{"gene":"SETD2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2007,"finding":"HYPB/SETD2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation (H3K36me3) in mammalian cells, but not H3K36 mono- or dimethylation. This was demonstrated by knockdown of HYPB/Setd2 in murine fibroblasts, which abolished H3K36me3 across c-fos and c-jun coding regions upon gene induction.","method":"siRNA knockdown of HYPB/Setd2 in murine fibroblasts combined with high-resolution ChIP mapping of histone modifications","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockdown with specific chromatin phenotype, replicated conceptually across multiple subsequent studies, specific separation of me1/me2 from me3 activity","pmids":["18157086"],"is_preprint":false},{"year":2008,"finding":"IWS1 (Iws1) recruits HYPB/SETD2 to the RNA polymerase II elongation complex via Spt6, and this recruitment is required for H3K36me3 across transcribed gene bodies. Knockdown of HYPB/SETD2 also caused nuclear accumulation of poly(A)+ mRNAs, indicating a role in mRNA export. Spt6 binds the CTD N-terminal consensus repeats and recruits Iws1, which bridges to HYPB/SETD2, forming a megacomplex.","method":"Co-immunoprecipitation, siRNA knockdown of Iws1 and HYPB/Setd2, ChIP for H3K36me3 across c-Myc, HIV-1, PABPC1 genes; in vitro binding assay (recombinant Spt6 binding to CTD)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro reconstitution of Spt6-CTD interaction, knockdown with two orthogonal phenotypic readouts (ChIP + mRNA export), multiple genes tested","pmids":["19141475"],"is_preprint":false},{"year":2010,"finding":"Homozygous knockout of Hypb/Setd2 in mice impairs H3K36 trimethylation (but not mono- or dimethylation) and causes embryonic lethality at E10.5–E11.5 with severe vascular remodeling defects. Hypb-deficient endothelial cells and embryonic bodies showed defects in cell migration and invasion, establishing an intrinsic role for Hypb in vascular development.","method":"Conditional knockout mouse model, immunofluorescence for histone modifications, tetraploid rescue experiment, siRNA knockdown in human endothelial cells, in vitro migration/invasion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — full KO mouse with multiple orthogonal phenotypic readouts (embryo, yolk sac, placenta, ES cell-derived bodies), tetraploid rescue controls, H3K36me3 specificity confirmed","pmids":["20133625"],"is_preprint":false},{"year":2013,"finding":"SETD2 downregulation in human cells leads to intragenic (cryptic) transcription initiation at ~11% of active genes. SETD2 coordinates FACT complex (SPT16/SSRP1) recruitment to H3K36me3-containing nucleosomes and regulates nucleosome occupancy and histone H2B exchange during transcription elongation. Co-immunoprecipitation showed SPT16 associates with H3K36me3-containing chromatin.","method":"siRNA knockdown of SETD2 in human cells, RNA-seq for cryptic transcription, ChIP for nucleosome occupancy and H2B/H3, co-immunoprecipitation of SPT16 with H3K36me3 chromatin, live-cell imaging with transcription inhibition","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, ChIP, Co-IP, live imaging), single lab, clear mechanistic chain from SETD2 loss to FACT displacement to cryptic transcription","pmids":["23325844"],"is_preprint":false},{"year":2014,"finding":"The WW domain of HYPB/SETD2 adopts an autoinhibitory closed conformation due to intramolecular binding of a C-terminal polyproline stretch to the WW core domain. This autoinhibitory structure regulates interaction between the HYPB WW domain and the proline-rich region (PRR) of huntingtin (Htt), as shown by NMR solution structure and immunofluorescence.","method":"NMR structure determination of the WW domain–polyproline complex, NMR chemical shift perturbation, immunofluorescence co-localization assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation by NMR perturbation and immunofluorescence, single lab but multiple orthogonal structural and cell-based methods","pmids":["24412394"],"is_preprint":false},{"year":2016,"finding":"SETD2 inactivation in human cells drives a DNA hypermethylation phenotype with ectopic gains of H3K36me3 centered on intergenic regions adjacent to low-expressing genes, and poised enhancers of developmental genes are prominent hypermethylation targets. SETD2 mutant primary ccRCC, papillary RCC, and lung adenocarcinomas all show this hypermethylation phenotype, demonstrating that SETD2 mutations coordinate disruption of both the epigenome and transcriptome.","method":"Genome-wide DNA methylation profiling (array), ChIP-seq for H3K36me3, cell line-based SETD2 inactivation models (long-term and acute), primary tumor analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq and methylation profiling with multiple model systems and primary tumor validation, single lab","pmids":["26646321"],"is_preprint":false},{"year":2017,"finding":"In MLL-rearranged leukemia, SETD2 inactivation leads to global reduction of H3K36me3 and further elevation of H3K79me2, revealing a crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis that deregulates tumor suppressors (e.g., ASXL1) and oncogenes (e.g., ERG) independently of canonical MLL fusion targets.","method":"ChIP-seq for H3K36me3 and H3K79me2, RNA-seq in SETD2-inactivated leukemia cells, patient sample analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with patient sample validation, single lab, mechanistic crosstalk between two histone marks identified","pmids":["29249820"],"is_preprint":false},{"year":2018,"finding":"Setd2 deficiency in hematopoietic stem cells (HSCs) impairs self-renewal and competitive fitness, induces DNA replication stress (evidenced by activated E2F network and repressed Rrm2b expression), and eventually leads to myelodysplastic syndrome-like malignancy. Gene expression profiles of Setd2-deleted HSPCs partially overlap with Dnmt3a/Tet2 double-KO HSPCs, with activation of the Klf1-related erythroid pathway.","method":"Conditional Setd2 knockout mice, serial bone marrow transplantation, gene expression profiling, cell cycle analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with serial transplantation demonstrating functional HSC defects, multiple in vivo phenotypic readouts, mechanistic pathway identified","pmids":["29531312"],"is_preprint":false},{"year":2019,"finding":"Setd2 acts as a tumor suppressor in KRAS-driven pancreatic carcinogenesis. Setd2 loss in acinar cells facilitates KRAS-induced acinar-to-ductal metaplasia through epigenetic dysregulation of Fbxw7 (reduced H3K36me3 at Fbxw7 locus). Setd2 ablation in pancreatic cancer cells enhances EMT via impaired epigenetic regulation of Ctnna1, and leads to sustained Akt activation through ECM production.","method":"PdxCreSetd2 flox/flox × KrasG12D conditional KO mice, CRISPR/Cas9 depletion in PDAC cells, RNA-seq and H3K36me3 ChIP-seq","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO combined with ChIP-seq and RNA-seq, CRISPR validation in cell lines, multiple downstream targets identified","pmids":["31300513"],"is_preprint":false},{"year":2019,"finding":"Setd2 deficiency causes a severe developmental block of thymocytes at the DN3 stage by reducing H3K36me3 at the TCRβ locus, impairing RAG1 binding and V(D)J recombination. Similarly, Setd2 loss blocks B cell development at the pro-B stage by impairing immunoglobulin V(D)J rearrangement.","method":"Conditional Setd2 knockout mice, ChIP for H3K36me3 and RAG1 at TCRβ locus, flow cytometry for lymphocyte developmental stages, DSB repair assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with ChIP demonstrating direct H3K36me3 loss at TCRβ locus plus RAG1 recruitment defect, replicated in B cell compartment with mechanistic specificity","pmids":["31350389"],"is_preprint":false},{"year":2020,"finding":"SETD2 trimethylates EZH2 on a specific lysine, promoting EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state (increased H3K27me3) enabling cells to acquire metastatic traits in prostate cancer. Metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression, linking metabolic and epigenetic pathways.","method":"Co-immunoprecipitation, in vitro methyltransferase assay with recombinant proteins, knock-in mice with nonmethylatable EZH2 mutant and SETD2 mutant defective in EZH2 binding, H3K27me3 ChIP-seq, AMPK/FOXO3 pathway epistasis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methyltransferase reconstitution plus multiple mouse models plus ChIP-seq, identifies EZH2 as non-histone substrate of SETD2","pmids":["32619406"],"is_preprint":false},{"year":2020,"finding":"SETD2 is an actin lysine methyltransferase that trimethylates lysine-68 of actin (ActK68me3) in cells via its interaction with huntingtin (HTT) and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration.","method":"Co-immunoprecipitation of SETD2-HTT-HIP1R complex, in vitro methyltransferase assay with purified actin and SETD2, mass spectrometry identification of ActK68me3, actin polymerization assays, cell migration assays with SETD2 knockdown/knockout","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of actin methyltransferase activity, MS identification of modification site, cell biology functional readouts; single lab but multiple orthogonal methods","pmids":["33008892"],"is_preprint":false},{"year":2020,"finding":"SETD2 deficiency in renal clear cell carcinoma cells is associated with aberrant accumulation of free ATG12 and a distinct ATG12-containing complex, and with increased expression of a short ATG12 spliced isoform at the expense of the canonical long isoform. This impairs the ATG12 conjugation system and decreases autophagic flux, establishing a role for SETD2 as a regulator of alternative splicing of ATG12 and autophagy.","method":"SETD2 rescue and knockdown in RCC cells, western blot for ATG12 complexes, RT-PCR for ATG12 isoforms, autophagic flux assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (rescue + knockdown), multiple readouts (splicing, protein complex, flux), single lab","pmids":["31988284"],"is_preprint":false},{"year":2022,"finding":"Setd2 deficiency in pancreatic tumor cells leads to ectopic H3K27me3 gain at the Cxadr locus, downregulating Cxadr expression, which boosts PI3K-AKT signaling and excessive CXCL1 and GM-CSF secretion. This promotes recruitment and reprogramming of neutrophils toward an immunosuppressive phenotype, fostering CD8+ T cell inhibition and tumor immune escape.","method":"Setd2 conditional KO mouse model, comprehensive immune profiling of TME, H3K27me3 and H3K36me3 ChIP-seq at Cxadr locus, cytokine measurement (CXCL1, GM-CSF), neutrophil co-culture assays with CD8+ T cells","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model combined with ChIP-seq mechanistic data and functional immune assays, single lab","pmids":["36453584"],"is_preprint":false},{"year":2022,"finding":"Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg cell survival and suppressive function by facilitating GATA3 and ST2 (IL1RL1) expression through H3K36me3 deposition at promoters and intragenic enhancers of target genes including Il1rl1. In human Treg cells, SETD2 sustains GATA3 expression.","method":"Foxp3Cre Setd2 conditional KO mice, H3K36me3 ChIP-seq at target gene loci, flow cytometry for Treg subsets, IL-33 stimulation assays, human Treg cell SETD2 knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP-seq mechanistic evidence and human validation, single lab","pmids":["36463230"],"is_preprint":false},{"year":2023,"finding":"SETD2 loss in kidneys causes extensive metabolic reprogramming including enhanced sphingomyelin biosynthesis, which promotes PKD-to-ccRCC tumor transition. Inhibition of sphingomyelin biosynthesis with myriocin relieves tumor symptoms in Setd2 knockout mice, establishing a causal mechanistic link between SETD2 deficiency and sphingolipid metabolism in renal tumorigenesis.","method":"Conditional Setd2 KO mouse model (PKD-ccRCC transition), metabolomics, lipidomics, transcriptomics, proteomics; myriocin pharmacological rescue; clinical ccRCC patient specimen validation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics in vivo KO model with pharmacological rescue, single lab but multiple orthogonal omics platforms","pmids":["37989747"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of mammalian RNA Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome elongation complexes reveal that SETD2 is positioned to methylate H3K36 on both downstream and upstream nucleosomes during transcription elongation. SPT6 binds the exposed H2A-H2B dimer on actively transcribed nucleosomes, and the SPT6 death-like domain mediates a direct interaction with SETD2 when it is bound to the upstream nucleosome.","method":"Cryo-electron microscopy structure determination of mammalian elongation complex with SETD2 and nucleosome","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with direct visualization of SETD2 positioning relative to nucleosome and SPT6 interaction interface","pmids":["39666822"],"is_preprint":false}],"current_model":"SETD2 is the sole histone H3K36 trimethylase in mammals, recruited to the RNA Pol II elongation complex via IWS1-SPT6 (structurally visualized by cryo-EM); it deposits H3K36me3 co-transcriptionally to suppress cryptic transcription (by coordinating FACT-dependent nucleosome dynamics), regulate pre-mRNA splicing, support V(D)J recombination via RAG1 recruitment, and maintain DNA methylation patterning. Beyond histones, SETD2 methylates EZH2 (promoting its degradation and restraining H3K27me3) and trimethylates actin lysine-68 via a SETD2-HTT-HIP1R complex to regulate actin polymerization and cell migration, with loss-of-function driving tumor progression across multiple cancer types."},"narrative":{"mechanistic_narrative":"SETD2 (HYPB) is the principal mammalian histone H3K36 trimethyltransferase, responsible for virtually all global and transcription-coupled H3K36me3 while leaving H3K36 mono- and dimethylation intact [PMID:18157086]. It is recruited co-transcriptionally to the RNA polymerase II elongation complex through an IWS1–SPT6 bridge that engages the Pol II CTD, and cryo-EM of the mammalian elongation machinery shows SETD2 positioned to methylate H3K36 on both downstream and upstream nucleosomes, with the SPT6 death-like domain making a direct contact when SETD2 acts on the upstream nucleosome [PMID:19141475, PMID:39666822]. Through this activity SETD2 enforces correct chromatin dynamics during elongation: H3K36me3 coordinates FACT (SPT16/SSRP1) recruitment and nucleosome/H2B exchange to suppress cryptic intragenic transcription [PMID:23325844], and SETD2 loss couples epigenome disruption to transcriptome dysregulation, producing DNA hypermethylation and ectopic gains of repressive marks [PMID:26646321]. The same elongation-linked mark governs developmental programs, including V(D)J recombination, where H3K36me3 at the TCRβ locus licenses RAG1 binding so that Setd2 loss arrests thymocyte and B-cell development [PMID:31350389], and immune-cell fate, where H3K36me3 sustains GATA3 and Il1rl1 expression in tissue Treg cells [PMID:36463230]. Beyond histones, SETD2 has non-histone substrates: it trimethylates EZH2 to drive its degradation and restrain H3K27me3 [PMID:32619406], and within a SETD2–HTT–HIP1R complex it trimethylates actin lysine-68 to regulate F-actin polymerization and cell migration [PMID:33008892], the latter mediated by an autoinhibited WW domain that interacts with the huntingtin proline-rich region [PMID:24412394]. Loss of SETD2 acts as a tumor suppressor across diverse cancers, driving replication stress and myelodysplasia in hematopoietic stem cells [PMID:29531312], KRAS-driven pancreatic metaplasia and immune escape [PMID:31300513, PMID:36453584], and renal tumorigenesis linked to metabolic reprogramming [PMID:37989747], establishing SETD2 as an integrator of transcription, chromatin, splicing, cytoskeletal regulation, and tumor suppression.","teleology":[{"year":2007,"claim":"Established which enzyme deposits H3K36me3 in mammals, resolving the source of the transcription-associated trimethyl mark versus lower methylation states.","evidence":"siRNA knockdown of HYPB/Setd2 in murine fibroblasts with high-resolution ChIP across induced c-fos/c-jun","pmids":["18157086"],"confidence":"High","gaps":["Did not define how SETD2 is targeted to transcribed genes","Mechanism distinguishing me3 from me1/me2 deposition unresolved"]},{"year":2008,"claim":"Answered how SETD2 reaches active gene bodies by identifying the IWS1–SPT6 bridge to elongating Pol II, and linked the enzyme to mRNA export.","evidence":"Reciprocal Co-IP, siRNA knockdown of Iws1/SETD2 with ChIP, in vitro Spt6–CTD binding across multiple genes","pmids":["19141475"],"confidence":"High","gaps":["Structural basis of the megacomplex not resolved","Mechanism connecting H3K36me3 to poly(A)+ mRNA export not defined"]},{"year":2010,"claim":"Demonstrated the physiological requirement for SETD2/H3K36me3 in vivo through embryonic lethality with vascular and migration defects.","evidence":"Conditional Setd2 knockout mice, tetraploid rescue, IF, endothelial migration/invasion assays","pmids":["20133625"],"confidence":"High","gaps":["Did not pinpoint the H3K36me3 target genes driving vascular defects","Cell-migration link to a direct molecular mechanism not established at this stage"]},{"year":2013,"claim":"Mechanistically connected H3K36me3 to suppression of cryptic transcription via FACT-dependent nucleosome dynamics during elongation.","evidence":"siRNA knockdown with RNA-seq for cryptic initiation, nucleosome/H2B ChIP, SPT16 Co-IP, live imaging","pmids":["23325844"],"confidence":"High","gaps":["Direct biochemical reader linking H3K36me3 to FACT recruitment not isolated","Single-lab observation"]},{"year":2016,"claim":"Showed SETD2 loss couples epigenome and transcriptome disruption by producing DNA hypermethylation and ectopic H3K36me3 gains, generalizable across tumor types.","evidence":"Genome-wide methylation arrays and H3K36me3 ChIP-seq in cell models plus primary RCC and lung tumors","pmids":["26646321"],"confidence":"Medium","gaps":["Causal mechanism linking H3K36me3 loss to DNA hypermethylation not fully resolved","Single lab"]},{"year":2017,"claim":"Revealed crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis in leukemia, expanding how SETD2 loss deregulates oncogenes and tumor suppressors.","evidence":"H3K36me3/H3K79me2 ChIP-seq and RNA-seq in SETD2-inactivated leukemia cells with patient samples","pmids":["29249820"],"confidence":"Medium","gaps":["Molecular basis of H3K79me2 elevation upon H3K36me3 loss not defined","Single lab"]},{"year":2018,"claim":"Defined a tumor-suppressive role in hematopoiesis, showing SETD2 loss induces replication stress and progresses to MDS-like malignancy.","evidence":"Conditional Setd2 KO mice, serial bone-marrow transplantation, expression profiling, cell-cycle analysis","pmids":["29531312"],"confidence":"High","gaps":["Direct H3K36me3 targets driving replication stress not pinpointed","Overlap with Dnmt3a/Tet2 pathways only partial"]},{"year":2019,"claim":"Identified SETD2 as a tumor suppressor in KRAS-driven pancreatic carcinogenesis acting through H3K36me3-dependent regulation of specific loci.","evidence":"PdxCre Setd2 flox × KrasG12D mice, CRISPR depletion in PDAC cells, H3K36me3 ChIP-seq and RNA-seq","pmids":["31300513"],"confidence":"High","gaps":["Relative contribution of Fbxw7, Ctnna1, and Akt arms not dissected","Mechanism of sustained Akt activation via ECM incompletely defined"]},{"year":2019,"claim":"Showed H3K36me3 directly licenses antigen-receptor recombination by enabling RAG1 binding, explaining lymphocyte developmental arrest upon SETD2 loss.","evidence":"Conditional Setd2 KO mice, H3K36me3 and RAG1 ChIP at TCRβ, flow cytometry, DSB repair assays","pmids":["31350389"],"confidence":"High","gaps":["Whether RAG1 directly reads H3K36me3 or requires a reader not established","Generality across all antigen-receptor loci not exhaustively mapped"]},{"year":2020,"claim":"Identified the first non-histone protein substrate, EZH2, defining a methylation-degradation circuit that restrains H3K27me3 and metastasis, with metabolic input via AMPK-FOXO3.","evidence":"Co-IP, in vitro methyltransferase assay, knock-in mice with nonmethylatable EZH2 and EZH2-binding-defective SETD2, H3K27me3 ChIP-seq","pmids":["32619406"],"confidence":"High","gaps":["The EZH2 lysine site and degradation machinery details not fully specified here","Tissue scope of the EZH2 axis beyond prostate not defined"]},{"year":2020,"claim":"Extended SETD2 catalytic scope to the cytoskeleton, showing it trimethylates actin K68 within a HTT-HIP1R complex to control polymerization and migration.","evidence":"Co-IP of SETD2-HTT-HIP1R, in vitro methyltransferase assay on purified actin, MS site identification, polymerization and migration assays","pmids":["33008892"],"confidence":"High","gaps":["Subcellular pool of SETD2 performing actin methylation not delineated","Single lab"]},{"year":2020,"claim":"Provided a structural basis for SETD2 regulation, showing an autoinhibited WW domain governing the huntingtin interaction.","evidence":"NMR structure of WW–polyproline complex, chemical shift perturbation, IF co-localization","pmids":["24412394"],"confidence":"High","gaps":["How autoinhibition is relieved in cells not defined","Functional consequence for catalysis not directly tested"]},{"year":2020,"claim":"Implicated SETD2 in alternative splicing control, linking its loss to defective ATG12 conjugation and reduced autophagic flux in RCC.","evidence":"SETD2 rescue/knockdown in RCC cells, western blot of ATG12 complexes, RT-PCR isoforms, autophagy flux assays","pmids":["31988284"],"confidence":"Medium","gaps":["Direct link from H3K36me3 to ATG12 splicing not mechanistically demonstrated","Single lab"]},{"year":2022,"claim":"Connected SETD2 loss to tumor immune escape via H3K27me3-mediated Cxadr silencing, PI3K-AKT activation, and immunosuppressive neutrophil reprogramming.","evidence":"Setd2 conditional KO mice, immune profiling, H3K27me3/H3K36me3 ChIP-seq at Cxadr, cytokine assays, neutrophil–CD8 co-culture","pmids":["36453584"],"confidence":"Medium","gaps":["Mechanism converting H3K36me3 loss to H3K27me3 gain at Cxadr not detailed","Single lab"]},{"year":2022,"claim":"Showed SETD2 sustains tissue Treg identity and suppressive function through H3K36me3 at GATA3 and Il1rl1 regulatory elements.","evidence":"Foxp3Cre Setd2 KO mice, H3K36me3 ChIP-seq, flow cytometry, IL-33 stimulation, human Treg knockdown","pmids":["36463230"],"confidence":"Medium","gaps":["Whether GATA3/Il1rl1 are direct primary targets vs downstream effects not fully resolved","Single lab"]},{"year":2023,"claim":"Linked SETD2 deficiency to metabolic reprogramming, identifying sphingomyelin biosynthesis as a causal, druggable driver of renal tumor transition.","evidence":"Conditional Setd2 KO PKD-ccRCC mice, multi-omics, myriocin pharmacological rescue, patient validation","pmids":["37989747"],"confidence":"Medium","gaps":["Direct chromatin targets controlling sphingolipid genes not pinpointed","Single lab"]},{"year":2024,"claim":"Resolved the structural architecture of SETD2 within the Pol II elongation complex, explaining how it accesses both upstream and downstream nucleosomes via SPT6.","evidence":"Cryo-EM of mammalian Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome complexes","pmids":["39666822"],"confidence":"High","gaps":["Catalytic conformational cycle during translocation not captured","Regulation of SETD2 dwell time per nucleosome unresolved"]},{"year":null,"claim":"How SETD2 substrate selection (histone H3K36 vs EZH2 vs actin) is partitioned across cellular compartments and signaling states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for how one enzyme selects histone vs non-histone substrates","Compartment-specific regulation of catalytic activity not defined","Direct readers translating H3K36me3 to DNA methylation and splicing outcomes incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,11]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,9]}],"complexes":["RNA Pol II elongation complex (with IWS1-SPT6)","SETD2-HTT-HIP1R complex"],"partners":["IWS1","SPT6","SPT16","EZH2","HTT","HIP1R","RAG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYW2","full_name":"Histone-lysine N-methyltransferase SETD2","aliases":["HIF-1","Huntingtin yeast partner B","Huntingtin-interacting protein 1","HIP-1","Huntingtin-interacting protein B","Lysine N-methyltransferase 3A","Protein-lysine N-methyltransferase SETD2","SET domain-containing protein 2","hSET2","p231HBP"],"length_aa":2564,"mass_kda":287.6,"function":"Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426) (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9BYW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SETD2","classification":"Not Classified","n_dependent_lines":487,"n_total_lines":1208,"dependency_fraction":0.4031456953642384},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SETD2","total_profiled":1310},"omim":[{"mim_id":"620157","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 70; MRD70","url":"https://www.omim.org/entry/620157"},{"mim_id":"620155","title":"RABIN-PAPPAS SYNDROME; RAPAS","url":"https://www.omim.org/entry/620155"},{"mim_id":"616831","title":"LUSCAN-LUMISH SYNDROME; LLS","url":"https://www.omim.org/entry/616831"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"612778","title":"SET DOMAIN-CONTAINING PROTEIN 2; SETD2","url":"https://www.omim.org/entry/612778"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SETD2"},"hgnc":{"alias_symbol":["HYPB","HIF-1","KIAA1732","FLJ23184","KMT3A"],"prev_symbol":[]},"alphafold":{"accession":"Q9BYW2","domains":[{"cath_id":"2.170.270.10","chopping":"1447-1709","consensus_level":"medium","plddt":88.462,"start":1447,"end":1709},{"cath_id":"1.10.1740.100","chopping":"2466-2564","consensus_level":"medium","plddt":85.5489,"start":2466,"end":2564},{"cath_id":"1.25.40","chopping":"1712-1788_1795-1820","consensus_level":"medium","plddt":83.1315,"start":1712,"end":1820}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYW2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYW2-F1-predicted_aligned_error_v6.png","plddt_mean":43.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SETD2","jax_strain_url":"https://www.jax.org/strain/search?query=SETD2"},"sequence":{"accession":"Q9BYW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYW2"}},"corpus_meta":[{"pmid":"13130303","id":"PMC_13130303","title":"Targeting HIF-1 for cancer therapy.","date":"2003","source":"Nature reviews. Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/13130303","citation_count":5451,"is_preprint":false},{"pmid":"10749844","id":"PMC_10749844","title":"HIF-1: mediator of physiological and pathophysiological responses to hypoxia.","date":"2000","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/10749844","citation_count":1438,"is_preprint":false},{"pmid":"16887934","id":"PMC_16887934","title":"Hypoxia-inducible factor-1 (HIF-1).","date":"2006","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16887934","citation_count":1320,"is_preprint":false},{"pmid":"19942427","id":"PMC_19942427","title":"HIF-1: upstream and downstream of cancer metabolism.","date":"2009","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/19942427","citation_count":1082,"is_preprint":false},{"pmid":"23999440","id":"PMC_23999440","title":"HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23999440","citation_count":1073,"is_preprint":false},{"pmid":"11248550","id":"PMC_11248550","title":"HIF-1 and mechanisms of hypoxia sensing.","date":"2001","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11248550","citation_count":1022,"is_preprint":false},{"pmid":"11927290","id":"PMC_11927290","title":"HIF-1 and tumor progression: pathophysiology and therapeutics.","date":"2002","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11927290","citation_count":829,"is_preprint":false},{"pmid":"17925579","id":"PMC_17925579","title":"Hypoxia-inducible factor 1 (HIF-1) pathway.","date":"2007","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/17925579","citation_count":733,"is_preprint":false},{"pmid":"25784597","id":"PMC_25784597","title":"HIF-1 at the crossroads of hypoxia, inflammation, and cancer.","date":"2015","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25784597","citation_count":457,"is_preprint":false},{"pmid":"18157086","id":"PMC_18157086","title":"Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18157086","citation_count":449,"is_preprint":false},{"pmid":"25689954","id":"PMC_25689954","title":"Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K.","date":"2015","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25689954","citation_count":431,"is_preprint":false},{"pmid":"19805192","id":"PMC_19805192","title":"Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19805192","citation_count":388,"is_preprint":false},{"pmid":"18809331","id":"PMC_18809331","title":"HIF-1 regulation: not so easy come, easy go.","date":"2008","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18809331","citation_count":279,"is_preprint":false},{"pmid":"15885571","id":"PMC_15885571","title":"Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue.","date":"2005","source":"Trends in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15885571","citation_count":268,"is_preprint":false},{"pmid":"30411685","id":"PMC_30411685","title":"Role of HIF-1 in Cancer Progression: Novel Insights. A Review.","date":"2018","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30411685","citation_count":252,"is_preprint":false},{"pmid":"17404612","id":"PMC_17404612","title":"HIF-1 and HIF-2: working alone or together in hypoxia?","date":"2007","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17404612","citation_count":232,"is_preprint":false},{"pmid":"15994012","id":"PMC_15994012","title":"Negative and positive regulation of HIF-1: a complex network.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/15994012","citation_count":228,"is_preprint":false},{"pmid":"17551816","id":"PMC_17551816","title":"HIF-1 mediates the Warburg effect in clear cell renal carcinoma.","date":"2007","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/17551816","citation_count":227,"is_preprint":false},{"pmid":"11191064","id":"PMC_11191064","title":"HIF-1: using two hands to flip the angiogenic switch.","date":"2000","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11191064","citation_count":208,"is_preprint":false},{"pmid":"19141475","id":"PMC_19141475","title":"The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19141475","citation_count":200,"is_preprint":false},{"pmid":"15144945","id":"PMC_15144945","title":"Intratumoral hypoxia, radiation resistance, and HIF-1.","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/15144945","citation_count":199,"is_preprint":false},{"pmid":"10849654","id":"PMC_10849654","title":"Hypoxia, HIF-1, and the pathophysiology of common human diseases.","date":"2000","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/10849654","citation_count":193,"is_preprint":false},{"pmid":"14726713","id":"PMC_14726713","title":"HIF-1: an oxygen and metal responsive transcription factor.","date":"2004","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/14726713","citation_count":191,"is_preprint":false},{"pmid":"19929412","id":"PMC_19929412","title":"Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress.","date":"2009","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/19929412","citation_count":189,"is_preprint":false},{"pmid":"10518614","id":"PMC_10518614","title":"HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation.","date":"1999","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10518614","citation_count":170,"is_preprint":false},{"pmid":"32619406","id":"PMC_32619406","title":"SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways.","date":"2020","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/32619406","citation_count":166,"is_preprint":false},{"pmid":"15601571","id":"PMC_15601571","title":"HIF-1 and p53: communication of transcription factors under hypoxia.","date":"2004","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15601571","citation_count":150,"is_preprint":false},{"pmid":"20133625","id":"PMC_20133625","title":"Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20133625","citation_count":142,"is_preprint":false},{"pmid":"17361105","id":"PMC_17361105","title":"RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17361105","citation_count":140,"is_preprint":false},{"pmid":"23325844","id":"PMC_23325844","title":"Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23325844","citation_count":132,"is_preprint":false},{"pmid":"32252351","id":"PMC_32252351","title":"Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32252351","citation_count":130,"is_preprint":false},{"pmid":"15108809","id":"PMC_15108809","title":"HIF-1 and hypoxic response: the plot thickens.","date":"2004","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/15108809","citation_count":128,"is_preprint":false},{"pmid":"15313402","id":"PMC_15313402","title":"New anticancer strategies targeting HIF-1.","date":"2004","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15313402","citation_count":128,"is_preprint":false},{"pmid":"19264039","id":"PMC_19264039","title":"HIF-1: a key mediator in hypoxia.","date":"2009","source":"Acta physiologica Hungarica","url":"https://pubmed.ncbi.nlm.nih.gov/19264039","citation_count":125,"is_preprint":false},{"pmid":"20711226","id":"PMC_20711226","title":"Hypoxia inducible factor 1 (HIF-1) and cardioprotection.","date":"2010","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/20711226","citation_count":124,"is_preprint":false},{"pmid":"22366374","id":"PMC_22366374","title":"HIF-1 versus HIF-2--is one more important than the other?","date":"2012","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22366374","citation_count":123,"is_preprint":false},{"pmid":"15313390","id":"PMC_15313390","title":"HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs.","date":"2004","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15313390","citation_count":119,"is_preprint":false},{"pmid":"27191891","id":"PMC_27191891","title":"SETD2: an epigenetic modifier with tumor suppressor functionality.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27191891","citation_count":119,"is_preprint":false},{"pmid":"17563752","id":"PMC_17563752","title":"Significance of HIF-1-active cells in angiogenesis and radioresistance.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17563752","citation_count":113,"is_preprint":false},{"pmid":"18325389","id":"PMC_18325389","title":"Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores.","date":"2007","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18325389","citation_count":112,"is_preprint":false},{"pmid":"30158902","id":"PMC_30158902","title":"HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30158902","citation_count":104,"is_preprint":false},{"pmid":"17627473","id":"PMC_17627473","title":"HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia.","date":"2007","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/17627473","citation_count":104,"is_preprint":false},{"pmid":"13678535","id":"PMC_13678535","title":"HIF-1 in cell cycle regulation, apoptosis, and tumor progression.","date":"2003","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/13678535","citation_count":101,"is_preprint":false},{"pmid":"28386724","id":"PMC_28386724","title":"Shaping the cellular landscape with Set2/SETD2 methylation.","date":"2017","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/28386724","citation_count":101,"is_preprint":false},{"pmid":"24735366","id":"PMC_24735366","title":"HIF-1 signaling in drug resistance to chemotherapy.","date":"2014","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24735366","citation_count":96,"is_preprint":false},{"pmid":"15456877","id":"PMC_15456877","title":"Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15456877","citation_count":95,"is_preprint":false},{"pmid":"26298291","id":"PMC_26298291","title":"HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26298291","citation_count":92,"is_preprint":false},{"pmid":"17878221","id":"PMC_17878221","title":"HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes.","date":"2007","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17878221","citation_count":91,"is_preprint":false},{"pmid":"26166446","id":"PMC_26166446","title":"BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies.","date":"2015","source":"Expert review of molecular diagnostics","url":"https://pubmed.ncbi.nlm.nih.gov/26166446","citation_count":90,"is_preprint":false},{"pmid":"16144691","id":"PMC_16144691","title":"Hypoxia and HIF-1 alpha in chondrogenesis.","date":"2005","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16144691","citation_count":84,"is_preprint":false},{"pmid":"11950150","id":"PMC_11950150","title":"The pVHL-hIF-1 system. A key mediator of oxygen homeostasis.","date":"2001","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/11950150","citation_count":83,"is_preprint":false},{"pmid":"17404504","id":"PMC_17404504","title":"HIF-1-regulated glucose metabolism: a key to apoptosis resistance?","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17404504","citation_count":79,"is_preprint":false},{"pmid":"27903434","id":"PMC_27903434","title":"Hypoxia and HIF-1 activation in bacterial infections.","date":"2016","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/27903434","citation_count":76,"is_preprint":false},{"pmid":"34228878","id":"PMC_34228878","title":"Regulation of redox signaling in HIF-1-dependent tumor angiogenesis.","date":"2021","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/34228878","citation_count":76,"is_preprint":false},{"pmid":"16144690","id":"PMC_16144690","title":"Neuroprotection by hypoxic preconditioning: HIF-1 and erythropoietin protect from retinal degeneration.","date":"2005","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16144690","citation_count":76,"is_preprint":false},{"pmid":"33401572","id":"PMC_33401572","title":"Flavonoids Targeting HIF-1: Implications on Cancer Metabolism.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33401572","citation_count":75,"is_preprint":false},{"pmid":"32335942","id":"PMC_32335942","title":"PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity.","date":"2021","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/32335942","citation_count":73,"is_preprint":false},{"pmid":"30808328","id":"PMC_30808328","title":"HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia.","date":"2019","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30808328","citation_count":73,"is_preprint":false},{"pmid":"31300513","id":"PMC_31300513","title":"Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis.","date":"2019","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/31300513","citation_count":70,"is_preprint":false},{"pmid":"32231741","id":"PMC_32231741","title":"Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32231741","citation_count":69,"is_preprint":false},{"pmid":"28159833","id":"PMC_28159833","title":"SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation.","date":"2017","source":"Cold Spring Harbor perspectives in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28159833","citation_count":69,"is_preprint":false},{"pmid":"18394600","id":"PMC_18394600","title":"Epigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18394600","citation_count":64,"is_preprint":false},{"pmid":"26346319","id":"PMC_26346319","title":"Modeling the interplay between the HIF-1 and p53 pathways in hypoxia.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26346319","citation_count":63,"is_preprint":false},{"pmid":"31217867","id":"PMC_31217867","title":"HIF-1-VEGF-Notch mediates angiogenesis in temporomandibular joint osteoarthritis.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31217867","citation_count":62,"is_preprint":false},{"pmid":"30818762","id":"PMC_30818762","title":"Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30818762","citation_count":60,"is_preprint":false},{"pmid":"29531312","id":"PMC_29531312","title":"Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.","date":"2018","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29531312","citation_count":58,"is_preprint":false},{"pmid":"26899267","id":"PMC_26899267","title":"Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: A review.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26899267","citation_count":57,"is_preprint":false},{"pmid":"9140970","id":"PMC_9140970","title":"The HypB protein from Bradyrhizobium japonicum can store nickel and is required for the nickel-dependent transcriptional regulation of hydrogenase.","date":"1997","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9140970","citation_count":57,"is_preprint":false},{"pmid":"36253570","id":"PMC_36253570","title":"PBRM1, SETD2 and BAP1 - the trinity of 3p in clear cell renal cell carcinoma.","date":"2022","source":"Nature reviews. Urology","url":"https://pubmed.ncbi.nlm.nih.gov/36253570","citation_count":56,"is_preprint":false},{"pmid":"18708172","id":"PMC_18708172","title":"HIF-1 and ventilatory acclimatization to chronic hypoxia.","date":"2008","source":"Respiratory physiology & neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18708172","citation_count":53,"is_preprint":false},{"pmid":"36453584","id":"PMC_36453584","title":"Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36453584","citation_count":52,"is_preprint":false},{"pmid":"25823824","id":"PMC_25823824","title":"Temporal regulation of HIF-1 and NF-κB in hypoxic hepatocarcinoma cells.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25823824","citation_count":51,"is_preprint":false},{"pmid":"20958262","id":"PMC_20958262","title":"HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention.","date":"2011","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20958262","citation_count":50,"is_preprint":false},{"pmid":"22179820","id":"PMC_22179820","title":"Metallo-GTPase HypB from Helicobacter pylori and its interaction with nickel chaperone protein HypA.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22179820","citation_count":47,"is_preprint":false},{"pmid":"12485909","id":"PMC_12485909","title":"ERK and calcium in activation of HIF-1.","date":"2002","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12485909","citation_count":47,"is_preprint":false},{"pmid":"26646321","id":"PMC_26646321","title":"Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26646321","citation_count":47,"is_preprint":false},{"pmid":"18269201","id":"PMC_18269201","title":"The role of HIF-1 in hypoxic response in the skeletal muscle.","date":"2007","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/18269201","citation_count":46,"is_preprint":false},{"pmid":"28894274","id":"PMC_28894274","title":"KDM4A regulates HIF-1 levels through H3K9me3.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28894274","citation_count":45,"is_preprint":false},{"pmid":"31988284","id":"PMC_31988284","title":"SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31988284","citation_count":44,"is_preprint":false},{"pmid":"15326390","id":"PMC_15326390","title":"Raising the bar: how HIF-1 helps determine tumor radiosensitivity.","date":"2004","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/15326390","citation_count":44,"is_preprint":false},{"pmid":"33008892","id":"PMC_33008892","title":"The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33008892","citation_count":43,"is_preprint":false},{"pmid":"35661267","id":"PMC_35661267","title":"SETD2: from chromatin modifier to multipronged regulator of the genome and beyond.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35661267","citation_count":43,"is_preprint":false},{"pmid":"31350389","id":"PMC_31350389","title":"The histone methyltransferase Setd2 is indispensable for V(D)J recombination.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31350389","citation_count":43,"is_preprint":false},{"pmid":"28004126","id":"PMC_28004126","title":"The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization.","date":"2016","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/28004126","citation_count":42,"is_preprint":false},{"pmid":"14562758","id":"PMC_14562758","title":"HIF-1 alpha and VEGF expression after transient global cerebral ischemia.","date":"2003","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/14562758","citation_count":41,"is_preprint":false},{"pmid":"24899725","id":"PMC_24899725","title":"Regulation of the VHL/HIF-1 pathway by DJ-1.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24899725","citation_count":38,"is_preprint":false},{"pmid":"24412394","id":"PMC_24412394","title":"Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin.","date":"2014","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/24412394","citation_count":37,"is_preprint":false},{"pmid":"35473600","id":"PMC_35473600","title":"Interaction between AhR and HIF-1 signaling pathways mediated by ARNT/HIF-1β.","date":"2022","source":"BMC pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35473600","citation_count":36,"is_preprint":false},{"pmid":"27031712","id":"PMC_27031712","title":"HIF-1--a big chapter in the cancer tale.","date":"2016","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27031712","citation_count":36,"is_preprint":false},{"pmid":"32372246","id":"PMC_32372246","title":"Dimethyloxalyl Glycine Regulates the HIF-1 Signaling Pathway in Mesenchymal Stem Cells.","date":"2020","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/32372246","citation_count":36,"is_preprint":false},{"pmid":"23899293","id":"PMC_23899293","title":"Metal transfer within the Escherichia coli HypB-HypA complex of hydrogenase accessory proteins.","date":"2013","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23899293","citation_count":35,"is_preprint":false},{"pmid":"29249820","id":"PMC_29249820","title":"SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.","date":"2017","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/29249820","citation_count":34,"is_preprint":false},{"pmid":"37989747","id":"PMC_37989747","title":"SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37989747","citation_count":33,"is_preprint":false},{"pmid":"30651591","id":"PMC_30651591","title":"Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer.","date":"2019","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30651591","citation_count":33,"is_preprint":false},{"pmid":"24507644","id":"PMC_24507644","title":"Neuroprotective effect of pAkt and HIF-1 α on ischemia rats.","date":"2014","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24507644","citation_count":33,"is_preprint":false},{"pmid":"36463230","id":"PMC_36463230","title":"Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36463230","citation_count":32,"is_preprint":false},{"pmid":"24558194","id":"PMC_24558194","title":"HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24558194","citation_count":32,"is_preprint":false},{"pmid":"37178248","id":"PMC_37178248","title":"HIF-1 signaling: an emerging mechanism for mitochondrial dynamics.","date":"2023","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37178248","citation_count":31,"is_preprint":false},{"pmid":"31043706","id":"PMC_31043706","title":"Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31043706","citation_count":31,"is_preprint":false},{"pmid":"39666822","id":"PMC_39666822","title":"Structural basis of H3K36 trimethylation by SETD2 during chromatin transcription.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39666822","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43392,"output_tokens":5132,"usd":0.103578,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13281,"output_tokens":5434,"usd":0.101127,"stage2_stop_reason":"end_turn"},"total_usd":0.204705,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"HYPB/SETD2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation (H3K36me3) in mammalian cells, but not H3K36 mono- or dimethylation. This was demonstrated by knockdown of HYPB/Setd2 in murine fibroblasts, which abolished H3K36me3 across c-fos and c-jun coding regions upon gene induction.\",\n      \"method\": \"siRNA knockdown of HYPB/Setd2 in murine fibroblasts combined with high-resolution ChIP mapping of histone modifications\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockdown with specific chromatin phenotype, replicated conceptually across multiple subsequent studies, specific separation of me1/me2 from me3 activity\",\n      \"pmids\": [\"18157086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IWS1 (Iws1) recruits HYPB/SETD2 to the RNA polymerase II elongation complex via Spt6, and this recruitment is required for H3K36me3 across transcribed gene bodies. Knockdown of HYPB/SETD2 also caused nuclear accumulation of poly(A)+ mRNAs, indicating a role in mRNA export. Spt6 binds the CTD N-terminal consensus repeats and recruits Iws1, which bridges to HYPB/SETD2, forming a megacomplex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Iws1 and HYPB/Setd2, ChIP for H3K36me3 across c-Myc, HIV-1, PABPC1 genes; in vitro binding assay (recombinant Spt6 binding to CTD)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro reconstitution of Spt6-CTD interaction, knockdown with two orthogonal phenotypic readouts (ChIP + mRNA export), multiple genes tested\",\n      \"pmids\": [\"19141475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Homozygous knockout of Hypb/Setd2 in mice impairs H3K36 trimethylation (but not mono- or dimethylation) and causes embryonic lethality at E10.5–E11.5 with severe vascular remodeling defects. Hypb-deficient endothelial cells and embryonic bodies showed defects in cell migration and invasion, establishing an intrinsic role for Hypb in vascular development.\",\n      \"method\": \"Conditional knockout mouse model, immunofluorescence for histone modifications, tetraploid rescue experiment, siRNA knockdown in human endothelial cells, in vitro migration/invasion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — full KO mouse with multiple orthogonal phenotypic readouts (embryo, yolk sac, placenta, ES cell-derived bodies), tetraploid rescue controls, H3K36me3 specificity confirmed\",\n      \"pmids\": [\"20133625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SETD2 downregulation in human cells leads to intragenic (cryptic) transcription initiation at ~11% of active genes. SETD2 coordinates FACT complex (SPT16/SSRP1) recruitment to H3K36me3-containing nucleosomes and regulates nucleosome occupancy and histone H2B exchange during transcription elongation. Co-immunoprecipitation showed SPT16 associates with H3K36me3-containing chromatin.\",\n      \"method\": \"siRNA knockdown of SETD2 in human cells, RNA-seq for cryptic transcription, ChIP for nucleosome occupancy and H2B/H3, co-immunoprecipitation of SPT16 with H3K36me3 chromatin, live-cell imaging with transcription inhibition\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, ChIP, Co-IP, live imaging), single lab, clear mechanistic chain from SETD2 loss to FACT displacement to cryptic transcription\",\n      \"pmids\": [\"23325844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The WW domain of HYPB/SETD2 adopts an autoinhibitory closed conformation due to intramolecular binding of a C-terminal polyproline stretch to the WW core domain. This autoinhibitory structure regulates interaction between the HYPB WW domain and the proline-rich region (PRR) of huntingtin (Htt), as shown by NMR solution structure and immunofluorescence.\",\n      \"method\": \"NMR structure determination of the WW domain–polyproline complex, NMR chemical shift perturbation, immunofluorescence co-localization assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation by NMR perturbation and immunofluorescence, single lab but multiple orthogonal structural and cell-based methods\",\n      \"pmids\": [\"24412394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SETD2 inactivation in human cells drives a DNA hypermethylation phenotype with ectopic gains of H3K36me3 centered on intergenic regions adjacent to low-expressing genes, and poised enhancers of developmental genes are prominent hypermethylation targets. SETD2 mutant primary ccRCC, papillary RCC, and lung adenocarcinomas all show this hypermethylation phenotype, demonstrating that SETD2 mutations coordinate disruption of both the epigenome and transcriptome.\",\n      \"method\": \"Genome-wide DNA methylation profiling (array), ChIP-seq for H3K36me3, cell line-based SETD2 inactivation models (long-term and acute), primary tumor analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq and methylation profiling with multiple model systems and primary tumor validation, single lab\",\n      \"pmids\": [\"26646321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In MLL-rearranged leukemia, SETD2 inactivation leads to global reduction of H3K36me3 and further elevation of H3K79me2, revealing a crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis that deregulates tumor suppressors (e.g., ASXL1) and oncogenes (e.g., ERG) independently of canonical MLL fusion targets.\",\n      \"method\": \"ChIP-seq for H3K36me3 and H3K79me2, RNA-seq in SETD2-inactivated leukemia cells, patient sample analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with patient sample validation, single lab, mechanistic crosstalk between two histone marks identified\",\n      \"pmids\": [\"29249820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Setd2 deficiency in hematopoietic stem cells (HSCs) impairs self-renewal and competitive fitness, induces DNA replication stress (evidenced by activated E2F network and repressed Rrm2b expression), and eventually leads to myelodysplastic syndrome-like malignancy. Gene expression profiles of Setd2-deleted HSPCs partially overlap with Dnmt3a/Tet2 double-KO HSPCs, with activation of the Klf1-related erythroid pathway.\",\n      \"method\": \"Conditional Setd2 knockout mice, serial bone marrow transplantation, gene expression profiling, cell cycle analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with serial transplantation demonstrating functional HSC defects, multiple in vivo phenotypic readouts, mechanistic pathway identified\",\n      \"pmids\": [\"29531312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Setd2 acts as a tumor suppressor in KRAS-driven pancreatic carcinogenesis. Setd2 loss in acinar cells facilitates KRAS-induced acinar-to-ductal metaplasia through epigenetic dysregulation of Fbxw7 (reduced H3K36me3 at Fbxw7 locus). Setd2 ablation in pancreatic cancer cells enhances EMT via impaired epigenetic regulation of Ctnna1, and leads to sustained Akt activation through ECM production.\",\n      \"method\": \"PdxCreSetd2 flox/flox × KrasG12D conditional KO mice, CRISPR/Cas9 depletion in PDAC cells, RNA-seq and H3K36me3 ChIP-seq\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO combined with ChIP-seq and RNA-seq, CRISPR validation in cell lines, multiple downstream targets identified\",\n      \"pmids\": [\"31300513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Setd2 deficiency causes a severe developmental block of thymocytes at the DN3 stage by reducing H3K36me3 at the TCRβ locus, impairing RAG1 binding and V(D)J recombination. Similarly, Setd2 loss blocks B cell development at the pro-B stage by impairing immunoglobulin V(D)J rearrangement.\",\n      \"method\": \"Conditional Setd2 knockout mice, ChIP for H3K36me3 and RAG1 at TCRβ locus, flow cytometry for lymphocyte developmental stages, DSB repair assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with ChIP demonstrating direct H3K36me3 loss at TCRβ locus plus RAG1 recruitment defect, replicated in B cell compartment with mechanistic specificity\",\n      \"pmids\": [\"31350389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD2 trimethylates EZH2 on a specific lysine, promoting EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state (increased H3K27me3) enabling cells to acquire metastatic traits in prostate cancer. Metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression, linking metabolic and epigenetic pathways.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methyltransferase assay with recombinant proteins, knock-in mice with nonmethylatable EZH2 mutant and SETD2 mutant defective in EZH2 binding, H3K27me3 ChIP-seq, AMPK/FOXO3 pathway epistasis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methyltransferase reconstitution plus multiple mouse models plus ChIP-seq, identifies EZH2 as non-histone substrate of SETD2\",\n      \"pmids\": [\"32619406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD2 is an actin lysine methyltransferase that trimethylates lysine-68 of actin (ActK68me3) in cells via its interaction with huntingtin (HTT) and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration.\",\n      \"method\": \"Co-immunoprecipitation of SETD2-HTT-HIP1R complex, in vitro methyltransferase assay with purified actin and SETD2, mass spectrometry identification of ActK68me3, actin polymerization assays, cell migration assays with SETD2 knockdown/knockout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of actin methyltransferase activity, MS identification of modification site, cell biology functional readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33008892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD2 deficiency in renal clear cell carcinoma cells is associated with aberrant accumulation of free ATG12 and a distinct ATG12-containing complex, and with increased expression of a short ATG12 spliced isoform at the expense of the canonical long isoform. This impairs the ATG12 conjugation system and decreases autophagic flux, establishing a role for SETD2 as a regulator of alternative splicing of ATG12 and autophagy.\",\n      \"method\": \"SETD2 rescue and knockdown in RCC cells, western blot for ATG12 complexes, RT-PCR for ATG12 isoforms, autophagic flux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (rescue + knockdown), multiple readouts (splicing, protein complex, flux), single lab\",\n      \"pmids\": [\"31988284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Setd2 deficiency in pancreatic tumor cells leads to ectopic H3K27me3 gain at the Cxadr locus, downregulating Cxadr expression, which boosts PI3K-AKT signaling and excessive CXCL1 and GM-CSF secretion. This promotes recruitment and reprogramming of neutrophils toward an immunosuppressive phenotype, fostering CD8+ T cell inhibition and tumor immune escape.\",\n      \"method\": \"Setd2 conditional KO mouse model, comprehensive immune profiling of TME, H3K27me3 and H3K36me3 ChIP-seq at Cxadr locus, cytokine measurement (CXCL1, GM-CSF), neutrophil co-culture assays with CD8+ T cells\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model combined with ChIP-seq mechanistic data and functional immune assays, single lab\",\n      \"pmids\": [\"36453584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg cell survival and suppressive function by facilitating GATA3 and ST2 (IL1RL1) expression through H3K36me3 deposition at promoters and intragenic enhancers of target genes including Il1rl1. In human Treg cells, SETD2 sustains GATA3 expression.\",\n      \"method\": \"Foxp3Cre Setd2 conditional KO mice, H3K36me3 ChIP-seq at target gene loci, flow cytometry for Treg subsets, IL-33 stimulation assays, human Treg cell SETD2 knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP-seq mechanistic evidence and human validation, single lab\",\n      \"pmids\": [\"36463230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD2 loss in kidneys causes extensive metabolic reprogramming including enhanced sphingomyelin biosynthesis, which promotes PKD-to-ccRCC tumor transition. Inhibition of sphingomyelin biosynthesis with myriocin relieves tumor symptoms in Setd2 knockout mice, establishing a causal mechanistic link between SETD2 deficiency and sphingolipid metabolism in renal tumorigenesis.\",\n      \"method\": \"Conditional Setd2 KO mouse model (PKD-ccRCC transition), metabolomics, lipidomics, transcriptomics, proteomics; myriocin pharmacological rescue; clinical ccRCC patient specimen validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics in vivo KO model with pharmacological rescue, single lab but multiple orthogonal omics platforms\",\n      \"pmids\": [\"37989747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of mammalian RNA Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome elongation complexes reveal that SETD2 is positioned to methylate H3K36 on both downstream and upstream nucleosomes during transcription elongation. SPT6 binds the exposed H2A-H2B dimer on actively transcribed nucleosomes, and the SPT6 death-like domain mediates a direct interaction with SETD2 when it is bound to the upstream nucleosome.\",\n      \"method\": \"Cryo-electron microscopy structure determination of mammalian elongation complex with SETD2 and nucleosome\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with direct visualization of SETD2 positioning relative to nucleosome and SPT6 interaction interface\",\n      \"pmids\": [\"39666822\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SETD2 is the sole histone H3K36 trimethylase in mammals, recruited to the RNA Pol II elongation complex via IWS1-SPT6 (structurally visualized by cryo-EM); it deposits H3K36me3 co-transcriptionally to suppress cryptic transcription (by coordinating FACT-dependent nucleosome dynamics), regulate pre-mRNA splicing, support V(D)J recombination via RAG1 recruitment, and maintain DNA methylation patterning. Beyond histones, SETD2 methylates EZH2 (promoting its degradation and restraining H3K27me3) and trimethylates actin lysine-68 via a SETD2-HTT-HIP1R complex to regulate actin polymerization and cell migration, with loss-of-function driving tumor progression across multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SETD2 (HYPB) is the principal mammalian histone H3K36 trimethyltransferase, responsible for virtually all global and transcription-coupled H3K36me3 while leaving H3K36 mono- and dimethylation intact [#0]. It is recruited co-transcriptionally to the RNA polymerase II elongation complex through an IWS1–SPT6 bridge that engages the Pol II CTD, and cryo-EM of the mammalian elongation machinery shows SETD2 positioned to methylate H3K36 on both downstream and upstream nucleosomes, with the SPT6 death-like domain making a direct contact when SETD2 acts on the upstream nucleosome [#1, #16]. Through this activity SETD2 enforces correct chromatin dynamics during elongation: H3K36me3 coordinates FACT (SPT16/SSRP1) recruitment and nucleosome/H2B exchange to suppress cryptic intragenic transcription [#3], and SETD2 loss couples epigenome disruption to transcriptome dysregulation, producing DNA hypermethylation and ectopic gains of repressive marks [#5]. The same elongation-linked mark governs developmental programs, including V(D)J recombination, where H3K36me3 at the TCRβ locus licenses RAG1 binding so that Setd2 loss arrests thymocyte and B-cell development [#9], and immune-cell fate, where H3K36me3 sustains GATA3 and Il1rl1 expression in tissue Treg cells [#14]. Beyond histones, SETD2 has non-histone substrates: it trimethylates EZH2 to drive its degradation and restrain H3K27me3 [#10], and within a SETD2–HTT–HIP1R complex it trimethylates actin lysine-68 to regulate F-actin polymerization and cell migration [#11], the latter mediated by an autoinhibited WW domain that interacts with the huntingtin proline-rich region [#4]. Loss of SETD2 acts as a tumor suppressor across diverse cancers, driving replication stress and myelodysplasia in hematopoietic stem cells [#7], KRAS-driven pancreatic metaplasia and immune escape [#8, #13], and renal tumorigenesis linked to metabolic reprogramming [#15], establishing SETD2 as an integrator of transcription, chromatin, splicing, cytoskeletal regulation, and tumor suppression.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established which enzyme deposits H3K36me3 in mammals, resolving the source of the transcription-associated trimethyl mark versus lower methylation states.\",\n      \"evidence\": \"siRNA knockdown of HYPB/Setd2 in murine fibroblasts with high-resolution ChIP across induced c-fos/c-jun\",\n      \"pmids\": [\"18157086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how SETD2 is targeted to transcribed genes\", \"Mechanism distinguishing me3 from me1/me2 deposition unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Answered how SETD2 reaches active gene bodies by identifying the IWS1–SPT6 bridge to elongating Pol II, and linked the enzyme to mRNA export.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown of Iws1/SETD2 with ChIP, in vitro Spt6–CTD binding across multiple genes\",\n      \"pmids\": [\"19141475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the megacomplex not resolved\", \"Mechanism connecting H3K36me3 to poly(A)+ mRNA export not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated the physiological requirement for SETD2/H3K36me3 in vivo through embryonic lethality with vascular and migration defects.\",\n      \"evidence\": \"Conditional Setd2 knockout mice, tetraploid rescue, IF, endothelial migration/invasion assays\",\n      \"pmids\": [\"20133625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint the H3K36me3 target genes driving vascular defects\", \"Cell-migration link to a direct molecular mechanism not established at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistically connected H3K36me3 to suppression of cryptic transcription via FACT-dependent nucleosome dynamics during elongation.\",\n      \"evidence\": \"siRNA knockdown with RNA-seq for cryptic initiation, nucleosome/H2B ChIP, SPT16 Co-IP, live imaging\",\n      \"pmids\": [\"23325844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical reader linking H3K36me3 to FACT recruitment not isolated\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SETD2 loss couples epigenome and transcriptome disruption by producing DNA hypermethylation and ectopic H3K36me3 gains, generalizable across tumor types.\",\n      \"evidence\": \"Genome-wide methylation arrays and H3K36me3 ChIP-seq in cell models plus primary RCC and lung tumors\",\n      \"pmids\": [\"26646321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking H3K36me3 loss to DNA hypermethylation not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed crosstalk between the SETD2-H3K36me3 axis and the DOT1L-H3K79me2 axis in leukemia, expanding how SETD2 loss deregulates oncogenes and tumor suppressors.\",\n      \"evidence\": \"H3K36me3/H3K79me2 ChIP-seq and RNA-seq in SETD2-inactivated leukemia cells with patient samples\",\n      \"pmids\": [\"29249820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of H3K79me2 elevation upon H3K36me3 loss not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a tumor-suppressive role in hematopoiesis, showing SETD2 loss induces replication stress and progresses to MDS-like malignancy.\",\n      \"evidence\": \"Conditional Setd2 KO mice, serial bone-marrow transplantation, expression profiling, cell-cycle analysis\",\n      \"pmids\": [\"29531312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct H3K36me3 targets driving replication stress not pinpointed\", \"Overlap with Dnmt3a/Tet2 pathways only partial\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SETD2 as a tumor suppressor in KRAS-driven pancreatic carcinogenesis acting through H3K36me3-dependent regulation of specific loci.\",\n      \"evidence\": \"PdxCre Setd2 flox × KrasG12D mice, CRISPR depletion in PDAC cells, H3K36me3 ChIP-seq and RNA-seq\",\n      \"pmids\": [\"31300513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Fbxw7, Ctnna1, and Akt arms not dissected\", \"Mechanism of sustained Akt activation via ECM incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed H3K36me3 directly licenses antigen-receptor recombination by enabling RAG1 binding, explaining lymphocyte developmental arrest upon SETD2 loss.\",\n      \"evidence\": \"Conditional Setd2 KO mice, H3K36me3 and RAG1 ChIP at TCRβ, flow cytometry, DSB repair assays\",\n      \"pmids\": [\"31350389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAG1 directly reads H3K36me3 or requires a reader not established\", \"Generality across all antigen-receptor loci not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the first non-histone protein substrate, EZH2, defining a methylation-degradation circuit that restrains H3K27me3 and metastasis, with metabolic input via AMPK-FOXO3.\",\n      \"evidence\": \"Co-IP, in vitro methyltransferase assay, knock-in mice with nonmethylatable EZH2 and EZH2-binding-defective SETD2, H3K27me3 ChIP-seq\",\n      \"pmids\": [\"32619406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The EZH2 lysine site and degradation machinery details not fully specified here\", \"Tissue scope of the EZH2 axis beyond prostate not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended SETD2 catalytic scope to the cytoskeleton, showing it trimethylates actin K68 within a HTT-HIP1R complex to control polymerization and migration.\",\n      \"evidence\": \"Co-IP of SETD2-HTT-HIP1R, in vitro methyltransferase assay on purified actin, MS site identification, polymerization and migration assays\",\n      \"pmids\": [\"33008892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular pool of SETD2 performing actin methylation not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a structural basis for SETD2 regulation, showing an autoinhibited WW domain governing the huntingtin interaction.\",\n      \"evidence\": \"NMR structure of WW–polyproline complex, chemical shift perturbation, IF co-localization\",\n      \"pmids\": [\"24412394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How autoinhibition is relieved in cells not defined\", \"Functional consequence for catalysis not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated SETD2 in alternative splicing control, linking its loss to defective ATG12 conjugation and reduced autophagic flux in RCC.\",\n      \"evidence\": \"SETD2 rescue/knockdown in RCC cells, western blot of ATG12 complexes, RT-PCR isoforms, autophagy flux assays\",\n      \"pmids\": [\"31988284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link from H3K36me3 to ATG12 splicing not mechanistically demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SETD2 loss to tumor immune escape via H3K27me3-mediated Cxadr silencing, PI3K-AKT activation, and immunosuppressive neutrophil reprogramming.\",\n      \"evidence\": \"Setd2 conditional KO mice, immune profiling, H3K27me3/H3K36me3 ChIP-seq at Cxadr, cytokine assays, neutrophil–CD8 co-culture\",\n      \"pmids\": [\"36453584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism converting H3K36me3 loss to H3K27me3 gain at Cxadr not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SETD2 sustains tissue Treg identity and suppressive function through H3K36me3 at GATA3 and Il1rl1 regulatory elements.\",\n      \"evidence\": \"Foxp3Cre Setd2 KO mice, H3K36me3 ChIP-seq, flow cytometry, IL-33 stimulation, human Treg knockdown\",\n      \"pmids\": [\"36463230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GATA3/Il1rl1 are direct primary targets vs downstream effects not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked SETD2 deficiency to metabolic reprogramming, identifying sphingomyelin biosynthesis as a causal, druggable driver of renal tumor transition.\",\n      \"evidence\": \"Conditional Setd2 KO PKD-ccRCC mice, multi-omics, myriocin pharmacological rescue, patient validation\",\n      \"pmids\": [\"37989747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets controlling sphingolipid genes not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the structural architecture of SETD2 within the Pol II elongation complex, explaining how it accesses both upstream and downstream nucleosomes via SPT6.\",\n      \"evidence\": \"Cryo-EM of mammalian Pol II–DSIF–SPT6–PAF1c–TFIIS–IWS1–SETD2–nucleosome complexes\",\n      \"pmids\": [\"39666822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic conformational cycle during translocation not captured\", \"Regulation of SETD2 dwell time per nucleosome unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SETD2 substrate selection (histone H3K36 vs EZH2 vs actin) is partitioned across cellular compartments and signaling states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for how one enzyme selects histone vs non-histone substrates\", \"Compartment-specific regulation of catalytic activity not defined\", \"Direct readers translating H3K36me3 to DNA methylation and splicing outcomes incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [\n      \"RNA Pol II elongation complex (with IWS1-SPT6)\",\n      \"SETD2-HTT-HIP1R complex\"\n    ],\n    \"partners\": [\n      \"IWS1\",\n      \"SPT6\",\n      \"SPT16\",\n      \"EZH2\",\n      \"HTT\",\n      \"HIP1R\",\n      \"RAG1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}