Affinage

SETD7

Histone-lysine N-methyltransferase SETD7 · UniProt Q8WTS6

Length
366 aa
Mass
40.7 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SETD7 (SET7/9, KMT7) is a lysine monomethyltransferase that uses its conserved SET domain to transfer a methyl group from S-adenosylmethionine (AdoMet) to histone H3K4 and a broad spectrum of non-histone substrates, thereby regulating chromatin state, transcription factor activity, protein stability, and subcellular localization across diverse signaling pathways. Structural studies reveal a narrow substrate-binding channel connecting opposite enzyme surfaces that accepts only unmethylated or monomethylated lysines, enforcing mono- (or limited di-) methyltransferase product specificity via an SN2 catalytic mechanism, with a conserved K/R-S/T/A recognition motif preceding the target lysine (PMID:12540855, PMID:16415881, PMID:16433545). SETD7 methylates key signaling effectors including p53 (K372, promoting Tip60-mediated acetylation), NF-κB RelA (K314/K315, triggering proteasomal degradation), DNMT1 (K142, destabilizing the methyltransferase), β-catenin (K180, promoting GSK-3β-mediated degradation), YAP (K494, enforcing cytoplasmic retention to restrain Hippo pathway output), Smad7 (triggering Arkadia-dependent ubiquitination), and PLK1 (K191, attenuating kinase activity during mitosis), placing it at the intersection of the DNA damage response, Wnt, Hippo, TGF-β, and cell cycle pathways (PMID:18280244, PMID:19262565, PMID:19282482, PMID:26116705, PMID:23850191, PMID:27292644, PMID:31863092). In vivo, Setd7-null mice display expanded intestinal progenitor compartments, glucose intolerance from impaired β-cell insulin secretion, protection from pulmonary fibrosis, and attenuated myocardial ischemia-reperfusion injury, underscoring SETD7's non-redundant physiological roles in tissue homeostasis and stress responses (PMID:23850191, PMID:25713082, PMID:27292644, PMID:35709329).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Determining the three-dimensional architecture of SET7/9 established how the N-terminal β-sheet and conserved SET domain organize the catalytic center around AdoMet, and identified two C-terminal residues essential for H3K4 methylation.

    Evidence Crystal structure with site-directed mutagenesis and biochemical assays on recombinant human SET7/9

    PMID:12372304

    Open questions at the time
    • No substrate peptide in the structure; substrate-binding mode unknown
    • Product specificity (mono- vs. di- vs. tri-methyl) not yet explained
  2. 2003 High

    Ternary complex structures resolved how the target lysine threads through a narrow channel between cofactor and substrate binding surfaces, explaining SET7/9's exclusive monomethyltransferase activity and the structural basis for substrate specificity.

    Evidence High-resolution crystal structures of SET7/9–H3K4 peptide–AdoMet ternary complex plus solution studies

    PMID:12514135 PMID:12540855

    Open questions at the time
    • Whether channel geometry permits any dimethylation in special contexts was debated
    • Non-histone substrate recognition not yet addressed
  3. 2004 High

    The discovery that SET7/9 monomethylates the non-histone protein TAF10, enhancing its affinity for RNA Pol II and potentiating transcription, established the precedent that SET7/9 functions beyond histone modification.

    Evidence In vitro methylation of TAF10, reporter assays, and genetic rescue with methylation-deficient TAF10 mutant in TAF10-null cells

    PMID:15099517

    Open questions at the time
    • Physiological importance in vivo not tested
    • Whether other TAF subunits are substrates was unclear
  4. 2006 High

    Definition of a conserved K/R-S/T/A substrate recognition motif, together with QM/MM-computed SN2 catalytic mechanism, provided predictive rules for new substrate identification and explained product specificity at the quantum-mechanical level.

    Evidence Crystal structure with TAF10 peptide, mutagenesis, peptide methylation assays, and ab initio QM/MM free energy calculations

    PMID:16415881 PMID:16433545

    Open questions at the time
    • Motif-based prediction not yet validated proteome-wide
    • Computational mechanism awaited experimental kinetic isotope effect confirmation
  5. 2008 High

    Multiple studies revealed that SET7/9 methylates diverse transcription factors and signaling proteins—ERα (K302, stabilization), p53 (K372, enabling Tip60 acetylation and DNA damage response), and NF-κB-target promoters (H3K4me1 deposition)—establishing it as a broad-spectrum signaling methyltransferase.

    Evidence Crystal structure of SET7–ERα peptide complex, Set7/9 knockout mouse p53 methylation studies, and ChIP/siRNA in TNF-α-stimulated cells

    PMID:18280244 PMID:18471979 PMID:18650421

    Open questions at the time
    • Relative importance of histone vs. non-histone methylation at each locus unclear
    • An independent KO later questioned in vivo p53 dependence on Set7/9
  6. 2009 High

    Identification of DNMT1-K142 and RelA-K314/K315 as SET7/9 substrates whose methylation triggers proteasomal degradation established a recurring mechanism: methylation marks proteins for destruction.

    Evidence Direct in vitro methylation, mass spectrometry, proteasome inhibitor rescue, siRNA and overexpression in human cells

    PMID:19262565 PMID:19282482

    Open questions at the time
    • The E3 ligase(s) recognizing methyl-DNMT1 were unknown
    • Whether RelA methylation-degradation operates in all NF-κB-dependent contexts was untested
  7. 2011 Medium

    An independent Set7/9-null mouse showed normal p53-dependent transcription and tumor suppression after genotoxic and oncogenic stress, challenging the earlier model that Set7/9-mediated p53-K372 methylation is essential for the DNA damage response in vivo.

    Evidence Independent Set7/9 knockout mouse, gene expression analysis, oncogenic stress assays

    PMID:21855805

    Open questions at the time
    • Discrepancy with the earlier KO study not fully resolved—may reflect strain or context differences
    • Whether Set7/9 has redundant or compensated roles in p53 activation in specific tissues remains open
  8. 2011 Medium

    Systematic peptide array screening expanded the validated substrate repertoire to dozens of proteins (including MeCP2, Cullin1, IRF1, histones H2A/H2B, H1.4) and demonstrated that substrate phosphorylation inhibits SET7/9, revealing crosstalk between modification pathways.

    Evidence Peptide array methylation, in vitro and in vivo confirmation by mass spectrometry

    PMID:21276944 PMID:23289424

    Open questions at the time
    • Many array-identified substrates lack in vivo functional validation
    • Stoichiometry and biological significance of most new substrates unknown
  9. 2013 High

    Discovery that SETD7 monomethylates YAP at K494 to enforce its cytoplasmic retention, with Set7-null mice showing expanded intestinal progenitors and elevated YAP target genes, established SETD7 as a Hippo pathway regulator in vivo.

    Evidence Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor cell analysis

    PMID:23850191

    Open questions at the time
    • The cytoplasmic reader recognizing methyl-YAP was not identified
    • Whether YAP methylation is dynamically reversed by a demethylase was unknown
  10. 2015 High

    Methylation of β-catenin at K180 by SET7/9, promoting GSK-3β-dependent degradation, together with methylation of Pdx1 activating insulin gene expression in β-cells, expanded the in vivo roles of SETD7 to Wnt signaling and glucose homeostasis.

    Evidence Mass spectrometry site identification, mutagenesis (K180R), conditional β-cell KO mouse with glucose intolerance phenotype

    PMID:25713082 PMID:26116705

    Open questions at the time
    • Whether β-catenin K180 methylation cooperates with YAP methylation in intestinal tumorigenesis was unknown
    • The demethylase counteracting β-catenin methylation was not identified
  11. 2016 High

    SETD7 was shown to integrate Hippo and Wnt pathways: it exists in a complex with YAP, AXIN1, and β-catenin, and is required for Wnt-driven intestinal tumorigenesis and regeneration, while also methylating Smad7 to promote TGF-β signaling via Arkadia-mediated degradation.

    Evidence SETD7 KO intestinal tumorigenesis model, Co-IP of quaternary complex, Set9-KO pulmonary fibrosis models

    PMID:27046831 PMID:27292644

    Open questions at the time
    • How SETD7 is dynamically recruited to the AXIN1 destruction complex is unclear
    • Whether the Smad7 methylation-degradation axis operates in all TGF-β contexts is untested
  12. 2018 Medium

    Identification of Rpl29-K5 as a major and exclusive SET7/9 substrate reversible by LSD1 provided a reliable cellular biomarker for SETD7 activity, validated with the selective chemical probe (R)-PFI-2.

    Evidence In vitro methylation, methyl-specific antibody, (R)-PFI-2 inhibitor treatment, subcellular fractionation

    PMID:29959229

    Open questions at the time
    • Functional consequence of Rpl29 methylation beyond localization change is unknown
    • Whether Rpl29 methylation affects ribosome biogenesis or translation of specific mRNAs was not addressed
  13. 2019 Medium

    SET7-mediated methylation of UHRF1, dependent on prior S-phase phosphorylation, promotes PCNA polyubiquitination and homologous recombination repair, placing SETD7 directly in the DNA double-strand break repair pathway.

    Evidence In vitro methylation, Co-IP, HR reporter assay, siRNA, cell viability after DNA damage

    PMID:30357346

    Open questions at the time
    • The specific UHRF1 methylation site was not mapped by mutagenesis
    • Independent replication in a second cell system not reported
  14. 2020 Medium

    SETD7 dimethylates PLK1 at K191 to attenuate its kinase activity during early mitosis, and TRIM21 ubiquitinates SETD7 for proteasomal degradation, defining both a mitotic role and a negative upstream regulator of SETD7 protein levels.

    Evidence In vitro methylation, K191R mutagenesis, kinase assays, mitotic arrest analysis; Co-IP, ubiquitination assay for TRIM21-SETD7 axis

    PMID:31863092 PMID:32102992

    Open questions at the time
    • Whether PLK1 dimethylation occurs on nucleosomes or free PLK1 in mitosis is unknown
    • TRIM21 regulation of SETD7 not yet validated in non-cancer cell types
  15. 2023 High

    In cardiomyocytes, energy deprivation activates SETD7, which methylates YAP to enforce cytoplasmic retention and suppress antioxidant gene transcription (MnSOD, CAT), driving mitochondrial ROS and ischemia-reperfusion injury; genetic deletion or pharmacological inhibition rescues this phenotype.

    Evidence SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP fractionation, ROS measurement, human ischemic cardiomyopathy tissue

    PMID:35709329

    Open questions at the time
    • Upstream signal activating SETD7 upon energy deprivation not identified
    • Whether other SETD7 substrates contribute to the cardioprotective phenotype is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the identity of 'reader' domains or proteins that recognize SETD7-installed methyl marks on most non-histone substrates; the full spectrum of demethylases that reverse SETD7 activity at each substrate; whether SETD7's histone versus non-histone methylation activities are functionally separable in vivo; and the discrepancy between knockout models regarding p53 dependence.
  • No systematic identification of methyl-readers for SETD7-modified non-histone substrates
  • Demethylase pairing established only for DNMT1 and Rpl29 (LSD1), not for most substrates
  • Discrepant p53 phenotypes between two independent knockouts remain unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 25
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-162582 Signal Transduction 5 R-HSA-4839726 Chromatin organization 5 R-HSA-73894 DNA Repair 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CTNNB1DNMT1PLK1RELASMAD7TP53UHRF1YAP1
Complex memberships
YAP-AXIN1-β-catenin-SETD7 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Crystal structure of human SET7/9 reveals a N-terminal beta-sheet domain and conserved SET domain; mutagenesis identified two C-terminal residues essential for catalytic activity toward H3K4; AdoMet cofactor binding mode and role of invariant residues in catalysis, substrate binding, and AdoMet binding were established. Crystal structure + site-directed mutagenesis + biochemical assays Cell High 12372304
2003 High-resolution crystal structure of ternary complex of human SET7/9 with histone H3K4 peptide and AdoMet cofactor shows the peptide and cofactor bind on opposite enzyme surfaces; the target lysine side chain inserts into a narrow channel connecting the two surfaces to access the active site; SET7/9 is exclusively a mono-methylase due to structural constraints. Crystal structure of ternary complex + solution studies Nature High 12540855
2003 Crystal structures of SET7/9 in complex with AdoMet reveal the active site architecture: a binding pocket between the SET domain and c-SET helix for AdoMet in an unusual conformation, a narrow substrate-specific channel permitting only unmethylated lysines, and a catalytic tyrosine residue; SET7/9 can transfer two but not three methyl groups to unmodified H3K4 without substrate dissociation. Crystal structure (1.7 Å and 2.3 Å) + biochemical assays The EMBO journal High 12514135
2004 SET7/9 (SET9) monomethylates the TBP-associated factor TAF10 at a single lysine in the loop 2 region of its histone-fold domain; methylated TAF10 has increased affinity for RNA polymerase II, linking this modification to preinitiation complex formation; SET9-mediated TAF10 methylation potentiates transcription of a subset of TAF10-dependent genes. In vitro methylation assay, reporter assays, TAF10-null cell complementation with methylation-deficient mutant, Co-IP Molecular cell High 15099517
2005 Crystal structure of Pr-Set7 (Set8) ternary complex shows it is exclusively a mono-methylase for H4K20; a histidine residue within the substrate near the target lysine is required for active site completion; the highly variable component of the SET domain governs interactions with the target histone peptide and ensures nucleosome specificity. Crystal structure + NMR + biochemical assays Genes & development High 15933069
2006 SET7/9 recognizes a conserved K/R-S/T/A motif preceding the target lysine and has a propensity to bind aspartates/asparagines C-terminal to the target; this consensus motif was used to identify novel substrates including TAF7 (methylated at K5 in vitro). Crystal structure with TAF10 peptide + mutagenesis + in vitro methylation assays Nature structural & molecular biology High 16415881
2006 Ab initio QM/MM-FE calculations demonstrate that SET7/9-catalyzed methyl transfer is a typical in-line SN2 nucleophilic substitution reaction with ~70% dissociative character; product specificity as a monomethyltransferase is achieved by disrupting near-attack conformations for the dimethylation reaction. Ab initio QM/MM free energy calculations + molecular dynamics simulations Journal of the American Chemical Society Medium 16433545
2008 SET7 directly methylates estrogen receptor alpha (ERα) at lysine 302 (K302); this monomethylation stabilizes ERα and is required for efficient ER recruitment to target gene promoters and transactivation; a breast cancer-associated mutation K303R alters K302 methylation in vitro and in vivo. Crystal structure of the SET7-ER peptide complex reveals the molecular basis for substrate recognition. In vitro methylation, crystal structure, ChIP, transactivation assays, cancer mutation analysis Molecular cell High 18471979
2008 SET7/9 functions as a coactivator of NF-κB: it is recruited to NF-κB-regulated inflammatory gene promoters in response to TNF-α, and its gene silencing reduces H3K4 monomethylation at these promoters and decreases NF-κB p65 recruitment, suppressing inflammatory gene induction. siRNA knockdown, ChIP, gene expression analysis The Journal of biological chemistry Medium 18650421
2008 Set7/9-mediated monomethylation of p53 at K369 (mouse; K372 in human) is required for subsequent Tip60 acetyltransferase binding to p53 and p53 acetylation; Set7/9 null mouse cells fail to methylate p53, cannot induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Set7/9 knockout mouse model, in vivo methylation assay, Co-IP, gene expression analysis Molecular cell High 18280244
2008 Set7/9 is required in pancreatic islet beta-cells for normal expression of glucose-stimulated insulin secretion genes (Ins1/2, Glut2, MafA); its depletion causes loss of H3K4 dimethylation and RNA polymerase II recruitment at insulin gene promoters, and impairs glucose-stimulated insulin secretion. siRNA knockdown in insulinoma cells and primary mouse islets, ChIP, Ca2+ mobilization assay, insulin secretion assay Diabetes Medium 18984737
2009 SET7 colocalizes and directly interacts with DNMT1 and specifically monomethylates DNMT1 at Lys-142; methylated DNMT1 peaks during S and G2 phases and is prone to proteasome-mediated degradation; SET7 overexpression decreases DNMT1 levels and siRNA knockdown stabilizes DNMT1. Co-localization, direct interaction (pulldown), in vitro methylation, cell cycle analysis, proteasome inhibition, siRNA/OE Proceedings of the National Academy of Sciences of the United States of America High 19282482
2009 Set9 (SETD7) physically associates with the RelA subunit of NF-κB in vitro and in vivo; it monomethylates RelA at K314 and K315; this methylation induces proteasome-mediated degradation of promoter-associated RelA, thereby inhibiting NF-κB action; depletion of Set9 or mutation of methylation sites prolongs NF-κB DNA binding and enhances TNF-α-induced target gene expression. Co-IP, GST pulldown, mass spectrometry, in vitro methylation, proteasome inhibition, siRNA knockdown, mutagenesis The EMBO journal High 19262565
2010 Set7/9 (KMT7) monomethylates the HIV Tat protein at lysine 51 located in the RNA-binding domain; Set7/9 itself binds TAR RNA and associates with Tat/P-TEFb complexes at the HIV promoter; knockdown of Set7/9 suppresses Tat transactivation while methylation-deficient Tat (K51A) is unaffected, demonstrating methylation-dependent coactivation of HIV transcription. In vitro methylation, RNA binding assay, ChIP, siRNA knockdown, transactivation assays Cell host & microbe High 20227666
2010 The androgen receptor (AR) directly interacts with and is methylated at lysine 632 by SET9 (SETD7); this methylation enhances AR transcriptional activity by facilitating N-C terminal interdomain communication and recruitment to androgen-target gene promoters. Co-IP, in vitro methylation, mutagenesis (K632A), ChIP, transactivation assays Nucleic acids research High 20959290
2011 Set7/9 interacts with SIRT1 both in vitro and in vivo; upon DNA damage, enhanced Set7/9-SIRT1 interaction suppresses SIRT1-p53 interaction, abrogating SIRT1-mediated p53 deacetylation and increasing p53 transcriptional activity; this is partially independent of SIRT1 methylation by Set7/9. Co-IP, in vitro binding, in vitro methylation, reporter assays, DNA damage response analysis Proceedings of the National Academy of Sciences of the United States of America Medium 21245319
2011 In Set7/9-deficient mice (independent knockout strain), p53-dependent transcription and tumor suppression are normal after genotoxic and oncogenic stress, indicating that Set7/9-mediated p53 methylation at K372 is not a major regulatory event for p53 activity in vivo. Independent Set7/9 knockout mouse model, gene expression analysis, oncogenic stress assays Molecular cell Medium 21855805
2011 Set7 directly interacts with MyoD and promotes myoblast differentiation; Set7 knockdown or dominant-negative expression impairs skeletal muscle differentiation and myofibril assembly, reduces H3K4me1, and decreases expression of myocyte enhancer factor 2 and contractile protein genes; Set7 also precludes Suv39h1-mediated H3K9 methylation on myogenic gene promoters. siRNA/dominant-negative expression, Co-IP, ChIP, differentiation assays The Journal of cell biology Medium 21859860
2011 Set9 methyltransferase directly methylates FoxO3 at lysine 271 in vitro and in cells; methylation by Set9 decreases FoxO3 protein stability while moderately increasing its transcriptional activity. In vitro methylation, tandem mass spectrometry, methyl-specific antibodies, stability assays, transcriptional reporter assays Aging Medium 22820736
2011 Peptide array methylation analysis determined an optimized target sequence for SET7/9, identifying 91 new peptide substrates from human proteins; nine non-histone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, TTK) and H2A/H2B were confirmed as SET7/9 substrates in vitro and in vivo; phosphorylation of substrate proteins inhibits SET7/9; SET7/9 can dimethylate MINT lysine in vitro and in vivo. Peptide array methylation, in vitro and in vivo methylation confirmation, mass spectrometry Chemistry & biology Medium 21276944
2012 Set7/9 directly methylates the FXR nuclear receptor at lysine 206 in vitro and in vivo; this methylation enhances FXR/RXRα binding to the FXR response element and is required for transcriptional activation of FXR target genes (SHP, BSEP); Set7/9 occupies the FXRE chromatin in vivo. In vitro methylation, mutagenesis (K206R), Co-IP, GST pulldown, mammalian two-hybrid, EMSA, ChIP, reporter assays American journal of physiology. Gastrointestinal and liver physiology High 22345554
2013 SET7/9 methylates the RelA/NF-κB-associated histone methyltransferase SUV39H1 at K105 and K123 in response to DNA damage; this methylation markedly reduces SUV39H1 methyltransferase activity, leading to decreased H3K9me3 in heterochromatin, satellite repeat derepression (heterochromatin relaxation), and genome instability. Co-IP, GST pulldown, Western blot with methyl-specific antibodies, mass spectrometry, MNase sensitivity assay, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 23509280
2013 SET7/9 methylates histone H1.4 at multiple lysines (K121, K129, K159, K171, K177, K192) in the C-terminal KAK motifs; ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9 but allows subsequent H1 methylation; H1 and H3 compete with each other for SET7/9-dependent methylation. In vitro methylation with isolated histones, PAR-ylation assays, site mapping Epigenetics & chromatin Medium 23289424
2013 SETD7 monomethylates YAP at K494; this methylation is critical for cytoplasmic retention of YAP; Set7-null mice have a larger intestinal progenitor compartment coinciding with increased YAP target gene expression, demonstrating in vivo regulation of the Hippo pathway by Set7-dependent YAP methylation. Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor analysis, gene expression Developmental cell High 23850191
2013 SET7/9 methylates ARTD1 (PARP1) at K508 in vitro and in vivo; ARTD1 methylation by SET7/9 enhances poly-ADP-ribose synthesis upon oxidative stress and promotes ARTD1 recruitment to DNA damage sites in a SET7/9-dependent manner; ARTD1 auto-modification inhibits its methylation by SET7/9. In vitro methylation, in vivo methylation (methyl-specific antibody), laser irradiation, PAR formation assay Open biology Medium 24088713
2013 SET7/9 negatively regulates the antiviral restriction factor IFITM3 by monomethylating it at K88; viral infection (VSV, influenza A) promotes IFITM3-SET7 interaction to increase IFITM3-K88me1 and reduce antiviral activity; IFN-α reduces IFITM3-K88me1 levels. In vitro and in vivo methylation, viral infection assays, Co-IP, methyl-specific antibody The Journal of biological chemistry Medium 24129573
2014 (R)-PFI-2 is a potent (Ki ~0.33 nM), selective, cell-active inhibitor of SETD7 that occupies the substrate peptide binding groove in a cofactor-dependent, substrate-competitive manner, making direct contact with the AdoMet methyl group; in cells, it phenocopies Setd7 deficiency by modulating YAP localization and Hippo pathway signaling. Biochemical inhibition assay, X-ray crystallography, chemoproteomics, cell-based YAP localization assay, MEF Setd7-null comparison Proceedings of the National Academy of Sciences of the United States of America High 25136132
2015 Set7 methylates HIF-1α at K32 and HIF-2α at K29; this methylation inhibits HIF-α transcriptional activity by impairing HIF-α occupancy at hypoxia response elements; Set7-null fibroblasts show upregulated HIF target genes and increased glucose uptake/ATP levels under hypoxia. In vitro methylation, Set7-null fibroblasts, shRNA knockdown, ChIP, metabolic assays Nucleic acids research Medium 25897119
2015 SET7/9 interacts with and methylates β-catenin at K180 in vitro and in vivo; methylated β-catenin is recognized by GSK-3β for degradation; non-methylatable β-catenin (K180R) has a longer half-life; SET7/9 knockdown or K180R mutation enhances Wnt/β-catenin target gene expression and cancer cell growth. Co-IP, in vitro methylation, mass spectrometry, mutagenesis, stability assays, gene expression FASEB journal High 26116705
2015 Set7/9 methylates the androgen receptor at K630; alanine substitution prevents methylation in vitro and in vivo; Set7 overexpression potentiates AR-mediated transactivation while depletion inhibits AR activity; methylation promotes AR N-C terminal interaction and co-occupies androgen response elements with activated histone marks. In vitro methylation, mutagenesis (K630A), Co-IP, ChIP, transactivation assays Molecular endocrinology Medium 21273441
2015 KMT Set7/9 physically interacts with Mdm2 and regulates its expression; several cancer cell lines with inverse expression of Set7/9 and Mdm2 show altered sensitivity to genotoxic stress, placing Set7/9 upstream of Mdm2 in the DNA damage response. Co-IP, gene expression, siRNA, cell viability assays, bioinformatics Oncotarget Low 26317544
2015 Set7/9 methylates Pdx1 at K123 and K131; K131 methylation (but not K123) is required for Set7/9-mediated augmentation of Pdx1 transcriptional activity; conditional beta-cell-specific Set7 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion with reduced Pdx1 target gene expression. Mass spectrometry, mutagenesis, Co-IP, reporter assays, conditional knockout mouse, glucose tolerance test The Journal of biological chemistry High 25713082
2016 SETD7 is part of a complex containing YAP, AXIN1, and β-catenin; SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of β-catenin; SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration, mechanistically linking the Hippo/YAP and Wnt/β-catenin pathways. Co-IP, SETD7 KO mouse intestinal tumorigenesis model, β-catenin nuclear fractionation, gene expression Developmental cell High 27046831
2016 Set9 methyltransferase promotes TGF-β signaling by methylating the inhibitory Smad7, which promotes Smad7 interaction with the E3 ligase Arkadia and subsequent ubiquitination-dependent degradation of Smad7; Set9-deficient mice show elevated Smad7 levels and are protected from bleomycin- and Ad-TGF-β-induced pulmonary fibrosis. In vitro methylation, Co-IP, ubiquitination assay, Set9-KO mouse fibrosis models Cell reports High 27292644
2016 Set7 methylates Gli3 (full-length form) at K436 and K595; methylation at K436 increases Gli3 stability and at K595 increases its DNA-binding ability, resulting in enhanced Shh signaling activation; Gli3 methylation contributes to tumor growth and metastasis in non-small cell lung cancer. In vitro methylation, mutagenesis, stability assays, DNA-binding assays, in vitro/in vivo tumor models eLife Medium 27146893
2016 SET7/9 methylates YY1 transcription factor at K173 and K411; this methylation regulates YY1 DNA-binding activity both in vitro and at specific genomic loci in cells and is involved in YY1-regulated gene transcription and cell proliferation. In vitro methylation, mutagenesis, EMSA, ChIP, reporter assays, cell proliferation assay Scientific reports Medium 26902152
2016 An asparagine residue in SET7/9 that mediates AdoMet sulfur-oxygen chalcogen bonding enhances AdoMet binding affinity over the product AdoHcy; structural, biochemical, and computational analyses show that S···O chalcogen bonds contribute to AdoMet recognition and enable substrate-product discrimination. X-ray crystallography, mutagenesis, biochemical binding assays, quantum mechanical calculations ACS chemical biology High 26713889
2018 Rpl29 (ribosomal protein L29) is a major substrate of Set7/9; Rpl29 K5 is methylated exclusively by Set7/9 and can be demethylated by Lsd1; Rpl29 K5 methylation affects Rpl29 subcellular localization but not global protein synthesis; Rpl29 K5 methylation serves as a reliable cellular biomarker for Set7/9 activity validated by (R)-PFI-2 treatment. In vitro methylation, methyl-specific antibody, siRNA, subcellular fractionation, inhibitor treatment (R)-PFI-2 The Journal of biological chemistry Medium 29959229
2018 Setd7 facilitates the transition from activated, proliferating myogenic stem cells (MuSCs) to differentiation-primed progenitors by regulating nuclear accumulation of β-catenin; genetic or pharmacological inhibition of Setd7 promotes in vitro MuSC expansion and enhances engraftment and therapeutic potential upon transplantation. Genetic Setd7 deletion, pharmacological inhibition (R)-PFI-2, β-catenin nuclear fractionation, transplantation assays, muscular dystrophy preclinical model Cell stem cell High 29395054
2019 UHRF1 is methylated by SET7 and demethylated by LSD1; DNA damage induces UHRF1 methylation, and UHRF1 phosphorylation in S phase is a prerequisite for its interaction with SET7; UHRF1 methylation promotes polyubiquitin chain conjugation to PCNA and facilitates homologous recombination for DNA double-strand break repair; SET7-mediated UHRF1 methylation is essential for cell viability against DNA damage. In vitro methylation, Co-IP, ubiquitination assay, siRNA, homologous recombination reporter assay, cell viability assay Nucleic acids research Medium 30357346
2019 The SUMO-specific isopeptidase SENP3 associates with SETD7 and deSUMOylates it; by recruiting deSUMOylated SETD7 to the MyHC-II gene locus, SENP3 promotes SETD7 association with active RNA Pol II and precludes Suv39h1; SENP3 is degraded in cachexia, impairing SETD7-dependent MyHC-II expression and sarcomere organization. Co-IP, deSUMOylation assay, ChIP, siRNA knockdown, sarcomere morphology analysis, muscle contractility assay Cell reports Medium 31141694
2020 SET7/9 dimethylates PLK1 at K191 during early mitosis, reducing PLK1 kinase activity by limiting ATP utilization; overexpression of non-methylatable PLK1 (K191R) or chemical inhibition of SET7/9 causes mitotic arrest due to destabilized kinetochore-microtubule attachments, revealing methylation-dependent regulation of accurate chromosome segregation. In vitro methylation, mutagenesis (K191R), kinase assays, mitotic arrest analysis, SET7/9 inhibitor treatment Journal of molecular cell biology Medium 31863092
2020 TRIM21 physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent ubiquitination mechanism; SET7/9 promotes breast cancer cell proliferation, migration, and invasion via activation of RUNX2. Co-IP, GST pulldown, ubiquitination assay, ChIP-seq, cell proliferation/migration/invasion assays, xenograft Cell death & disease Medium 32102992
2023 SETD7 is activated upon energy deprivation in cardiomyocytes and methylates YAP, leading to YAP cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT; this drives mitochondrial ROS accumulation, organelle swelling, and apoptosis; pharmacological SETD7 inhibition with (R)-PFI-2 or genetic SETD7 deletion restores YAP nuclear localization and MnSOD/CAT expression, attenuating myocardial ischemia/reperfusion injury. SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP nuclear fractionation, ROS measurement, mitochondrial morphology, Ca2+-activated tension, NRVMs, human ICM LV samples Cardiovascular research High 35709329

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 308 12540855
2008 Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation. The Journal of biological chemistry 290 18650421
2012 PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes & development 275 22345514
2009 Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 256 19282482
2008 Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Molecular cell 250 18471979
2004 Gene-specific modulation of TAF10 function by SET9-mediated methylation. Molecular cell 223 15099517
2002 Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes. Genes & development 207 12208845
2010 Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Molecular cell 202 21035370
2008 Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Molecular cell 186 18280244
2002 Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell 186 12372304
2009 Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. The EMBO journal 184 19262565
2005 Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes & development 158 15933069
2014 (R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proceedings of the National Academy of Sciences of the United States of America 155 25136132
2013 Control of the hippo pathway by Set7-dependent methylation of Yap. Developmental cell 146 23850191
2006 Structural basis for the methylation site specificity of SET7/9. Nature structural & molecular biology 142 16415881
2014 Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus. Circulation. Cardiovascular genetics 141 25472959
2011 Specificity analysis-based identification of new methylation targets of the SET7/9 protein lysine methyltransferase. Chemistry & biology 141 21276944
2007 PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase. The Journal of cell biology 139 18158331
2012 Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circulation research 133 22403242
2020 METTL3/YTHDF2 m6 A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer. Journal of cellular and molecular medicine 125 32126149
2011 Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1). Proceedings of the National Academy of Sciences of the United States of America 118 21245319
2010 Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. Genes & development 110 20966048
2003 Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. The EMBO journal 108 12514135
2010 Regulation of the androgen receptor by SET9-mediated methylation. Nucleic acids research 105 20959290
2006 Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9: an ab initio QM/MM-FE study with multiple initial structures. Journal of the American Chemical Society 105 16433545
2016 SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling. Developmental cell 103 27046831
2009 SET7/9 mediated methylation of non-histone proteins in mammalian cells. Epigenetics 102 19684477
2012 The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes & development 98 23152447
2011 The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly. The Journal of cell biology 97 21859860
2009 Regulation of Set9-mediated H4K20 methylation by a PWWP domain protein. Molecular cell 93 19250904
2013 Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability. Proceedings of the National Academy of Sciences of the United States of America 91 23509280
2015 Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation. Nucleic acids research 90 25897119
2008 Methyltransferase Set7/9 maintains transcription and euchromatin structure at islet-enriched genes. Diabetes 90 18984737
2014 ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice. American journal of physiology. Renal physiology 85 24452638
2010 The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription. Cell host & microbe 85 20227666
2012 Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells. Acta pharmacologica Sinica 82 23247593
2018 Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer. Signal transduction and targeted therapy 81 30013796
2012 Methylation by Set9 modulates FoxO3 stability and transcriptional activity. Aging 81 22820736
2016 Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9. ACS chemical biology 73 26713889
2011 Lysine methylation and functional modulation of androgen receptor by Set9 methyltransferase. Molecular endocrinology (Baltimore, Md.) 72 21273441
2013 CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Molecular cell 69 23478445
2013 Transcriptional regulation by the Set7 lysine methyltransferase. Epigenetics 68 23478572
2016 SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis. Cell reports 67 27292644
2011 p53-dependent transcription and tumor suppression are not affected in Set7/9-deficient mice. Molecular cell 67 21855805
2015 SET7/9 regulates cancer cell proliferation by influencing β-catenin stability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 26116705
2007 Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: the case of histone lysine methyltransferase SET7/9. The journal of physical chemistry. B 65 17388541
2016 A Common Variant in the SETD7 Gene Predicts Serum Lycopene Concentrations. Nutrients 63 26861389
2018 Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential. Cell stem cell 58 29395054
2008 PR-SET7 and SUV4-20H regulate H4 lysine-20 methylation at imprinting control regions in the mouse. EMBO reports 58 18724273
2016 Set7 mediated Gli3 methylation plays a positive role in the activation of Sonic Hedgehog pathway in mammals. eLife 56 27146893
2019 Resveratrol induces p53 in colorectal cancer through SET7/9. Oncology letters 55 30881498
2016 Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription. Journal of medicinal chemistry 55 27088648
2015 Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening. Journal of medicinal chemistry 53 26390175
2011 Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes. Diabetes 53 21896933
2015 KMT Set7/9 affects genotoxic stress response via the Mdm2 axis. Oncotarget 50 26317544
2013 Crosstalk between SET7/9-dependent methylation and ARTD1-mediated ADP-ribosylation of histone H1.4. Epigenetics & chromatin 50 23289424
2017 The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling. Cell reports 48 28249161
2010 Development of novel bisubstrate-type inhibitors of histone methyltransferase SET7/9. Bioorganic & medicinal chemistry 48 21036620
2014 KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress. Cell death and differentiation 47 25124555
2020 SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21. Cell death & disease 45 32102992
2015 Lysine Methyltransferase SETD7 (SET7/9) Regulates ROS Signaling through mitochondria and NFE2L2/ARE pathway. Scientific reports 45 26435321
2013 Negative regulation of interferon-induced transmembrane protein 3 by SET7-mediated lysine monomethylation. The Journal of biological chemistry 45 24129573
2016 Regulation of Transcription Factor Yin Yang 1 by SET7/9-mediated Lysine Methylation. Scientific reports 44 26902152
2011 A new regulator of the cell cycle: the PR-Set7 histone methyltransferase. Cell cycle (Georgetown, Tex.) 44 21200139
2018 Histone Methyltransferase Setd7 Regulates Nrf2 Signaling Pathway by Phenethyl Isothiocyanate and Ursolic Acid in Human Prostate Cancer Cells. Molecular nutrition & food research 43 29383876
2012 Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes. American journal of physiology. Gastrointestinal and liver physiology 43 22345554
2011 Coupling mitosis to DNA replication: the emerging role of the histone H4-lysine 20 methyltransferase PR-Set7. Trends in cell biology 43 21632252
2019 Methylation of UHRF1 by SET7 is essential for DNA double-strand break repair. Nucleic acids research 42 30357346
2016 Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression. Oncotarget 41 26701885
2014 Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers. The EMBO journal 40 25515659
2015 Transcriptional activity of the islet β cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. The Journal of biological chemistry 39 25713082
2013 SET7/9-dependent methylation of ARTD1 at K508 stimulates poly-ADP-ribose formation after oxidative stress. Open biology 38 24088713
2015 SCF(β-TRCP) promotes cell growth by targeting PR-Set7/Set8 for degradation. Nature communications 37 26666832
2018 Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis. PloS one 34 29723250
2016 Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis. Oncogene 34 27132511
2019 SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury. Brain, behavior, and immunity 32 31505256
2018 Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients. EBioMedicine 31 30361067
2018 Identification of Rpl29 as a major substrate of the lysine methyltransferase Set7/9. The Journal of biological chemistry 29 29959229
2015 Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase. Biochimica et biophysica acta 28 25637186
2021 lncRNA SNHG6 promotes hepatocellular carcinoma progression by interacting with HNRNPL/PTBP1 to facilitate SETD7/LZTFL1 mRNA destabilization. Cancer letters 27 34252487
2020 Downregulation of SETD7 promotes migration and invasion of lung cancer cells via JAK2/STAT3 pathway. International journal of molecular medicine 27 32323737
2013 MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation. Cell cycle (Georgetown, Tex.) 27 23475131
2023 Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study. Cardiovascular research 26 35709329
2021 SETD7 regulates chondrocyte differentiation and glycolysis via the Hippo signaling pathway and HIF‑1α. International journal of molecular medicine 26 34617577
2017 Quercus infectoria inhibits Set7/NF-κB inflammatory pathway in macrophages exposed to a diabetic environment. Cytokine 26 28408068
2016 Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila. Nucleic acids research 25 27131378
2016 SET7/9 inhibits oncogenic activities through regulation of Gli-1 expression in breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 26779630
2012 Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells. Biochimie 24 22709867
2020 Methylation of PLK1 by SET7/9 ensures accurate kinetochore-microtubule dynamics. Journal of molecular cell biology 23 31863092
2018 Inhibition of SETD7 protects cardiomyocytes against hypoxia/reoxygenation-induced injury through regulating Keap1/Nrf2 signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 30119254
2013 Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives. Acta crystallographica. Section D, Biological crystallography 23 23519668
2021 IL-6 regulates the bone metabolism and inflammatory microenvironment in aging mice by inhibiting Setd7. Acta histochemica 22 33962150
2019 Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia. Cell reports 22 31141694
2014 Deep sequencing reveals novel Set7 networks. Cellular and molecular life sciences : CMLS 22 24875254
2022 A Systematic Review to Define the Multi-Faceted Role of Lysine Methyltransferase SETD7 in Cancer. Cancers 21 35326563
2021 Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation. EMBO reports 21 33565211
2021 Loss of SPTBN1 Suppresses Autophagy Via SETD7-mediated YAP Methylation in Hepatocellular Carcinoma Initiation and Development. Cellular and molecular gastroenterology and hepatology 21 34737104
2017 Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis. Scientific reports 21 28417976
2017 Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells. Journal of Cancer 21 28819408
2008 Mechanism of product specificity of AdoMet methylation catalyzed by lysine methyltransferases: transcriptional factor p53 methylation by histone lysine methyltransferase SET7/9. Biochemistry 21 18260647