs indirect effects not fully separated
    • Clinical translatability of KDM2A inhibition untested
  23. 2024 High

    Ranked NSD1 atop the H3K36 methyltransferase hierarchy, establishing it as the predominant depositor of broad intergenic H3K36me2.

    Evidence CRISPR KO of five K36MTs with genome-wide ChIP-seq for H3K36me1/2/3 and RNA-seq in mouse mesenchymal stem cells

    PMID:39390582

    Open questions at the time
    • Cell-type dependence of the hierarchy not exhaustively tested
    • Mechanism of intergenic targeting specificity unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NSD1 is recruited to specific genomic loci and how it physically hands off H3K36me2 to DNMT3A and excludes PRC2 remain incompletely defined at the biochemical level.
  • No reconstituted NSD1-DNMT3A handoff
  • Locus-targeting determinants for intergenic H3K36me2 unknown
  • Non-catalytic coactivator mechanism for Pol II pause release undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ARBPTFDNMT3AEP300EZH2NIZP1NUP98SMARCA5

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NSD1 contains two distinct nuclear receptor interaction domains (NID-L and NID+L): NID-L interacts with unliganded ligand-binding domains (LBDs) of RAR and TR via helix-1-dependent contacts (corepressor-like), while NID+L interacts with liganded LBDs of RAR, TR, RXR, and ER via a novel FxxLL variant of the NR box motif (coactivator-like). NSD1 also contains separate repression and activation domains, establishing it as a bifunctional transcriptional intermediary factor. Yeast two-hybrid, GST pulldown, LBD mutagenesis, co-transfection reporter assays The EMBO journal High 9628876
2003 NSD1's SET domain possesses intrinsic histone methyltransferase activity with specificity for H3K36 and H4K20. NSD1-null embryos die during gastrulation, demonstrating it is essential for early post-implantation development. In vitro histone methyltransferase assay with recombinant SET domain; gene-targeted knockout mice The EMBO journal High 12805229
2001 NSD1 is fused in-frame to NUP98 by the t(5;11)(q35;p15.5) translocation in childhood AML, producing a chimeric NUP98-NSD1 mRNA and the reciprocal NSD1-NUP98 transcript. This was the first implication of NSD1 in human malignancy. 3'-RACE PCR, RT-PCR, FISH Blood Medium 11493482
2001 NSD1 (also known as ARA267-alpha) functions as an androgen receptor (AR) coregulator: both its N-terminal and C-terminal regions interact with the AR DNA- and ligand-binding domains, and it enhances AR transactivation in a dihydrotestosterone-dependent manner in prostate cancer cells. Yeast two-hybrid, GST pulldown, luciferase and CAT reporter assays in PC-3 and H1299 cells The Journal of biological chemistry Medium 11509567
2007 The NUP98-NSD1 fusion induces AML in vivo, sustains myeloid stem cell self-renewal in vitro, and enforces expression of HoxA7, HoxA9, HoxA10, and Meis1. Mechanistically, NUP98-NSD1 binds genomic elements at the Hox-A locus, maintains H3K36 methylation and histone acetylation there, and prevents EZH2-mediated transcriptional repression. Deletion of the NUP98 FG-repeat domain or inactivating mutations of the NSD1 SET domain (H3K36 methyltransferase activity) abolished Hox-A activation and progenitor immortalization. Retroviral transduction + murine bone marrow transplantation (in vivo AML), methylcellulose colony assay, ChIP, SET-domain point mutagenesis, gene-expression analysis Nature cell biology High 17589499
2009 NSD1 methylates p65 (NF-κB subunit) at K218 and K221, activating NF-κB target gene expression. The lysine demethylase FBXL11 reverses this modification. Overexpression of NSD1 activates NF-κB and reverses FBXL11-mediated inhibition; knockdown of NSD1 decreases NF-κB activation. NF-κB-dependent gene expression in mouse embryo fibroblasts relies on K218/K221 methylation. Overexpression/knockdown in cells, MS-based identification of methylation sites, luciferase reporter assays, MEF gene-expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 20080798
2009 Epigenetic inactivation of NSD1 by CpG island promoter hypermethylation in neuroblastoma and glioma cells causes specifically diminished H4K20 and H3K36 methylation. Restored NSD1 expression reduces colony formation and inhibits cell growth (tumor-suppressor-like activity). ChIP analysis identified MEIS1 as a direct NSD1 target in neuroblastoma. Bisulfite sequencing, ChIP, expression microarray, colony formation assay, re-expression experiments in cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 20018718
2010 The 1.7 Å crystal structure of the NSD1 catalytic domain reveals that a regulatory (autoinhibitory) loop occludes the H3K36 substrate access channel to the bound SAM cofactor. Molecular dynamics and docking show this loop can adopt an active conformation, and that the nucleosome likely stabilizes the active state, explaining NSD1's preference for nucleosomal substrate and its dimethyl-H3K36 product specificity. X-ray crystallography (1.7 Å), molecular dynamics simulation, computational docking The Journal of biological chemistry High 21196496
2010 NSD1 binds near promoter elements of target genes (e.g., BMP4, ZFP36L1), regulates H3K36 methylation primarily in the promoter-proximal region, reduces RNA Pol II recruitment to the BMP4 promoter, and causes inappropriate persistence of Ser5-phosphorylated RNAP II with reduced Ser2 phosphorylation within the CTD, linking NSD1-dependent H3K36 methylation to RNAP II elongation control. ChIP-seq, ChIP-qPCR, siRNA knockdown, Western blot for RNAP II CTD phospho-forms Proceedings of the National Academy of Sciences of the United States of America Medium 20837538
2011 NSD1 PHD domains 1, 4, 5, and 6 bind histone H3 methylated at K4 or K9. Eleven of twelve Sotos-syndrome-associated missense mutations in PHD4, PHD5, and PHD6 disrupt binding to these methylated lysines, and 8 of 9 mutations in PHD4 and PHD6 severely impair binding to the transcription cofactor Nizp1. Histone peptide binding assays (peptide pulldown), mutagenesis of PHD domains, co-immunoprecipitation with Nizp1 Human mutation Medium 21972110
2004 Nizp1 interacts with NSD1 through a novel C2HR zinc-finger motif that docks to the cysteine-rich (C5HCH) domain of NSD1 in a Zn(II)-dependent manner. This interaction is required for Nizp1-mediated transcriptional repression at RNA Pol II promoters. Mutations of the C2HR cysteine/histidine residues or conversion to a canonical C2H2 zinc finger abolish NSD1 binding and transcriptional repression. Co-immunoprecipitation, GST pulldown, zinc-dependence assay, transcriptional repression assay, domain mutagenesis Molecular and cellular biology High 15169884
2014 NSD1 preferentially methylates substrates with aromatic/hydrophobic residues at the −2/−1 positions and basic residues at +1/+2 of the target peptide. NSD1 methylates 25 non-histone peptide substrates in vitro; the best protein substrate identified is H1.5 K168. H4K44 is also methylated. Methylation of H4K20 and p65 was NOT observed in this assay. Sotos-syndrome missense mutations in the SET domain inactivate enzymatic activity. SPOT peptide array assay, in vitro methyltransferase assay with recombinant NSD1, SET-domain mutagenesis Chemistry & biology High 24412544
2019 CRISPR/Cas9-mediated NSD1 knockout in hepatocellular carcinoma cells increases H3K27me3 and reduces H3K36me2 at the Wnt10b promoter, suppressing Wnt10b expression and inactivating Wnt/β-catenin signaling, thereby inhibiting cell proliferation, migration, and invasion in vitro and tumor growth in vivo. CRISPR/Cas9 knockout, ChIP, Western blot, proliferation/migration/invasion assays, xenograft model Journal of experimental & clinical cancer research Medium 31727171
2020 In mouse prospermatogonia (male germline), NSD1 deposits broad H3K36me2 in euchromatic regions and is required for de novo DNA methylation by DNMT3A/DNMT3L, including at imprinted genes. Males with germline NSD1 deficiency show more severe spermatogenesis defects than Dnmt3l-/- males. NSD1 also safeguards a subset of genes against H3K27me3-associated silencing. In oocytes, H3K36me2 is predominantly dependent on SETD2, and NSD1-deficient oocytes support normal female fertility. Conditional knockout mice, whole-genome bisulfite sequencing, ChIP-seq, RNA-seq Nature genetics High 32929285
2020 Crystal structure of NSD1 SET domain in complex with a covalently bound inhibitor (BT5) reveals a conformational change in the autoinhibitory loop, exposing a channel-like pocket. The covalent inhibitor inhibits H3K36 dimethylation and downregulates NUP98-NSD1 target genes and impairs colony formation in NUP98-NSD1 patient-derived AML cells. Fragment-based screening, chemical synthesis, X-ray crystallography, cell-based H3K36me2 assay, colony formation assay Nature chemical biology High 32868895
2021 NSD1 loss in skeletal mesenchymal progenitors (Prx1+) impairs chondrogenic differentiation, skeletal growth, and fracture healing. NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 at the Sox9 promoter; NSD1 also directly activates HIF1α, which regulates Sox9. Conditional KO in Col2+ chondrocytes does not recapitulate the phenotype, placing NSD1 function upstream in the progenitor compartment. Conditional knockout mice (Prx1-Cre; Col2-Cre), RNA-seq, ChIP-seq, in vitro differentiation assays Bone research High 34099628
2022 NSD1 antagonizes Polycomb repressor complex (PRC2/EZH2) activity via cooperation with SWI/SNF chromatin remodelers. Loss of NSD1 causes resistance to EZH2 inhibition in SMARCB1-mutant rhabdoid tumor cells; H3K36me2 itself is essential for activation of polycomb target genes. Inhibition of the H3K36me2 demethylase KDM2A restores EZH2 inhibitor efficacy in SWI/SNF-deficient NSD1-null cells. CRISPR screen, CRISPR KO, KDM2A inhibitor treatment, ChIP-seq, gene expression analysis Molecular cell High 35537449
2022 NUP98-NSD1 fusion protein forms liquid-like phase-separated nuclear condensates dependent on the NUP98 FG-repeat domains. These condensates co-interact with the ISWI-family chromatin remodeler SMARCA5 and BPTF (NURF complex members), which are identified as core interactome partners by AP-MS. SMARCA5 is functionally required for NUP98-NSD1/FLT3-ITD-mediated hematopoietic cell transformation; inhibition of SMARCA5 activity (not condensate formation per se) abrogates transformation. Affinity purification–mass spectrometry (AP-MS), inducible shRNA knockdown, pharmacological SMARCA5 inhibition, FRAP, proximity ligation assay, methylcellulose colony assay Journal of experimental & clinical cancer research Medium 35073946
2023 NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers. NSD1's enhancer association is mediated by a tandem quadruple PHD-PWWP (qPHD-PWWP) module that recognizes p300-catalyzed H3K18ac. Acute NSD1 depletion reduces enhancer activity and impairs RNA Pol II pause release at target genes. Importantly, NSD1 can act as a transcriptional coactivator independently of its catalytic (H3K36 methyltransferase) activity. NSD1 also controls embryonic stem cell multilineage differentiation. Auxin-inducible degron (acute depletion), ChIP-seq, ATAC-seq, GRO-seq, domain binding assays (PHD-PWWP module), catalytic-dead mutant rescue experiments, ESC differentiation assays Molecular cell High 37402365
2023 In mouse neurons, NSD1 deposits megabase-scale H3K36me2 that recruits DNMT3A to pattern non-CG DNA methylation. Brain-specific NSD1 deletion causes altered DNA methylation overlapping with DNMT3A-disorder models, driving convergent dysregulation of key neuronal genes. Loss of H3K36me2 (via NSD1 deletion) disrupts the H3K36me2–DNMT3A–non-CG-methylation pathway required for neuronal gene regulation. Brain-specific conditional KO, ChIP-seq, whole-genome bisulfite sequencing (non-CG methylation), RNA-seq Molecular cell High 37098340
2023 NSD1-mediated H3K36me2 in postmitotic neocortical neurons establishes and maintains area- and layer-specific pyramidal neuron identities. Nsd1 conditional KO causes area-shift of all four primary cortical regions, aberrant cortico-thalamic wiring, and progressive mis-expression of deep-layer markers in superficial neurons; neurons remain morphologically and electrophysiologically immature. Loss of Nsd1 causes genome-wide H3K36me2 loss and redistribution of DNA methylation. Conditional knockout mice, RNA-seq, ChIP-seq, DNA methylation profiling, electrophysiology, axonal tracing Cell reports High 37995181
2023 NSD1 inactivation in HNSCC reduces H3K36me2 and elevates H3K27me3 at promoters of T-cell chemokines CXCL9 and CXCL10, suppressing their expression and excluding T cells from the tumor microenvironment. Inhibition of KDM2A (the primary H3K36 demethylase) reverses these altered histone marks, restores CXCL9/10 expression, and rescues T-cell infiltration. KDM2A suppression reduces NSD1-deficient tumor growth in immunocompetent but not immunodeficient mice. NSD1-mutant HNSCC cell lines/patient samples, ChIP-seq, KDM2A inhibitor treatment, in vivo syngeneic tumor models, flow cytometry for T-cell infiltration Cancer research Medium 37311054
2024 Among H3K36 methyltransferases, NSD1 is the predominant depositor of intergenic H3K36me2 (with NSD2 contributing partially), while SETD2 deposits most H3K36me3 within gene bodies. Systematic perturbation in mouse mesenchymal stem cells places NSD1 at the top of a K36MT hierarchy: NSD1 > NSD2 > NSD3 > ASH1L for broad H3K36me2 deposition. CRISPR KO of individual K36MTs, ChIP-seq for H3K36me1/2/3, RNA-seq in mouse mesenchymal stem cells Genome biology High 39390582
2013 Murine NSD1 diminishes caspase-1 activity and downstream IL-1β/IL-18 maturation during macrophage stimulation with listeriolysin O (LLO). Silencing Nsd1 enhances caspase-1 activation, cytokine maturation, and pyroptosis. NSD1 does not affect NF-κB signaling or NLRP3 gene expression at the chromatin or transcriptional level during LLO stimulation. siRNA knockdown, caspase-1 activity assay, ELISA for cytokines, cell death assay in macrophages PloS one Low 24058709

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature cell biology 354 17589499
2003 NSD1 is essential for early post-implantation development and has a catalytically active SET domain. The EMBO journal 286 12805229
2005 Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American journal of human genetics 262 15942875
2002 STO-609, a specific inhibitor of the Ca(2+)/calmodulin-dependent protein kinase kinase. The Journal of biological chemistry 258 11867640
2009 Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proceedings of the National Academy of Sciences of the United States of America 246 20080798
2002 NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. American journal of human genetics 225 12464997
1998 Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. The EMBO journal 218 9628876
2001 A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 211 11493482
2009 Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proceedings of the National Academy of Sciences of the United States of America 165 20018718
2015 NSD1 mutations generate a genome-wide DNA methylation signature. Nature communications 158 26690673
2010 The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. The Journal of biological chemistry 142 21196496
2020 NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing. Nature genetics 128 32929285
2010 Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. Proceedings of the National Academy of Sciences of the United States of America 120 20837538
2007 Salt tolerance (STO), a stress-related protein, has a major role in light signalling. The Plant journal : for cell and molecular biology 112 17605755
2003 Establishment and maintenance of human embryonic stem cells on STO, a permanently growing cell line. Biology of reproduction 109 12930726
2003 Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. European journal of human genetics : EJHG 101 14571271
2003 Spectrum of NSD1 mutations in Sotos and Weaver syndromes. Journal of medical genetics 99 12807965
2004 Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. American journal of human genetics 92 14997421
2001 Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Gene 82 11733144
2011 Nuclear localization and interaction with COP1 are required for STO/BBX24 function during photomorphogenesis. Plant physiology 81 21685177
2017 NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma. Scientific reports 76 29213088
2004 Clinical features of NSD1-positive Sotos syndrome. Clinical dysmorphology 76 15365454
2020 Covalent inhibition of NSD1 histone methyltransferase. Nature chemical biology 71 32868895
2001 Identification and characterization of a novel androgen receptor coregulator ARA267-alpha in prostate cancer cells. The Journal of biological chemistry 62 11509567
2007 Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. Human mutation 58 17565729
2004 Establishment of human embryonic stem cell lines from frozen-thawed blastocysts using STO cell feeder layers. Human reproduction (Oxford, England) 58 14998970
2005 Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth. American journal of medical genetics. Part A 57 15742365
2019 Extreme resistance to Potato virus Y in potato carrying the Rysto gene is mediated by a TIR-NLR immune receptor. Plant biotechnology journal 56 31397954
2021 Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma. Cell reports 54 33626351
2018 Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia. Leukemia 52 30568173
2019 CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway. Journal of experimental & clinical cancer research : CR 49 31727171
2014 Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction. Haematologica 49 24951466
2018 Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation. Molecular cancer therapeutics 48 29636367
2014 Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1. Chemistry & biology 48 24412544
2022 NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition. Molecular cell 47 35537449
2022 The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. Cellular and molecular life sciences : CMLS 45 35532818
2017 Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD. Scientific reports 44 28924233
2003 A single amino acid difference between alpha and beta Ca2+/calmodulin-dependent protein kinase kinase dictates sensitivity to the specific inhibitor, STO-609. The Journal of biological chemistry 44 12540834
2011 NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome. Human mutation 42 21972110
2005 NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory. Genetics in medicine : official journal of the American College of Medical Genetics 42 16247291
2004 Nizp1, a novel multitype zinc finger protein that interacts with the NSD1 histone lysine methyltransferase through a unique C2HR motif. Molecular and cellular biology 42 15169884
2017 NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas. Cancer research 41 28754676
2005 NSD1 mutations in Sotos syndrome. American journal of medical genetics. Part C, Seminars in medical genetics 40 16010675
2020 Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia. Cancers 39 32993115
2013 Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly. Molecular syndromology 39 23599694
2023 Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1. Molecular cell 35 37402365
2018 Perioperative chemotherapy with or without epidermal growth factor receptor blockade in unselected patients with locally advanced oesophagogastric adenocarcinoma: Randomized phase II study with advanced biomarker program of the German Cancer Society (AIO/CAO STO-0801). European journal of cancer (Oxford, England : 1990) 35 29501977
2011 Crystal structure of the Ca²⁺/calmodulin-dependent protein kinase kinase in complex with the inhibitor STO-609. The Journal of biological chemistry 34 21504895
2011 Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person. American journal of medical genetics. Part A 33 21834047
2021 H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair. Bone research 32 34099628
2022 SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation. Journal of experimental & clinical cancer research : CR 31 35073946
2023 NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons. Molecular cell 30 37098340
2014 A sensitive luminescent assay for the histone methyltransferase NSD1 and other SAM-dependent enzymes. Assay and drug development technologies 29 24927133
2008 Activation of the aryl hydrocarbon receptor by the calcium/calmodulin-dependent protein kinase kinase inhibitor 7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid (STO-609). Drug metabolism and disposition: the biological fate of chemicals 27 18755850
1994 Colony isolation and secondary culture of fetal porcine hepatocytes on STO feeder cells. In vitro cellular & developmental biology. Animal 27 7534592
2011 Quantitative and semiquantitative immunoassay of growth factors and cytokines in the conditioned medium of STO and CF-1 mouse feeder cells. In vitro cellular & developmental biology. Animal 24 22179674
1993 Development of ovine embryos co-cultured on oviductal cells, embryonic fibroblasts, or STO cell monolayers. Biology of reproduction 23 8218643
2021 NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer. Life (Basel, Switzerland) 22 34575025
2019 NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents. Cancers of the head & neck 22 31321084
1987 Signet ring stomach cancer: morphological characterization and antigenic profile of a newly established cell line (Mz-Sto-1). European journal of cancer & clinical oncology 22 2820743
2020 Membrane-bottomed microwell array added to Transwell insert to facilitate non-contact co-culture of spermatogonial stem cell and STO feeder cell. Biofabrication 21 32975217
2011 Comparison of colony formation in adult mouse spermatogonial stem cells developed in Sertoli and STO coculture systems. Andrologia 21 21762195
2021 Role of NSD1 as potential therapeutic target in tumor. Pharmacological research 20 34536546
2020 Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1. Genes, brain, and behavior 20 31909872
2021 Pazopanib with 5-FU and oxaliplatin as first line therapy in advanced gastric cancer: A randomized phase-II study-The PaFLO trial. A study of the Arbeitsgemeinschaft Internistische Onkologie AIO-STO-0510. International journal of cancer 19 34741530
2018 Targeting skeletal muscle tissue oxygenation (StO2) in adults with severe sepsis and septic shock: a randomised controlled trial (OTO-StS Study). BMJ open 19 29555789
2006 Psychosocial, cognitive, and motor functioning in patients with suspected Sotos syndrome: a comparison between patients with and without NSD1 gene alterations. Developmental medicine and child neurology 19 16780628
2004 Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system. European journal of endocrinology 19 15362962
2022 NSD1 mutations deregulate transcription and DNA methylation of bivalent developmental genes in Sotos syndrome. Human molecular genetics 18 35094088
2022 The Rysto immune receptor recognises a broadly conserved feature of potyviral coat proteins. The New phytologist 18 35491734
2022 Knockdown of nuclear receptor binding SET domain-containing protein 1 (NSD1) inhibits proliferation and facilitates apoptosis in paclitaxel-resistant breast cancer cells via inactivating the Wnt/β-catenin signaling pathway. Bioengineered 17 35200072
2020 Comparison of RNA m6A and DNA methylation profiles between mouse female germline stem cells and STO cells. Molecular therapy. Nucleic acids 17 33473328
2020 Quantitative Proteomic Analyses Identify STO/BBX24 -Related Proteins Induced by UV-B. International journal of molecular sciences 16 32260266
2015 Analysis of Distinct Roles of CaMKK Isoforms Using STO-609-Resistant Mutants in Living Cells. Biochemistry 16 26050738
2007 Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly. BMC medical genetics 16 18001468
2024 Systematic perturbations of SETD2, NSD1, NSD2, NSD3, and ASH1L reveal their distinct contributions to H3K36 methylation. Genome biology 15 39390582
2023 Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma. Cancer research 15 37311054
2023 H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis. Cell death and differentiation 15 38012390
2019 Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations. American journal of medical genetics. Part A 15 30719864
2023 Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome. Genes 13 36833222
2023 Clinical implications of NUP98::NSD1 fusion at diagnosis in adult FLT3-ITD positive AML. European journal of haematology 13 37465857
2023 Histone methylation mediated by NSD1 is required for the establishment and maintenance of neuronal identities. Cell reports 13 37995181
2012 Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations. Journal of human genetics 13 23190751
2005 Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. Chinese medical journal 13 16232326
2024 Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1. Cell death discovery 12 38719811
2013 NSD1 mitigates caspase-1 activation by listeriolysin O in macrophages. PloS one 12 24058709
2013 Improvement of Expression of α6 and β1 Integrins by the Co-culture of Adult Mouse Spermatogonial Stem Cells with SIM Mouse Embryonic Fibroblast Cells (STO) and Growth Factors. Iranian journal of basic medical sciences 12 24298380
2011 Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene. American journal of medical genetics. Part A 12 22012791
2022 Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying NSD1 Variants. Genes 11 36421837
2016 GDNF-expressing STO feeder layer supports the long-term propagation of undifferentiated mouse spermatogonia with stem cell properties. Scientific reports 11 27827452
2006 Immune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell lines. Immunology 11 16836618
1998 A hypersensitive response-like mechanism is involved in resistance of potato plants bearing the Ry(sto) gene to the potyviruses potato virus Y and tobacco etch virus. The Journal of general virology 11 9460939
2024 Ramucirumab, Avelumab, and Paclitaxel as Second-Line Treatment in Esophagogastric Adenocarcinoma: The Phase 2 RAP (AIO-STO-0218) Nonrandomized Controlled Trial. JAMA network open 10 38261316
2021 5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation. Human genetics 10 33389145
2003 Hepatic progenitor cell lines from allyl alcohol-treated adult rats are derived from gamma-irradiated mouse STO cells. Stem cells (Dayton, Ohio) 10 12832698
2022 Identification of alternative transcripts of NSD1 gene in Sotos Syndrome patients and healthy subjects. Gene 9 36261088
2020 Development and Characterization of Novel Molecular Probes for Ca2+/Calmodulin-Dependent Protein Kinase Kinase, Derived from STO-609. Biochemistry 9 32298102
2017 A Novel Missense Mutation of the NSD1 Gene Associated with Overgrowth in Three Generations of an Italian Family: Case Report, Differential Diagnosis, and Review of Mutations of NSD1 Gene in Familial Sotos Syndrome. Frontiers in pediatrics 9 29164086
2016 Development and Validation of High-Resolution Melting Markers Derived from Rysto STS Markers for High-Throughput Marker-Assisted Selection of Potato Carrying Rysto. Phytopathology 9 27442536
2009 Premolar hypodontia is a common feature in Sotos syndrome with a mutation in the NSD1 gene. American journal of medical genetics. Part A 9 19876911

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