{"gene":"SETD5","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2019,"finding":"SETD5 directly deposits H3K36me3 on active gene bodies genome-wide; Setd5 inactivation in neural stem cells, zebrafish, and mice reduces H3K36me3, impairs RNA elongation dynamics, and causes abnormal transcription with defective RNA maturation and splicing.","method":"ChIP-seq, genetic KO/haploinsufficiency in mice and zebrafish, RNA-seq, in vitro assays in neural stem cells","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, genetic models in three systems), replicated across neural stem cells, zebrafish, and mice in a single rigorous study","pmids":["31515109"],"is_preprint":false},{"year":2016,"finding":"SETD5 co-immunoprecipitates with multiple components of the PAF1 co-transcriptional complex and the HDAC-containing NCoR co-repressor complex; in its absence, histone acetylation is increased at transcription start sites and downstream regions, indicating SETD5 regulates co-transcriptional histone acetylation rather than solely histone methylation.","method":"Co-immunoprecipitation, histone modification analysis (ChIP), genetic KO in mouse embryos and ESCs","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with PAF1 and NCoR complex components, plus ChIP-based histone acetylation phenotype in KO cells; single lab but multiple orthogonal methods","pmids":["27864380"],"is_preprint":false},{"year":2020,"finding":"SETD5 lacks histone methyltransferase activity but functions as a scaffold for a co-repressor complex containing HDAC3 and G9a; this SETD5 complex silences gene expression to drive adaptive resistance to MEK1/2 inhibition in pancreatic cancer.","method":"In vitro enzymatic assay (no HMT activity detected), co-immunoprecipitation, genetic deletion in mouse models and patient-derived xenografts, pharmacological co-targeting","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct enzymatic assay establishing lack of HMT activity, Co-IP of HDAC3/G9a complex, in vivo rescue experiments; single lab but multiple orthogonal methods","pmids":["32442403"],"is_preprint":false},{"year":2020,"finding":"SETD5 recruits the HDAC3 complex to the rDNA promoter, resulting in removal of H4K16ac and its reader protein TIP5 (a repressor of rDNA expression), thereby positively regulating rDNA transcription, translational activity, and neural cell proliferation; cyclin D1 mRNA translation is specifically down-regulated in SETD5-insufficient cells, and TIP5 ablation rescues these effects.","method":"Co-immunoprecipitation (SETD5–HDAC3), ChIP (H4K16ac, TIP5 at rDNA promoter), siRNA knockdown, rescue by TIP5 depletion, ribosome profiling/translation assays in Setd5+/- mouse brain","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP at rDNA locus, genetic epistasis rescue experiment (TIP5 KD reverses SETD5 KD phenotype); single lab with multiple orthogonal methods","pmids":["32299058"],"is_preprint":false},{"year":2021,"finding":"SETD5 forms a complex with NCoR-HDAC3 that maintains enhancers for Cebpa and Pparg in a hypoacetylated primed state during early adipogenesis; APC/C-mediated ubiquitin-proteasome degradation of SETD5, triggered by CDC20 induction, releases this repression and enables enhancer hyperacetylation and adipogenic gene activation.","method":"Co-immunoprecipitation (SETD5–NCoR–HDAC3), ChIP-seq (histone acetylation at enhancers), SETD5 protein degradation assays, genetic/pharmacological inhibition of APC/C-CDC20","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, ChIP-seq for enhancer acetylation, identification of CDC20/APC/C-mediated degradation; single lab with multiple orthogonal methods","pmids":["34857762"],"is_preprint":false},{"year":2021,"finding":"SETD5 regulates HSC quiescence by mediating release of promoter-proximal paused RNA polymerase II (Pol II) on E2F target genes, and this function requires cooperation with HCF-1 and the PAF1 complex; Setd5-deficient HSCs show disrupted quiescence and exhaustion under transplantation pressure.","method":"Conditional KO (Setd5 in hematopoietic system), RNA-seq, ChIP for paused Pol II, Co-IP (SETD5–HCF-1–PAF1), transplantation assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying HCF-1/PAF1 partnership, Pol II pausing ChIP, conditional KO phenotype; single lab with multiple methods but mechanistic resolution limited by abstract detail","pmids":["34853439"],"is_preprint":false},{"year":2018,"finding":"SETD5 controls Sema3A expression independently of its SET domain and co-immunoprecipitates with the bromodomain protein BRD2; both SETD5 and BRD2 bind to the transcription start site and upstream promoter regions of the Sema3a locus, and BRD2 is required for SETD5-mediated regulation of Sema3A.","method":"Co-immunoprecipitation (SETD5–BRD2), ChIP at Sema3a locus, SET-domain deletion mutant analysis, in vitro cell culture with miR-126-5p manipulation","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of SETD5–BRD2, ChIP at Sema3a, SET-domain-independent function established by mutant; single lab with two orthogonal methods","pmids":["29180574"],"is_preprint":false},{"year":2022,"finding":"The SET domain of SETD5 is essential for both retinal cell survival and proliferation; a truncation mutant (SETD5S1257*) that cannot interact with HDAC3 and PAF1 complexes rescues proliferation but not apoptosis caused by Setd5 knockdown, indicating the SETD5–HDAC3/PAF1 interaction is specifically required for the pro-survival function.","method":"shRNA knockdown in mouse retinal explants, structure-function analysis with SET-domain deletion and S1257* truncation mutants, histology/immunostaining","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutant rescue experiments dissecting two functions; single lab, single organism model","pmids":["36349512"],"is_preprint":false},{"year":2025,"finding":"SETD5 methylates nuclear LC3B at lysines 5 and 65, causing its nuclear retention; methylated LC3B then binds transcription factor PRDM10 at promoters of ATG genes (ATG2a, ATG7, ATG12, ATG16L1), suppressing their transcription and reducing autophagosome formation in ovarian cancer cells.","method":"Co-IP (SETD5–LC3B), in vitro methylation assay, site-directed mutagenesis of LC3B K5/K65, ChIP (LC3B/PRDM10 at ATG promoters), autophagy flux assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro methylation assay + mutagenesis + ChIP establish mechanism, but single lab and limited replication","pmids":["40497358"],"is_preprint":false},{"year":2023,"finding":"SETD5 mediates O-GlcNAc transferase (OGT)-catalyzed O-GlcNAcylation of RNA Pol II; SETD5–Pol II interaction weakens in OGT-depleted cells, and SETD5 loss reduces Pol II occupancy at PI3K-AKT pathway genes and CD133 promoters in colorectal cancer cells.","method":"Co-IP (SETD5–Pol II, SETD5–OGT), OGT depletion affecting Pol II glycosylation, ChIP (Pol II at gene promoters), KD/OE of SETD5","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and ChIP supporting functional interdependence of SETD5, OGT, and Pol II; single lab, single paper","pmids":["37963940"],"is_preprint":false},{"year":2023,"finding":"SETD5 as H3K36me3 writer facilitates METTL14-dependent m6A modification and YTHDF1 recruitment to PKM2 mRNA, mediating PKM2 nuclear translocation and phosphorylation (Tyr105), which regulates GPX4-mediated ferroptosis resistance and SOX9-mediated stemness in NSCLC.","method":"m6A-seq, RIP, Co-IP, nuclear fractionation, site-specific phosphorylation detection, KD/OE in vitro and in vivo","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — complex mechanistic chain claimed in a single paper with limited methodological detail in abstract; single lab, no independent replication","pmids":["40307507"],"is_preprint":false},{"year":2014,"finding":"miR-126-5p represses SETD5 expression in endothelial cells; loss of SETD5 repression (via target protectors blocking miR-126-5p/SetD5 mRNA pairing) reduces leucocyte adhesion, identifying SetD5 as a functional target of miR-126-5p that promotes leucocyte adhesion when expressed.","method":"Gain- and loss-of-function of miR-126-5p, target protectors (miRNA/mRNA pairing disruption), leucocyte adhesion assays","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — target-protector approach specifically demonstrates SETD5's role downstream of miR-126-5p; functional cell biology readout; single lab","pmids":["24562769"],"is_preprint":false},{"year":2025,"finding":"TBLR1 physically connects SETD5 and ANKRD11 to the NCoR complex, forming an assembly that resembles the yeast SET3 complex (SET3C); pathogenic missense mutations in SETD5 disrupt this assembly; an engineered mutation specifically abolishing SETD5 incorporation into SET3C causes severe developmental impairments in mice; SET3C disruption produces highly correlated gene expression changes including upregulation of highly transcribed genes.","method":"Co-IP/protein interaction mapping, engineered mouse mutation, transcriptomics in multiple NDD models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction mapping plus in vivo engineered mutation phenotype; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.30.657039"],"is_preprint":true},{"year":2025,"finding":"ANKRD11 interacts with the Setd5 promoter and recruits WDR5 (a component of the H3K4 methyltransferase complex) to promote H3K4 methylation and SETD5 transcription; ANKRD11-deficient neural cells have reduced H3K4 methylation at the Setd5 promoter, reduced SETD5 expression, and consequently reduced rRNA and translation, which is rescued by SETD5 overexpression.","method":"ChIP (ANKRD11/WDR5/H3K4me at Setd5 promoter), genetic KD/OE, rRNA quantification, translation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and genetic rescue experiments define ANKRD11→H3K4me→SETD5→rRNA axis; single lab with multiple orthogonal methods","pmids":["40520101"],"is_preprint":false},{"year":2021,"finding":"Setd5 is required in cardiopharyngeal mesoderm for heart development; conditional deletion in this lineage causes failure of heart tube ballooning, leading to double outlet right ventricle and ventricular septal defect; no genetic interaction with Tbx1 was detected.","method":"Conditional mutagenesis (Cre-lox), cardiac phenotype analysis, genetic epistasis with Tbx1 (negative result)","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO in specific lineage with defined phenotype, plus negative epistasis result; single lab","pmids":["34050709"],"is_preprint":false},{"year":2026,"finding":"SETD5-deficient human astrocytes (hiPSC-derived) show elevated extracellular IL-6 and ROS; elevated IL-6 exerts non-cell-autonomous harm to healthy neurons; JAK/STAT pathway inhibition restores IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits.","method":"hiPSC-derived astrocyte KO, conditioned medium transfer to neurons, cytokine measurement, pharmacological JAK/STAT inhibition rescue","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell biology with pharmacological rescue; preprint, single lab, limited mechanistic depth in abstract","pmids":["41993368"],"is_preprint":true}],"current_model":"SETD5 is a SET-domain-containing protein that directly deposits H3K36me3 on active gene bodies to regulate RNA elongation and splicing, and also scaffolds a multi-subunit co-repressor complex (NCoR–HDAC3, PAF1, and, with TBLR1/ANKRD11, a mammalian SET3C-like assembly) that controls histone acetylation at enhancers and promoters, Pol II pausing, rDNA transcription via HDAC3-mediated H4K16ac removal, and LC3B methylation to suppress autophagy, with its own levels regulated by APC/C-CDC20-mediated proteasomal degradation; haploinsufficiency of SETD5 in neurons and neural progenitors disrupts H3K36me3 levels, transcriptional fidelity, synaptic connectivity, and mitochondrial homeostasis, collectively causing the neurodevelopmental phenotypes associated with intellectual disability and autism spectrum disorder."},"narrative":{"mechanistic_narrative":"SETD5 is a chromatin regulator that couples transcriptional output to histone modification at active genes and developmental loci, with its disruption driving neurodevelopmental disease [PMID:31515109, PMID:bio_10.1101_2025.05.30.657039]. Although it carries a SET domain and deposits H3K36me3 on active gene bodies to support proper RNA elongation, maturation, and splicing [PMID:31515109], a parallel body of work shows SETD5 also acts largely as a scaffold that nucleates HDAC-containing co-repressor assemblies: it co-immunoprecipitates with the PAF1 co-transcriptional complex and the NCoR–HDAC3 co-repressor complex, and its loss raises histone acetylation around transcription start sites [PMID:27864380]. Through HDAC3 recruitment it represses target chromatin in multiple contexts — silencing genes to drive MEK-inhibitor resistance in pancreatic cancer [PMID:32442403], removing H4K16ac and the repressor TIP5 at the rDNA promoter to positively control rRNA transcription and translation [PMID:32299058], and holding adipogenic enhancers (Cebpa, Pparg) in a hypoacetylated primed state until APC/C-CDC20 triggers SETD5 proteasomal degradation [PMID:34857762]. SETD5 further controls release of promoter-proximal paused RNA Pol II at E2F target genes in cooperation with HCF-1 and PAF1 [PMID:34853439]. TBLR1 bridges SETD5 and ANKRD11 into a mammalian SET3C-like assembly within the NCoR complex, and pathogenic SETD5 missense mutations or engineered mutations that block SETD5 incorporation into SET3C cause severe developmental impairment [PMID:bio_10.1101_2025.05.30.657039]; reciprocally, ANKRD11 recruits WDR5 to the Setd5 promoter to drive SETD5 transcription and downstream rRNA synthesis [PMID:40520101]. SET-domain-independent activities include regulation of Sema3A expression via the bromodomain protein BRD2 [PMID:29180574]. Structure-function dissection shows the SETD5–HDAC3/PAF1 interaction is specifically required for cell survival, whereas proliferation can be supported independently [PMID:36349512].","teleology":[{"year":2014,"claim":"Established SETD5 as a functionally regulated gene whose expression has cell-biological consequences, providing an early handle on its role before its chromatin mechanism was known.","evidence":"miR-126-5p gain/loss-of-function with target protectors and leucocyte adhesion assays in endothelial cells","pmids":["24562769"],"confidence":"Medium","gaps":["Does not define a molecular activity for SETD5","No chromatin or complex data"]},{"year":2016,"claim":"Revealed that SETD5 acts not solely as a methyltransferase but as a regulator of co-transcriptional histone acetylation through physical association with PAF1 and the NCoR–HDAC3 co-repressor complex.","evidence":"Reciprocal Co-IP with PAF1 and NCoR components plus ChIP for histone acetylation in KO mouse embryos and ESCs","pmids":["27864380"],"confidence":"High","gaps":["Did not resolve whether SETD5 has intrinsic catalytic activity","Direct vs. indirect recruitment of HDAC complex unresolved"]},{"year":2018,"claim":"Demonstrated a SET-domain-independent gene-regulatory function, showing SETD5 partners with BRD2 to control a specific developmental target gene.","evidence":"Co-IP of SETD5–BRD2, ChIP at the Sema3a locus, and SET-domain deletion mutant analysis","pmids":["29180574"],"confidence":"Medium","gaps":["Generality beyond Sema3a unknown","Mechanism of BRD2 dependence not resolved"]},{"year":2019,"claim":"Provided the strongest evidence that SETD5 directly deposits H3K36me3 on active gene bodies and that its loss impairs RNA elongation, maturation, and splicing, linking the enzyme to transcriptional fidelity in neural development.","evidence":"ChIP-seq, RNA-seq, and genetic KO/haploinsufficiency across neural stem cells, zebrafish, and mice","pmids":["31515109"],"confidence":"High","gaps":["Apparent conflict with reports of absent HMT activity not reconciled","Direct vs. indirect contribution to H3K36me3 not fully isolated"]},{"year":2020,"claim":"Reframed SETD5 as a catalytically inactive scaffold for an HDAC3/G9a co-repressor complex that silences genes to confer therapeutic resistance, directly challenging the methyltransferase model.","evidence":"In vitro enzymatic assay showing no HMT activity, Co-IP of HDAC3/G9a, and genetic deletion plus pharmacological co-targeting in pancreatic cancer models","pmids":["32442403"],"confidence":"High","gaps":["Does not reconcile with H3K36me3-deposition findings","Scope of scaffold vs. enzymatic roles across tissues unclear"]},{"year":2020,"claim":"Connected SETD5–HDAC3 recruitment to a defined locus, showing it strips H4K16ac and the repressor TIP5 from the rDNA promoter to positively regulate rRNA transcription, translation, and neural proliferation.","evidence":"Co-IP, ChIP at rDNA promoter, siRNA knockdown, and TIP5-depletion epistasis rescue with ribosome profiling in Setd5+/- mouse brain","pmids":["32299058"],"confidence":"High","gaps":["How SETD5 is targeted to rDNA not defined","Link between rDNA control and behavioral phenotypes indirect"]},{"year":2021,"claim":"Showed SETD5 protein abundance is itself controlled by APC/C-CDC20-mediated degradation, providing a switch that converts primed hypoacetylated enhancers into active ones during adipogenesis.","evidence":"Co-IP of SETD5–NCoR–HDAC3, ChIP-seq for enhancer acetylation, and degradation assays with APC/C-CDC20 inhibition","pmids":["34857762"],"confidence":"High","gaps":["Degron and ubiquitination sites on SETD5 not mapped","Generality of APC/C control beyond adipogenesis unknown"]},{"year":2021,"claim":"Defined a Pol II pause-release function for SETD5 at E2F targets requiring HCF-1 and PAF1, linking the protein to cell quiescence control in hematopoietic stem cells.","evidence":"Conditional KO, RNA-seq, paused-Pol II ChIP, Co-IP of SETD5–HCF-1–PAF1, and transplantation assays","pmids":["34853439"],"confidence":"Medium","gaps":["Mechanistic resolution limited","Direct vs. indirect role in pause release unresolved"]},{"year":2021,"claim":"Established a lineage-specific developmental requirement for Setd5 in cardiopharyngeal mesoderm during heart morphogenesis.","evidence":"Conditional Cre-lox deletion with cardiac phenotyping and negative genetic epistasis with Tbx1","pmids":["34050709"],"confidence":"Medium","gaps":["Molecular mechanism in cardiac lineage not defined","Relevant chromatin targets unknown"]},{"year":2022,"claim":"Dissected SETD5 into separable functions, showing the SETD5–HDAC3/PAF1 interaction is specifically required for cell survival while proliferation can be supported by a truncation mutant lacking it.","evidence":"shRNA knockdown in mouse retinal explants with SET-domain deletion and S1257* truncation mutant rescue","pmids":["36349512"],"confidence":"Medium","gaps":["Molecular basis of the survival-specific requirement unclear","Single organ system"]},{"year":2023,"claim":"Tied SETD5 to RNA Pol II modification by linking SETD5–Pol II association to OGT-catalyzed O-GlcNAcylation in colorectal cancer.","evidence":"Co-IP of SETD5–Pol II and SETD5–OGT, OGT depletion, and Pol II ChIP at target promoters","pmids":["37963940"],"confidence":"Medium","gaps":["Causal direction between SETD5 and OGT activity not resolved","Single lab, single cancer context"]},{"year":2023,"claim":"Placed SETD5 H3K36me3 writing upstream of an m6A/PKM2 metabolic axis influencing ferroptosis and stemness in lung cancer.","evidence":"m6A-seq, RIP, Co-IP, nuclear fractionation, and KD/OE in vitro and in vivo","pmids":["40307507"],"confidence":"Low","gaps":["Complex mechanistic chain claimed in a single paper without independent replication","Each step in the cascade not isolated"]},{"year":2025,"claim":"Identified TBLR1 as the bridge assembling SETD5 and ANKRD11 into a mammalian SET3C-like complex and showed that disrupting SETD5 incorporation causes severe developmental defects, unifying two NDD genes in one assembly.","evidence":"Protein interaction mapping, engineered mouse mutation, and transcriptomics across NDD models (preprint)","pmids":["bio_10.1101_2025.05.30.657039"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural organization of mammalian SET3C not resolved"]},{"year":2025,"claim":"Established a feedback loop in which ANKRD11 recruits WDR5 to the Setd5 promoter to drive H3K4 methylation, SETD5 transcription, and downstream rRNA synthesis.","evidence":"ChIP of ANKRD11/WDR5/H3K4me at the Setd5 promoter, genetic KD/OE, rRNA and translation assays with SETD5-overexpression rescue","pmids":["40520101"],"confidence":"Medium","gaps":["Whether this loop operates outside neural cells unknown","Single lab"]},{"year":2025,"claim":"Extended SETD5 methyltransferase activity to a non-histone substrate, showing it methylates nuclear LC3B to suppress autophagy gene transcription via PRDM10.","evidence":"In vitro methylation assay, LC3B K5/K65 mutagenesis, Co-IP, ChIP at ATG promoters, and autophagy flux assays in ovarian cancer cells","pmids":["40497358"],"confidence":"Medium","gaps":["Reconciliation with reports of absent HMT activity not addressed","Single lab, limited replication"]},{"year":2026,"claim":"Demonstrated a non-cell-autonomous disease mechanism in which SETD5-deficient astrocytes secrete IL-6 that harms neurons, rescuable by JAK/STAT inhibition.","evidence":"hiPSC-derived astrocyte KO, conditioned-medium transfer, cytokine measurement, and pharmacological rescue (preprint)","pmids":["41993368"],"confidence":"Low","gaps":["Preprint, single lab","How SETD5 loss drives IL-6/ROS molecularly not defined"]},{"year":null,"claim":"The central unresolved question is reconciling SETD5's reported intrinsic methyltransferase activity (on H3K36 and LC3B) with the in vitro evidence that it lacks HMT activity and acts primarily as an HDAC-complex scaffold.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the SETD5 SET domain catalytic state","Direct vs. scaffold contributions to chromatin marks not cleanly separated","Substrate determinants for any catalytic activity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,4,8]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]}],"complexes":["NCoR-HDAC3 co-repressor complex","PAF1 complex","SET3C-like complex (SETD5-TBLR1-ANKRD11)"],"partners":["HDAC3","PAF1","NCOR","G9A","BRD2","HCF-1","TBLR1","ANKRD11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0A6","full_name":"Histone-lysine N-methyltransferase SETD5","aliases":["SET domain-containing protein 5"],"length_aa":1442,"mass_kda":157.5,"function":"Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. May act by mediating trimethylation of 'Lys-36' of histone H3 (H3K36me3), which is essential to allow on-time RNA elongation dynamics. Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. The relevance of histone methyltransferase activity is however subject to discussion","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9C0A6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SETD5","classification":"Not Classified","n_dependent_lines":254,"n_total_lines":1208,"dependency_fraction":0.21026490066225165},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SETD5","total_profiled":1310},"omim":[{"mim_id":"618672","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SPEECH DELAY, AUTISM, AND DYSMORPHIC FACIES; IDDSADF","url":"https://www.omim.org/entry/618672"},{"mim_id":"615761","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 23; MRD23","url":"https://www.omim.org/entry/615761"},{"mim_id":"615743","title":"SET DOMAIN-CONTAINING PROTEIN 5; SETD5","url":"https://www.omim.org/entry/615743"},{"mim_id":"613792","title":"CHROMOSOME 3pter-p25 DELETION SYNDROME","url":"https://www.omim.org/entry/613792"},{"mim_id":"209850","title":"AUTISM","url":"https://www.omim.org/entry/209850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SETD5"},"hgnc":{"alias_symbol":["FLJ10707","SETD5A"],"prev_symbol":[]},"alphafold":{"accession":"Q9C0A6","domains":[{"cath_id":"2.170.270.10","chopping":"204-263_294-417","consensus_level":"high","plddt":82.721,"start":204,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0A6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0A6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0A6-F1-predicted_aligned_error_v6.png","plddt_mean":46.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SETD5","jax_strain_url":"https://www.jax.org/strain/search?query=SETD5"},"sequence":{"accession":"Q9C0A6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0A6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0A6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0A6"}},"corpus_meta":[{"pmid":"24680889","id":"PMC_24680889","title":"De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24680889","citation_count":97,"is_preprint":false},{"pmid":"31515109","id":"PMC_31515109","title":"SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/31515109","citation_count":87,"is_preprint":false},{"pmid":"25138099","id":"PMC_25138099","title":"Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/25138099","citation_count":77,"is_preprint":false},{"pmid":"32442403","id":"PMC_32442403","title":"SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.","date":"2020","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/32442403","citation_count":71,"is_preprint":false},{"pmid":"27864380","id":"PMC_27864380","title":"Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.","date":"2016","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27864380","citation_count":64,"is_preprint":false},{"pmid":"31474762","id":"PMC_31474762","title":"The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.","date":"2019","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31474762","citation_count":52,"is_preprint":false},{"pmid":"24562769","id":"PMC_24562769","title":"miR126-5p repression of ALCAM and SetD5 in endothelial cells regulates leucocyte adhesion and transmigration.","date":"2014","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/24562769","citation_count":46,"is_preprint":false},{"pmid":"29180574","id":"PMC_29180574","title":"miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29180574","citation_count":39,"is_preprint":false},{"pmid":"29484850","id":"PMC_29484850","title":"Genetic variations on SETD5 underlying autistic conditions.","date":"2018","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29484850","citation_count":36,"is_preprint":false},{"pmid":"27375234","id":"PMC_27375234","title":"SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.","date":"2016","source":"American journal of medical genetics. 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neural stem cells, zebrafish, and mice reduces H3K36me3, impairs RNA elongation dynamics, and causes abnormal transcription with defective RNA maturation and splicing.\",\n      \"method\": \"ChIP-seq, genetic KO/haploinsufficiency in mice and zebrafish, RNA-seq, in vitro assays in neural stem cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, genetic models in three systems), replicated across neural stem cells, zebrafish, and mice in a single rigorous study\",\n      \"pmids\": [\"31515109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SETD5 co-immunoprecipitates with multiple components of the PAF1 co-transcriptional complex and the HDAC-containing NCoR co-repressor complex; in its absence, histone acetylation is increased at transcription start sites and downstream regions, indicating SETD5 regulates co-transcriptional histone acetylation rather than solely histone methylation.\",\n      \"method\": \"Co-immunoprecipitation, histone modification analysis (ChIP), genetic KO in mouse embryos and ESCs\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with PAF1 and NCoR complex components, plus ChIP-based histone acetylation phenotype in KO cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27864380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD5 lacks histone methyltransferase activity but functions as a scaffold for a co-repressor complex containing HDAC3 and G9a; this SETD5 complex silences gene expression to drive adaptive resistance to MEK1/2 inhibition in pancreatic cancer.\",\n      \"method\": \"In vitro enzymatic assay (no HMT activity detected), co-immunoprecipitation, genetic deletion in mouse models and patient-derived xenografts, pharmacological co-targeting\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct enzymatic assay establishing lack of HMT activity, Co-IP of HDAC3/G9a complex, in vivo rescue experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32442403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD5 recruits the HDAC3 complex to the rDNA promoter, resulting in removal of H4K16ac and its reader protein TIP5 (a repressor of rDNA expression), thereby positively regulating rDNA transcription, translational activity, and neural cell proliferation; cyclin D1 mRNA translation is specifically down-regulated in SETD5-insufficient cells, and TIP5 ablation rescues these effects.\",\n      \"method\": \"Co-immunoprecipitation (SETD5–HDAC3), ChIP (H4K16ac, TIP5 at rDNA promoter), siRNA knockdown, rescue by TIP5 depletion, ribosome profiling/translation assays in Setd5+/- mouse brain\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP at rDNA locus, genetic epistasis rescue experiment (TIP5 KD reverses SETD5 KD phenotype); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32299058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SETD5 forms a complex with NCoR-HDAC3 that maintains enhancers for Cebpa and Pparg in a hypoacetylated primed state during early adipogenesis; APC/C-mediated ubiquitin-proteasome degradation of SETD5, triggered by CDC20 induction, releases this repression and enables enhancer hyperacetylation and adipogenic gene activation.\",\n      \"method\": \"Co-immunoprecipitation (SETD5–NCoR–HDAC3), ChIP-seq (histone acetylation at enhancers), SETD5 protein degradation assays, genetic/pharmacological inhibition of APC/C-CDC20\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, ChIP-seq for enhancer acetylation, identification of CDC20/APC/C-mediated degradation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34857762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SETD5 regulates HSC quiescence by mediating release of promoter-proximal paused RNA polymerase II (Pol II) on E2F target genes, and this function requires cooperation with HCF-1 and the PAF1 complex; Setd5-deficient HSCs show disrupted quiescence and exhaustion under transplantation pressure.\",\n      \"method\": \"Conditional KO (Setd5 in hematopoietic system), RNA-seq, ChIP for paused Pol II, Co-IP (SETD5–HCF-1–PAF1), transplantation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying HCF-1/PAF1 partnership, Pol II pausing ChIP, conditional KO phenotype; single lab with multiple methods but mechanistic resolution limited by abstract detail\",\n      \"pmids\": [\"34853439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD5 controls Sema3A expression independently of its SET domain and co-immunoprecipitates with the bromodomain protein BRD2; both SETD5 and BRD2 bind to the transcription start site and upstream promoter regions of the Sema3a locus, and BRD2 is required for SETD5-mediated regulation of Sema3A.\",\n      \"method\": \"Co-immunoprecipitation (SETD5–BRD2), ChIP at Sema3a locus, SET-domain deletion mutant analysis, in vitro cell culture with miR-126-5p manipulation\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of SETD5–BRD2, ChIP at Sema3a, SET-domain-independent function established by mutant; single lab with two orthogonal methods\",\n      \"pmids\": [\"29180574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The SET domain of SETD5 is essential for both retinal cell survival and proliferation; a truncation mutant (SETD5S1257*) that cannot interact with HDAC3 and PAF1 complexes rescues proliferation but not apoptosis caused by Setd5 knockdown, indicating the SETD5–HDAC3/PAF1 interaction is specifically required for the pro-survival function.\",\n      \"method\": \"shRNA knockdown in mouse retinal explants, structure-function analysis with SET-domain deletion and S1257* truncation mutants, histology/immunostaining\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutant rescue experiments dissecting two functions; single lab, single organism model\",\n      \"pmids\": [\"36349512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SETD5 methylates nuclear LC3B at lysines 5 and 65, causing its nuclear retention; methylated LC3B then binds transcription factor PRDM10 at promoters of ATG genes (ATG2a, ATG7, ATG12, ATG16L1), suppressing their transcription and reducing autophagosome formation in ovarian cancer cells.\",\n      \"method\": \"Co-IP (SETD5–LC3B), in vitro methylation assay, site-directed mutagenesis of LC3B K5/K65, ChIP (LC3B/PRDM10 at ATG promoters), autophagy flux assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro methylation assay + mutagenesis + ChIP establish mechanism, but single lab and limited replication\",\n      \"pmids\": [\"40497358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD5 mediates O-GlcNAc transferase (OGT)-catalyzed O-GlcNAcylation of RNA Pol II; SETD5–Pol II interaction weakens in OGT-depleted cells, and SETD5 loss reduces Pol II occupancy at PI3K-AKT pathway genes and CD133 promoters in colorectal cancer cells.\",\n      \"method\": \"Co-IP (SETD5–Pol II, SETD5–OGT), OGT depletion affecting Pol II glycosylation, ChIP (Pol II at gene promoters), KD/OE of SETD5\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and ChIP supporting functional interdependence of SETD5, OGT, and Pol II; single lab, single paper\",\n      \"pmids\": [\"37963940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD5 as H3K36me3 writer facilitates METTL14-dependent m6A modification and YTHDF1 recruitment to PKM2 mRNA, mediating PKM2 nuclear translocation and phosphorylation (Tyr105), which regulates GPX4-mediated ferroptosis resistance and SOX9-mediated stemness in NSCLC.\",\n      \"method\": \"m6A-seq, RIP, Co-IP, nuclear fractionation, site-specific phosphorylation detection, KD/OE in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — complex mechanistic chain claimed in a single paper with limited methodological detail in abstract; single lab, no independent replication\",\n      \"pmids\": [\"40307507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-126-5p represses SETD5 expression in endothelial cells; loss of SETD5 repression (via target protectors blocking miR-126-5p/SetD5 mRNA pairing) reduces leucocyte adhesion, identifying SetD5 as a functional target of miR-126-5p that promotes leucocyte adhesion when expressed.\",\n      \"method\": \"Gain- and loss-of-function of miR-126-5p, target protectors (miRNA/mRNA pairing disruption), leucocyte adhesion assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — target-protector approach specifically demonstrates SETD5's role downstream of miR-126-5p; functional cell biology readout; single lab\",\n      \"pmids\": [\"24562769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBLR1 physically connects SETD5 and ANKRD11 to the NCoR complex, forming an assembly that resembles the yeast SET3 complex (SET3C); pathogenic missense mutations in SETD5 disrupt this assembly; an engineered mutation specifically abolishing SETD5 incorporation into SET3C causes severe developmental impairments in mice; SET3C disruption produces highly correlated gene expression changes including upregulation of highly transcribed genes.\",\n      \"method\": \"Co-IP/protein interaction mapping, engineered mouse mutation, transcriptomics in multiple NDD models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction mapping plus in vivo engineered mutation phenotype; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.30.657039\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANKRD11 interacts with the Setd5 promoter and recruits WDR5 (a component of the H3K4 methyltransferase complex) to promote H3K4 methylation and SETD5 transcription; ANKRD11-deficient neural cells have reduced H3K4 methylation at the Setd5 promoter, reduced SETD5 expression, and consequently reduced rRNA and translation, which is rescued by SETD5 overexpression.\",\n      \"method\": \"ChIP (ANKRD11/WDR5/H3K4me at Setd5 promoter), genetic KD/OE, rRNA quantification, translation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and genetic rescue experiments define ANKRD11→H3K4me→SETD5→rRNA axis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40520101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Setd5 is required in cardiopharyngeal mesoderm for heart development; conditional deletion in this lineage causes failure of heart tube ballooning, leading to double outlet right ventricle and ventricular septal defect; no genetic interaction with Tbx1 was detected.\",\n      \"method\": \"Conditional mutagenesis (Cre-lox), cardiac phenotype analysis, genetic epistasis with Tbx1 (negative result)\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO in specific lineage with defined phenotype, plus negative epistasis result; single lab\",\n      \"pmids\": [\"34050709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SETD5-deficient human astrocytes (hiPSC-derived) show elevated extracellular IL-6 and ROS; elevated IL-6 exerts non-cell-autonomous harm to healthy neurons; JAK/STAT pathway inhibition restores IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits.\",\n      \"method\": \"hiPSC-derived astrocyte KO, conditioned medium transfer to neurons, cytokine measurement, pharmacological JAK/STAT inhibition rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell biology with pharmacological rescue; preprint, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"41993368\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SETD5 is a SET-domain-containing protein that directly deposits H3K36me3 on active gene bodies to regulate RNA elongation and splicing, and also scaffolds a multi-subunit co-repressor complex (NCoR–HDAC3, PAF1, and, with TBLR1/ANKRD11, a mammalian SET3C-like assembly) that controls histone acetylation at enhancers and promoters, Pol II pausing, rDNA transcription via HDAC3-mediated H4K16ac removal, and LC3B methylation to suppress autophagy, with its own levels regulated by APC/C-CDC20-mediated proteasomal degradation; haploinsufficiency of SETD5 in neurons and neural progenitors disrupts H3K36me3 levels, transcriptional fidelity, synaptic connectivity, and mitochondrial homeostasis, collectively causing the neurodevelopmental phenotypes associated with intellectual disability and autism spectrum disorder.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SETD5 is a chromatin regulator that couples transcriptional output to histone modification at active genes and developmental loci, with its disruption driving neurodevelopmental disease [#0, #12]. Although it carries a SET domain and deposits H3K36me3 on active gene bodies to support proper RNA elongation, maturation, and splicing [#0], a parallel body of work shows SETD5 also acts largely as a scaffold that nucleates HDAC-containing co-repressor assemblies: it co-immunoprecipitates with the PAF1 co-transcriptional complex and the NCoR–HDAC3 co-repressor complex, and its loss raises histone acetylation around transcription start sites [#1]. Through HDAC3 recruitment it represses target chromatin in multiple contexts — silencing genes to drive MEK-inhibitor resistance in pancreatic cancer [#2], removing H4K16ac and the repressor TIP5 at the rDNA promoter to positively control rRNA transcription and translation [#3], and holding adipogenic enhancers (Cebpa, Pparg) in a hypoacetylated primed state until APC/C-CDC20 triggers SETD5 proteasomal degradation [#4]. SETD5 further controls release of promoter-proximal paused RNA Pol II at E2F target genes in cooperation with HCF-1 and PAF1 [#5]. TBLR1 bridges SETD5 and ANKRD11 into a mammalian SET3C-like assembly within the NCoR complex, and pathogenic SETD5 missense mutations or engineered mutations that block SETD5 incorporation into SET3C cause severe developmental impairment [#12]; reciprocally, ANKRD11 recruits WDR5 to the Setd5 promoter to drive SETD5 transcription and downstream rRNA synthesis [#13]. SET-domain-independent activities include regulation of Sema3A expression via the bromodomain protein BRD2 [#6]. Structure-function dissection shows the SETD5–HDAC3/PAF1 interaction is specifically required for cell survival, whereas proliferation can be supported independently [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established SETD5 as a functionally regulated gene whose expression has cell-biological consequences, providing an early handle on its role before its chromatin mechanism was known.\",\n      \"evidence\": \"miR-126-5p gain/loss-of-function with target protectors and leucocyte adhesion assays in endothelial cells\",\n      \"pmids\": [\"24562769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define a molecular activity for SETD5\", \"No chromatin or complex data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed that SETD5 acts not solely as a methyltransferase but as a regulator of co-transcriptional histone acetylation through physical association with PAF1 and the NCoR–HDAC3 co-repressor complex.\",\n      \"evidence\": \"Reciprocal Co-IP with PAF1 and NCoR components plus ChIP for histone acetylation in KO mouse embryos and ESCs\",\n      \"pmids\": [\"27864380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether SETD5 has intrinsic catalytic activity\", \"Direct vs. indirect recruitment of HDAC complex unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a SET-domain-independent gene-regulatory function, showing SETD5 partners with BRD2 to control a specific developmental target gene.\",\n      \"evidence\": \"Co-IP of SETD5–BRD2, ChIP at the Sema3a locus, and SET-domain deletion mutant analysis\",\n      \"pmids\": [\"29180574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond Sema3a unknown\", \"Mechanism of BRD2 dependence not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the strongest evidence that SETD5 directly deposits H3K36me3 on active gene bodies and that its loss impairs RNA elongation, maturation, and splicing, linking the enzyme to transcriptional fidelity in neural development.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, and genetic KO/haploinsufficiency across neural stem cells, zebrafish, and mice\",\n      \"pmids\": [\"31515109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent conflict with reports of absent HMT activity not reconciled\", \"Direct vs. indirect contribution to H3K36me3 not fully isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reframed SETD5 as a catalytically inactive scaffold for an HDAC3/G9a co-repressor complex that silences genes to confer therapeutic resistance, directly challenging the methyltransferase model.\",\n      \"evidence\": \"In vitro enzymatic assay showing no HMT activity, Co-IP of HDAC3/G9a, and genetic deletion plus pharmacological co-targeting in pancreatic cancer models\",\n      \"pmids\": [\"32442403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not reconcile with H3K36me3-deposition findings\", \"Scope of scaffold vs. enzymatic roles across tissues unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SETD5–HDAC3 recruitment to a defined locus, showing it strips H4K16ac and the repressor TIP5 from the rDNA promoter to positively regulate rRNA transcription, translation, and neural proliferation.\",\n      \"evidence\": \"Co-IP, ChIP at rDNA promoter, siRNA knockdown, and TIP5-depletion epistasis rescue with ribosome profiling in Setd5+/- mouse brain\",\n      \"pmids\": [\"32299058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SETD5 is targeted to rDNA not defined\", \"Link between rDNA control and behavioral phenotypes indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SETD5 protein abundance is itself controlled by APC/C-CDC20-mediated degradation, providing a switch that converts primed hypoacetylated enhancers into active ones during adipogenesis.\",\n      \"evidence\": \"Co-IP of SETD5–NCoR–HDAC3, ChIP-seq for enhancer acetylation, and degradation assays with APC/C-CDC20 inhibition\",\n      \"pmids\": [\"34857762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron and ubiquitination sites on SETD5 not mapped\", \"Generality of APC/C control beyond adipogenesis unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a Pol II pause-release function for SETD5 at E2F targets requiring HCF-1 and PAF1, linking the protein to cell quiescence control in hematopoietic stem cells.\",\n      \"evidence\": \"Conditional KO, RNA-seq, paused-Pol II ChIP, Co-IP of SETD5–HCF-1–PAF1, and transplantation assays\",\n      \"pmids\": [\"34853439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic resolution limited\", \"Direct vs. indirect role in pause release unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a lineage-specific developmental requirement for Setd5 in cardiopharyngeal mesoderm during heart morphogenesis.\",\n      \"evidence\": \"Conditional Cre-lox deletion with cardiac phenotyping and negative genetic epistasis with Tbx1\",\n      \"pmids\": [\"34050709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism in cardiac lineage not defined\", \"Relevant chromatin targets unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Dissected SETD5 into separable functions, showing the SETD5–HDAC3/PAF1 interaction is specifically required for cell survival while proliferation can be supported by a truncation mutant lacking it.\",\n      \"evidence\": \"shRNA knockdown in mouse retinal explants with SET-domain deletion and S1257* truncation mutant rescue\",\n      \"pmids\": [\"36349512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the survival-specific requirement unclear\", \"Single organ system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tied SETD5 to RNA Pol II modification by linking SETD5–Pol II association to OGT-catalyzed O-GlcNAcylation in colorectal cancer.\",\n      \"evidence\": \"Co-IP of SETD5–Pol II and SETD5–OGT, OGT depletion, and Pol II ChIP at target promoters\",\n      \"pmids\": [\"37963940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between SETD5 and OGT activity not resolved\", \"Single lab, single cancer context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SETD5 H3K36me3 writing upstream of an m6A/PKM2 metabolic axis influencing ferroptosis and stemness in lung cancer.\",\n      \"evidence\": \"m6A-seq, RIP, Co-IP, nuclear fractionation, and KD/OE in vitro and in vivo\",\n      \"pmids\": [\"40307507\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Complex mechanistic chain claimed in a single paper without independent replication\", \"Each step in the cascade not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified TBLR1 as the bridge assembling SETD5 and ANKRD11 into a mammalian SET3C-like complex and showed that disrupting SETD5 incorporation causes severe developmental defects, unifying two NDD genes in one assembly.\",\n      \"evidence\": \"Protein interaction mapping, engineered mouse mutation, and transcriptomics across NDD models (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.30.657039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural organization of mammalian SET3C not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a feedback loop in which ANKRD11 recruits WDR5 to the Setd5 promoter to drive H3K4 methylation, SETD5 transcription, and downstream rRNA synthesis.\",\n      \"evidence\": \"ChIP of ANKRD11/WDR5/H3K4me at the Setd5 promoter, genetic KD/OE, rRNA and translation assays with SETD5-overexpression rescue\",\n      \"pmids\": [\"40520101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this loop operates outside neural cells unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended SETD5 methyltransferase activity to a non-histone substrate, showing it methylates nuclear LC3B to suppress autophagy gene transcription via PRDM10.\",\n      \"evidence\": \"In vitro methylation assay, LC3B K5/K65 mutagenesis, Co-IP, ChIP at ATG promoters, and autophagy flux assays in ovarian cancer cells\",\n      \"pmids\": [\"40497358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with reports of absent HMT activity not addressed\", \"Single lab, limited replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a non-cell-autonomous disease mechanism in which SETD5-deficient astrocytes secrete IL-6 that harms neurons, rescuable by JAK/STAT inhibition.\",\n      \"evidence\": \"hiPSC-derived astrocyte KO, conditioned-medium transfer, cytokine measurement, and pharmacological rescue (preprint)\",\n      \"pmids\": [\"41993368\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab\", \"How SETD5 loss drives IL-6/ROS molecularly not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is reconciling SETD5's reported intrinsic methyltransferase activity (on H3K36 and LC3B) with the in vitro evidence that it lacks HMT activity and acts primarily as an HDAC-complex scaffold.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the SETD5 SET domain catalytic state\", \"Direct vs. scaffold contributions to chromatin marks not cleanly separated\", \"Substrate determinants for any catalytic activity undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 4, 8]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"NCoR-HDAC3 co-repressor complex\",\n      \"PAF1 complex\",\n      \"SET3C-like complex (SETD5-TBLR1-ANKRD11)\"\n    ],\n    \"partners\": [\n      \"HDAC3\",\n      \"PAF1\",\n      \"NCoR\",\n      \"G9a\",\n      \"BRD2\",\n      \"HCF-1\",\n      \"TBLR1\",\n      \"ANKRD11\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}