Affinage

SETD2

Histone-lysine N-methyltransferase SETD2 · UniProt Q9BYW2

Length
2564 aa
Mass
287.6 kDa
Annotated
2026-04-28
100 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SETD2 is the principal mammalian histone H3 lysine-36 trimethyltransferase, recruited to elongating RNA Polymerase II via the Spt6–Iws1 bridge and through splicing-dependent mechanisms, where it deposits H3K36me3 across transcribed gene bodies to coordinate chromatin integrity, suppression of cryptic intragenic transcription, alternative splicing, DNA methylation patterning, and DNA damage repair (PMID:18157086, PMID:19141475, PMID:21792193, PMID:23325844, PMID:26646321). Beyond histones, SETD2 methylates non-histone substrates including α-tubulin-associated actin at K68 (regulating cytoskeletal dynamics via the HTT–HIP1R complex) and EZH2 (promoting its proteasomal degradation to antagonize H3K27me3-driven Polycomb repression), and catalyzes H3K14me3 under replication stress to recruit RPA and activate ATR signaling (PMID:33008892, PMID:32619406, PMID:34074749). SETD2 protein stability is controlled by SPOP/CUL3-mediated ubiquitination and an N-terminal degron that targets it for proteasomal turnover (PMID:27614073, PMID:33023640). In vivo, Setd2 is essential for embryonic vascular remodeling, hematopoietic stem cell maintenance, V(D)J recombination during lymphocyte development, and T cell subset differentiation including Treg and Th17 polarization, and its loss drives myelodysplastic disease, renal cell carcinoma progression, and pancreatic tumorigenesis through epigenetic deregulation (PMID:20133625, PMID:29531312, PMID:31350389, PMID:36463230, PMID:38359295, PMID:36453584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2007 High

    Establishing the enzymatic specificity of SETD2 resolved which methyltransferase is responsible for the H3K36me3 mark genome-wide, showing it acts exclusively at the trimethylation step and not mono- or dimethylation.

    Evidence Setd2 knockdown in murine fibroblasts with ChIP-based histone modification mapping across inducible genes

    PMID:18157086

    Open questions at the time
    • Catalytic mechanism and substrate recognition at the structural level not resolved
    • Whether other methyltransferases can partially compensate in specific tissues unknown
  2. 2008 High

    Identifying the Spt6–Iws1–SETD2 bridge to elongating RNA Pol II explained how H3K36me3 is coupled to active transcription and revealed an unexpected link to mRNA export.

    Evidence Knockdown and ChIP across multiple gene loci in HeLa cells; in vitro binding assays with recombinant proteins

    PMID:19141475

    Open questions at the time
    • Mechanism by which H3K36me3 loss causes nuclear poly(A)+ RNA accumulation not molecularly defined
    • Direct contact between SETD2 and Pol II CTD phosphoforms not fully mapped
  3. 2010 High

    Demonstrating embryonic lethality of Setd2 knockout at E10.5–E11.5 with vascular defects established SETD2 as essential for mammalian development and endothelial cell function.

    Evidence Conditional Setd2 knockout mice; siRNA in human endothelial cells; migration/invasion assays

    PMID:20133625

    Open questions at the time
    • Downstream transcriptional targets driving vascular phenotype not fully identified
    • Whether vascular defect is cell-autonomous to endothelium not definitively resolved
  4. 2011 High

    Showing that pre-mRNA splicing enhances SETD2 recruitment and H3K36me3 deposition revealed a bidirectional coupling between splicing and chromatin modification, explaining why intron-containing genes carry higher H3K36me3.

    Evidence Genome-wide H3K36me3 ChIP-seq with splicing inhibition/activation experiments in human cells and mouse T cells

    PMID:21792193

    Open questions at the time
    • Molecular contacts between splicing machinery and SETD2 not identified
    • Whether specific splicing factors mediate the recruitment unknown
  5. 2013 High

    Linking SETD2-dependent H3K36me3 to FACT complex recruitment and suppression of cryptic intragenic transcription defined a major chromatin maintenance function for the mark.

    Evidence SETD2 knockdown in human cells; Co-IP of SPT16; RNA-seq for cryptic transcripts; ChIP for H2B exchange

    PMID:23325844

    Open questions at the time
    • Whether FACT is the sole reader mediating suppression of cryptic initiation not tested
    • Genome-wide extent of cryptic transcription consequences on proteome unknown
  6. 2014 High

    Solving the NMR structure of the SETD2 WW domain revealed an autoinhibitory intramolecular fold that gates the interaction with huntingtin, providing the first structural insight into SETD2 regulation.

    Evidence NMR solution structure; chemical shift perturbation mapping; immunofluorescence

    PMID:24412394

    Open questions at the time
    • Full-length SETD2 structure not available
    • Functional consequence of huntingtin interaction on histone methylation not resolved at this time
  7. 2016 High

    Identifying SPOP/CUL3 as the E3 ligase targeting SETD2 for ubiquitin-dependent degradation revealed how SETD2 protein levels and H3K36me3-coupled alternative splicing are post-translationally controlled, with implications for SPOP-mutant cancers.

    Evidence Co-IP; in vivo and in vitro ubiquitination assays; ChIP-seq; alternative splicing analysis

    PMID:27614073

    Open questions at the time
    • SPOP recognition degron on SETD2 not mapped to specific residues
    • Whether other E3 ligases also target SETD2 not excluded
  8. 2016 High

    Genome-wide profiling in SETD2-mutant clear cell RCC established that H3K36me3 normally restricts DNA methylation at gene bodies and its loss causes ectopic hypermethylation at developmental enhancers, linking SETD2 to DNA methylation patterning.

    Evidence 450K DNA methylation arrays in SETD2-depleted cell lines and primary ccRCC tumors; H3K36me3 ChIP-seq

    PMID:26646321

    Open questions at the time
    • Whether DNMT3A/B recruitment is directly modulated by H3K36me3 loss not biochemically tested here
    • Contribution of DNA hypermethylation to specific ccRCC phenotypes unclear
  9. 2017 High

    Demonstrating that SETD2 mutations impair DNA damage response and increase mutational burden at H3K36me3-depleted loci established SETD2 as a guardian of genomic integrity and explained chemotherapy resistance in SETD2-mutant leukemias.

    Evidence Isogenic SETD2-mutant leukemia cell lines; conditional Setd2 KO mouse leukemia model; DDR assays; mutation rate analysis; pharmacologic rescue with JIB-04

    PMID:29018079

    Open questions at the time
    • Which specific DDR effectors are directly recruited by H3K36me3 in this context not identified
    • Clinical applicability of KDM4A inhibition to restore H3K36me3 not tested in patients
  10. 2018 High

    Conditional knockout in hematopoietic stem cells showed SETD2 is required for HSC self-renewal and genomic stability, with loss inducing replication stress via E2F network activation, establishing a tumor-suppressive role in hematopoiesis.

    Evidence Conditional Setd2 KO mice; serial bone marrow transplantation; gene expression profiling; cell cycle analysis

    PMID:29531312

    Open questions at the time
    • Precise mechanism linking H3K36me3 loss to E2F/replication stress deregulation not resolved
    • Whether myelodysplastic phenotype is reversible upon SETD2 restoration not tested
  11. 2019 High

    Demonstrating that Setd2 is required for V(D)J recombination by enabling RAG1 recruitment to TCRβ loci via H3K36me3 explained how chromatin state controls antigen receptor assembly during lymphocyte development.

    Evidence Setd2 KO mice; ChIP for H3K36me3 and RAG1 at TCRβ; flow cytometry; DSB repair assays

    PMID:31350389

    Open questions at the time
    • Whether RAG1 directly reads H3K36me3 or uses an intermediate reader not biochemically resolved
    • Contribution to immunoglobulin heavy chain recombination at individual loci not detailed
  12. 2019 High

    In pancreatic cancer, Setd2 loss cooperated with oncogenic KRAS to drive acinar-to-ductal metaplasia through Fbxw7 epigenetic deregulation and EMT via Ctnna1 loss, defining SETD2 as a pancreatic tumor suppressor.

    Evidence Conditional Setd2 KO × KrasG12D mice; CRISPR Setd2 depletion in PDAC cells; RNA-seq; H3K36me3 ChIP-seq

    PMID:31300513

    Open questions at the time
    • Whether SETD2 restoration can reverse metaplasia not tested
    • Downstream mechanism linking Fbxw7 deregulation to metaplasia not fully dissected
  13. 2020 High

    Discovery that SETD2 methylates actin at K68 via a HTT–HIP1R complex, regulating actin polymerization dynamics, expanded the substrate repertoire beyond histones and connected SETD2 to cytoskeletal regulation.

    Evidence In vitro methyltransferase assay with recombinant SETD2/actin; mass spectrometry; Co-IP of SETD2–HTT–HIP1R; cell migration assays

    PMID:33008892

    Open questions at the time
    • Stoichiometry and kinetics of ActK68me3 relative to H3K36me3 not quantified
    • In vivo physiological consequence of ActK68me3 loss not yet characterized in animal models
  14. 2020 High

    Showing that SETD2 methylates EZH2 to promote its degradation revealed a direct enzymatic antagonism between activating (H3K36me3) and repressive (H3K27me3) chromatin pathways, with loss of this circuit driving metastatic prostate cancer.

    Evidence In vitro methyltransferase assay; Co-IP; mouse models with nonmethylatable EZH2; ChIP for H3K27me3/H3K36me3

    PMID:32619406

    Open questions at the time
    • EZH2 methylation site identity and reader/effector mechanism not fully characterized
    • Whether SETD2–EZH2 antagonism operates genome-wide or at specific loci unclear
  15. 2020 Medium

    Characterization of SETD2's N-terminal region as a degron controlling proteasomal turnover explained why truncated SETD2 causes ectopic, Pol II-independent H3K36me3 deposition.

    Evidence N-terminal truncation mutants; proteasome inhibition; H3K36me3 immunoblot; nuclear fractionation

    PMID:33023640

    Open questions at the time
    • Identity of the E3 ligase recognizing the N-terminal degron not determined
    • Relationship to SPOP-mediated degradation not clarified
    • Single-lab finding awaits independent confirmation
  16. 2021 High

    Identifying H3K14me3 as a second histone mark catalyzed by SETD2 under replication stress, which recruits RPA70 to activate ATR, fundamentally expanded SETD2's substrate specificity and linked it to replication fork restart.

    Evidence In vitro and in vivo methyltransferase assays; direct RPA70–H3K14me3 peptide pulldown; replication fork restart assays

    PMID:34074749

    Open questions at the time
    • Stimulus-dependent switch between H3K36 and H3K14 methylation not mechanistically explained
    • Whether H3K14me3 has functions beyond RPA recruitment not explored
  17. 2022 High

    Demonstrating that Setd2 loss in tumors creates an immunosuppressive microenvironment via ectopic H3K27me3 gain, CXCL1/GM-CSF secretion, and neutrophil reprogramming revealed an immune evasion mechanism downstream of epigenetic dysregulation.

    Evidence Conditional Setd2 KO pancreatic cancer mouse model; ChIP for H3K36me3/H3K27me3; immune profiling; CD8+ T cell cytotoxicity assays

    PMID:36453584

    Open questions at the time
    • Whether immune checkpoint blockade can overcome SETD2-loss-driven immunosuppression not tested
    • Generalizability to tumor types beyond pancreatic cancer unknown
  18. 2022 High

    Showing that Setd2 deposits H3K36me3 at GATA3 and ST2 promoters to maintain thymic-derived intestinal Treg cells established SETD2 as a regulator of peripheral immune tolerance.

    Evidence Foxp3Cre Setd2 conditional KO mice; ChIP for H3K36me3 at GATA3/IL1RL1 loci; IL-33 stimulation; flow cytometry

    PMID:36463230

    Open questions at the time
    • Whether SETD2 directly regulates other Treg-associated gene programs not surveyed genome-wide
    • Mechanism by which H3K36me3 enables GATA3 expression not molecularly defined
  19. 2024 High

    Linking SETD2 to Th17/Treg balance through phospholipid remodeling (H3K36me3 at Lpcat4 → PC(16:0,18:2) → ER stress suppression → HIF-1α attenuation) revealed an unexpected metabolic–epigenetic axis in T cell fate determination.

    Evidence T cell-specific Setd2 KO mice; H3K36me3 ChIP at Lpcat4; lipidomics; Th17/Treg differentiation assays; EAE mouse model

    PMID:38359295

    Open questions at the time
    • Whether other lipid-metabolic genes are similarly regulated by SETD2 not determined
    • Applicability of this pathway to human autoimmune disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis for SETD2's multi-substrate selectivity (H3K36, H3K14, actin, EZH2); the stimulus-dependent switching mechanism between histone and non-histone substrates; and whether SETD2 restoration strategies can reverse tumor immune evasion or chemoresistance in clinical settings.
  • No full-length SETD2 structure available
  • Regulatory logic governing substrate switching unknown
  • No clinical trials targeting SETD2 restoration reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0042393 histone binding 3
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-4839726 Chromatin organization 5 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-69306 DNA Replication 2 R-HSA-73894 DNA Repair 2
Partners
EZH2HIP1RHTTIWS1SPOPSPT16SPT6
Complex memberships
SPOP-CUL3 E3 ubiquitin ligase complexSpt6-Iws1-SETD2-Pol II elongation complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HYPB/SETD2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation (H3K36me3) in mammalian cells, but not H3K36 mono- or dimethylation; this trimethylation is transcription-dependent and increases across coding regions upon gene induction. Knockdown of HYPB/Setd2 in murine fibroblasts combined with high-resolution ChIP-based mapping of histone modifications across inducible genes (c-fos, c-jun) The EMBO journal High 18157086
2008 HYPB/SETD2 is recruited to the RNA Pol II elongation complex via Iws1 (which bridges Spt6 and SETD2) and is required for H3K36me3 across transcribed gene bodies; SETD2 knockdown also causes nuclear accumulation of poly(A)+ mRNA, linking H3K36me3 to mRNA export. Iws1/SETD2 knockdown in HeLa cells, ChIP across c-Myc/HIV-1/PABPC1 genes, in vitro binding assays with recombinant Spt6 and CTD Genes & development High 19141475
2010 Hypb/Setd2 is essential for embryonic vascular remodeling; homozygous knockout mice die at E10.5–E11.5 with severe vascular defects, and loss of Hypb impairs H3K36me3 but not H3K36me1 or me2, confirming its specific trimethylase role in vivo. Endothelial cell migration and invasion are intrinsically impaired upon HYPB loss. Conditional Hypb knockout mice; siRNA knockdown in human endothelial cells; H3K36me3 immunoblot; gene expression profiling; in vitro cell migration/invasion assays Proceedings of the National Academy of Sciences of the United States of America High 20133625
2011 Splicing enhances recruitment of HYPB/SETD2 to elongating RNA Pol II and increases H3K36me3 at intron-containing genes; splicing inhibition impairs SETD2 recruitment and reduces H3K36me3, while splicing activation has the opposite effect, demonstrating bidirectional coupling between splicing and SETD2-mediated histone methylation. Genome-wide H3K36me3 ChIP-seq in human cell lines and mouse T cells; splicing inhibition/activation experiments; SETD2 ChIP Nature structural & molecular biology High 21792193
2013 SETD2 activity coordinates FACT complex (SPT16/SSRP1) recruitment to H3K36me3-containing nucleosomes; SETD2 knockdown reduces FACT loading, decreases nucleosome occupancy, and leads to cryptic intragenic transcription initiation in at least 11% of active genes. SETD2 also regulates transcription-coupled histone H2B exchange via FACT. SETD2 knockdown in human cells; co-immunoprecipitation of SPT16; RNA-seq for cryptic transcripts; ChIP for H3K36me3, H2B, H3; live-cell imaging Nucleic acids research High 23325844
2014 The WW domain of HYPB/SETD2 adopts an autoinhibitory conformation via intramolecular interaction with an adjacent polyproline stretch at the SETD2 C-terminus; this autoinhibitory structure regulates the interaction between the SETD2 WW domain and the proline-rich region (PRR) of huntingtin (Htt). NMR solution structure determination; NMR chemical shift perturbation; immunofluorescence Structure (London, England : 1993) High 24412394
2016 SPOP, a subunit of the CUL3 ubiquitin E3 ligase complex, interacts with SETD2 and promotes its polyubiquitination and proteasomal degradation both in vivo and in vitro; SPOP-mediated SETD2 degradation modulates H3K36me3 levels and H3K36me3-coupled alternative splicing events. Co-immunoprecipitation; in vivo and in vitro ubiquitination assays; ChIP-seq; SPOP knockdown/overexpression; alternative splicing analysis Nucleic acids research High 27614073
2017 SETD2 mutations impair DNA damage response (DDR) by preventing H3K36me3-mediated local recruitment of DDR components; this leads to resistance to DNA-damaging chemotherapy agents. Genomic regions with higher H3K36me3 show lower mutation rates, which increases upon SETD2 loss. JIB-04 (KDM4A inhibitor) can restore H3K36me3 and chemotherapy sensitivity. Isogenic leukemia cell lines with SETD2 mutations; conditional Setd2 knockout mouse leukemia model; DDR assays; mutation rate analysis; pharmacologic rescue with JIB-04 Blood High 29018079
2018 Setd2 deficiency impairs hematopoietic stem cell (HSC) self-renewal and competitiveness, causes myelodysplastic syndrome-like malignancy over time, and induces DNA replication stress (activated E2F network, repressed Rrm2b) and genomic instability in HSCs. Conditional Setd2 knockout mice; serial bone marrow transplantation; gene expression profiling; cell cycle analysis Cell research High 29531312
2019 Setd2 is indispensable for V(D)J recombination during lymphocyte development; Setd2 deficiency reduces H3K36me3 at the TCRβ locus, impairs RAG1 binding to TCRβ loci, and impairs DNA double-strand break repair, causing a block at the DN3 thymocyte stage and pro-B cell stage. Setd2 knockout mice; ChIP for H3K36me3 and RAG1 at TCRβ locus; flow cytometry for developmental stages; DSB repair assays Nature communications High 31350389
2020 SETD2 methylates EZH2 at a specific site, promoting EZH2 degradation; SETD2 deficiency increases EZH2-catalyzed H3K27me3 and creates a Polycomb-repressive chromatin state enabling metastatic traits in prostate cancer. Metformin-stimulated AMPK signaling induces FOXO3 to stimulate SETD2 expression, integrating metabolic and epigenetic signaling. In vitro methyltransferase assay with recombinant SETD2 and EZH2; co-immunoprecipitation; mouse models with nonmethylatable EZH2 mutant; ChIP for H3K27me3/H3K36me3 Cancer cell High 32619406
2020 SETD2 is an actin lysine methyltransferase that trimethylates actin at lysine-68 (ActK68me3) via its interaction with huntingtin (HTT) and the actin-binding adapter HIP1R; ActK68me3 localizes to insoluble F-actin and regulates actin polymerization/depolymerization dynamics and cell migration. In vitro methyltransferase assay with recombinant SETD2 and actin; mass spectrometry identification of ActK68me3; co-immunoprecipitation of SETD2-HTT-HIP1R; cell fractionation; actin polymerization assays; cell migration assays with SETD2/HTT/HIP1R disruption Science advances High 33008892
2020 The N-terminal region (amino acids 1–1403) of SETD2 regulates its proteasomal degradation and protein stability; removal of this segment stabilizes SETD2 and causes Pol II-independent H3K36me3 deposition, and full-length SETD2 forms insoluble nuclear aggregates upon proteasome inhibition. N-terminal truncation mutants of SETD2; proteasome inhibition; H3K36me3 immunoblot; nuclear fractionation Epigenetics & chromatin Medium 33023640
2021 SETD2 mediates H3K14 trimethylation (in addition to H3K36me3) in response to replication stress; H3K14me3 recruits the RPA complex to chromatin via direct interaction with RPA70, thereby activating ATR and enabling stalled replication fork restart. In vivo and in vitro methyltransferase assays (SETD2 catalyzing H3K14me3); SETD2 depletion; RPA ChIP; direct pulldown of RPA70 with H3K14me3 peptide; replication fork restart assays; cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 34074749
2019 Setd2 loss in pancreatic acinar cells facilitates KRAS-induced acinar-to-ductal metaplasia through epigenetic dysregulation of Fbxw7; in pancreatic cancer cells, Setd2 ablation enhances EMT through impaired epigenetic regulation of Ctnna1, and sustained Akt activation via ECM production. Conditional Setd2 KO crossed with KrasG12D mice; CRISPR/Cas9 Setd2 depletion in PDAC cells; RNA-seq; H3K36me3 ChIP-seq Gut High 31300513
2022 Setd2-H3K36me3 loss in pancreatic tumor cells leads to ectopic gain of H3K27me3 at the Cxadr locus, boosting PI3K-AKT signaling and excessive CXCL1/GM-CSF expression, which recruits and reprograms neutrophils to an immunosuppressive phenotype that inhibits CD8+ T cell cytotoxicity. Conditional Setd2 KO in pancreatic cancer mouse model; comprehensive immune profiling; ChIP for H3K36me3/H3K27me3; cytokine measurement; CD8+ T cell cytotoxicity assays Advanced science High 36453584
2022 Setd2 supports GATA3+ST2+ thymic-derived Treg cells in the intestine by facilitating GATA3 and ST2 (IL1RL1) expression through H3K36me3 deposition at their promoters and intragenic enhancers; Setd2 deficiency shifts IL-33 response toward Th2 cells rather than GATA3+ Treg cells. Foxp3Cre Setd2 conditional KO mice; ChIP for H3K36me3; flow cytometry; gene expression analysis; IL-33 stimulation experiments Nature communications High 36463230
2024 Setd2 suppresses Th17 development and promotes iTreg polarization through phospholipid remodeling: Setd2 directly catalyzes H3K36me3 at the Lpcat4 gene promoter to upregulate Lpcat4, whose product PC(16:0,18:2) limits ER stress and oxidative stress, thereby reducing HIF-1α transcriptional activity and shifting Th17/Treg balance. T cell-specific Setd2 KO mice; H3K36me3 ChIP at Lpcat4 locus; lipidomics; Th17/Treg differentiation assays; HIF-1α reporter assays; EAE mouse model Proceedings of the National Academy of Sciences of the United States of America High 38359295
2017 In MLL-rearranged leukemia, SETD2 inactivation causes global reduction of H3K36me3 and further elevation of DOT1L-mediated H3K79me2, with transcriptional deregulation of tumor suppressors (e.g., ASXL1) and oncogenes (e.g., ERG) at co-enriched loci, revealing a crosstalk between H3K36me3 and H3K79me2 axes in leukemogenesis. SETD2 inactivation in MLLr leukemia cells; ChIP-seq for H3K36me3 and H3K79me2; RNA-seq; patient sample analysis Leukemia High 29249820
2016 SETD2 loss in clear cell renal cell carcinoma causes genome-wide DNA hypermethylation; H3K36me3 normally restricts DNA methylation at active gene bodies, and SETD2 deficiency leads to ectopic H3K36me3 gains at intergenic regions and DNA hypermethylation at poised enhancers of developmental genes. Genome-wide DNA methylation profiling (450K arrays) in SETD2-depleted cell lines and SETD2-mutant primary ccRCC tumors; H3K36me3 ChIP-seq Oncotarget High 26646321
2020 SETD2 deficiency in renal cell carcinoma causes aberrant accumulation of free ATG12 and an alternative ATG12-containing complex (distinct from ATG5-ATG12), associated with a short ATG12 spliced isoform, leading to decreased autophagic flux. SETD2 rescue and knockdown in RCC cells; immunoprecipitation; Western blot for ATG complexes; autophagic flux assays Cell death & disease Medium 31988284

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Targeting HIF-1 for cancer therapy. Nature reviews. Cancer 5417 13130303
2000 HIF-1: mediator of physiological and pathophysiological responses to hypoxia. Journal of applied physiology (Bethesda, Md. : 1985) 1430 10749844
2006 Hypoxia-inducible factor-1 (HIF-1). Molecular pharmacology 1311 16887934
1998 HIF-1 alpha is required for solid tumor formation and embryonic vascularization. The EMBO journal 1305 9606183
2009 HIF-1: upstream and downstream of cancer metabolism. Current opinion in genetics & development 1072 19942427
2013 HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of clinical investigation 1050 23999440
2001 HIF-1 and mechanisms of hypoxia sensing. Current opinion in cell biology 1010 11248550
2015 HIF-1 at the crossroads of hypoxia, inflammation, and cancer. International journal of cancer 452 25784597
2007 Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. The EMBO journal 447 18157086
2007 Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nature cell biology 410 17220880
2009 Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proceedings of the National Academy of Sciences of the United States of America 388 19805192
2010 P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 337 20308559
2003 Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. The Journal of biological chemistry 279 12606552
2005 Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends in cardiovascular medicine 268 15885571
2018 Role of HIF-1 in Cancer Progression: Novel Insights. A Review. Current molecular medicine 249 30411685
2005 Negative and positive regulation of HIF-1: a complex network. Biochimica et biophysica acta 228 15994012
2007 HIF-1 mediates the Warburg effect in clear cell renal carcinoma. Journal of bioenergetics and biomembranes 225 17551816
2011 Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nature structural & molecular biology 208 21792193
2008 The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes & development 199 19141475
2004 Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer cell 197 15144945
2000 Hypoxia, HIF-1, and the pathophysiology of common human diseases. Advances in experimental medicine and biology 192 10849654
2004 HIF-1: an oxygen and metal responsive transcription factor. Cancer biology & therapy 189 14726713
2009 Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiation research 188 19929412
2014 Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 169 25288734
2020 SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways. Cancer cell 162 32619406
2001 Requirement of nickel metabolism proteins HypA and HypB for full activity of both hydrogenase and urease in Helicobacter pylori. Molecular microbiology 155 11123699
1993 The product of the hypB gene, which is required for nickel incorporation into hydrogenases, is a novel guanine nucleotide-binding protein. Journal of bacteriology 147 8423137
2010 Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proceedings of the National Academy of Sciences of the United States of America 141 20133625
2007 RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization. Cell cycle (Georgetown, Tex.) 140 17361105
2013 Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription. Nucleic acids research 131 23325844
2004 New anticancer strategies targeting HIF-1. Biochemical pharmacology 128 15313402
2020 Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK. Cancers 127 32252351
2007 HIF-1 regulation of chondrocyte apoptosis: induction of the autophagic pathway. Autophagy 127 17224629
2012 HIF-1 versus HIF-2--is one more important than the other? Vascular pharmacology 121 22366374
2004 HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochemical pharmacology 118 15313390
2007 Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 113 17563752
2007 Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 110 18325389
2017 SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia. Blood 108 29018079
2007 HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia. Antioxidants & redox signaling 104 17627473
2008 Extracellular matrix and HIF-1 signaling: the role of prolidase. International journal of cancer 103 17999410
2017 Shaping the cellular landscape with Set2/SETD2 methylation. Cellular and molecular life sciences : CMLS 101 28386724
2005 Hypoxia and HIF-1 alpha in chondrogenesis. Seminars in cell & developmental biology 84 16144691
2001 The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Advances in experimental medicine and biology 83 11950150
2008 Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arteriosclerosis, thrombosis, and vascular biology 78 18658046
2005 Neuroprotection by hypoxic preconditioning: HIF-1 and erythropoietin protect from retinal degeneration. Seminars in cell & developmental biology 76 16144690
2021 Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy. NPJ precision oncology 75 34127768
2016 Hypoxia and HIF-1 activation in bacterial infections. Microbes and infection 74 27903434
2021 Flavonoids Targeting HIF-1: Implications on Cancer Metabolism. Cancers 73 33401572
2021 PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity. Hepatology (Baltimore, Md.) 72 32335942
2021 Regulation of redox signaling in HIF-1-dependent tumor angiogenesis. The FEBS journal 72 34228878
2019 HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia. BMC medical genetics 70 30808328
2017 SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation. Cold Spring Harbor perspectives in medicine 69 28159833
2020 Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers. Journal of Cancer 68 32231741
2019 Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut 66 31300513
2016 SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing. Nucleic acids research 65 27614073
2007 The role of complex formation between the Escherichia coli hydrogenase accessory factors HypB and SlyD. The Journal of biological chemistry 62 17426034
2019 Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond. International journal of molecular sciences 60 30818762
2015 Modeling the interplay between the HIF-1 and p53 pathways in hypoxia. Scientific reports 60 26346319
2005 Metal binding activity of the Escherichia coli hydrogenase maturation factor HypB. Biochemistry 59 16142921
2016 Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: A review. Biochimica et biophysica acta 57 26899267
1997 The HypB protein from Bradyrhizobium japonicum can store nickel and is required for the nickel-dependent transcriptional regulation of hydrogenase. Molecular microbiology 57 9140970
2018 Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell research 56 29531312
2015 Temporal regulation of HIF-1 and NF-κB in hypoxic hepatocarcinoma cells. Oncotarget 51 25823824
2011 HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Current molecular pharmacology 50 20958262
2022 Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 49 36453584
2002 Harnessing the response to tissue hypoxia: HIF-1 alpha and therapeutic angiogenesis. Trends in cardiovascular medicine 49 12536123
2016 Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget 47 26646321
2002 ERK and calcium in activation of HIF-1. Annals of the New York Academy of Sciences 47 12485909
2011 Metallo-GTPase HypB from Helicobacter pylori and its interaction with nickel chaperone protein HypA. The Journal of biological chemistry 46 22179820
2007 The role of HIF-1 in hypoxic response in the skeletal muscle. Advances in experimental medicine and biology 46 18269201
2014 Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling pathway for liver damage. Free radical biology & medicine 45 24632196
2020 SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. Cell death & disease 44 31988284
2004 Raising the bar: how HIF-1 helps determine tumor radiosensitivity. Cell cycle (Georgetown, Tex.) 44 15326390
2017 KDM4A regulates HIF-1 levels through H3K9me3. Scientific reports 43 28894274
2019 Modeling the regulation of p53 activation by HIF-1 upon hypoxia. FEBS letters 42 31282018
2019 The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nature communications 42 31350389
2016 The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. Journal of molecular medicine (Berlin, Germany) 42 28004126
2022 SETD2: from chromatin modifier to multipronged regulator of the genome and beyond. Cellular and molecular life sciences : CMLS 41 35661267
2020 The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science advances 41 33008892
2016 Mechanism of Selective Nickel Transfer from HypB to HypA, Escherichia coli [NiFe]-Hydrogenase Accessory Proteins. Biochemistry 38 27951644
2008 Structural and biological analysis of the metal sites of Escherichia coli hydrogenase accessory protein HypB. Biochemistry 38 18942856
2014 Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin. Structure (London, England : 1993) 37 24412394
2020 Dimethyloxalyl Glycine Regulates the HIF-1 Signaling Pathway in Mesenchymal Stem Cells. Stem cell reviews and reports 34 32372246
2017 SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia. Leukemia 34 29249820
2013 Metal transfer within the Escherichia coli HypB-HypA complex of hydrogenase accessory proteins. Biochemistry 34 23899293
2008 HIF-1: an age-dependent regulator of lens cell proliferation. Investigative ophthalmology & visual science 33 18586877
2023 SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer. Nature communications 32 37989747
2014 Neuroprotective effect of pAkt and HIF-1 α on ischemia rats. Asian Pacific journal of tropical medicine 32 24507644
2014 HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 24558194
2019 Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene 31 31043706
2022 Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation. Nature communications 29 36463230
2021 SETD2-mediated H3K14 trimethylation promotes ATR activation and stalled replication fork restart in response to DNA replication stress. Proceedings of the National Academy of Sciences of the United States of America 29 34074749
2014 Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid. Experimental & molecular medicine 29 25523098
2019 HIF 1 inhibits STAR transcription and testosterone synthesis in murine Leydig cells. Journal of molecular endocrinology 28 30400066
2024 Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling. Proceedings of the National Academy of Sciences of the United States of America 27 38359295
2022 Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway. iScience 27 35784791
2010 Inflammation, HIF-1, and the epigenetics that follows. Mediators of inflammation 27 21197398
2022 Role of prolyl hydroxylase/HIF-1 signaling in vascular calcification. Clinical kidney journal 26 36755843
2020 Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition. Epigenetics & chromatin 26 33023640
2011 Relationship between the GTPase, metal-binding, and dimerization activities of E. coli HypB. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 26 21544686