{"gene":"SETD1B","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2007,"finding":"SETD1B (Set1B/KIAA1076) forms an ~450 kDa histone methyltransferase complex containing five non-catalytic subunits: CFP1, Rbbp5, Ash2, Wdr5, and Wdr82. In vitro assays demonstrate the complex produces H3K4me3. A 123-amino acid fragment upstream of the SET domain is required for interaction with CFP1, Ash2, Rbbp5, and Wdr5. Confocal microscopy reveals SETD1B localizes to a largely non-overlapping set of euchromatic nuclear speckles compared to SETD1A, suggesting non-redundant target gene binding.","method":"Immunoprecipitation, mass spectrometry, in vitro histone methyltransferase assay, deletion mutagenesis, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro activity, complex defined by Co-IP + MS, mutagenesis of interaction domain, localization by direct imaging; multiple orthogonal methods in one rigorous study","pmids":["17355966"],"is_preprint":false},{"year":2007,"finding":"SETD1B stability depends on its association with the methyltransferase complex: inducible expression of the carboxyl terminus of SETD1A or SETD1B decreases steady-state levels of both endogenous SETD1A and SETD1B protein without altering levels of the non-catalytic components, indicating feedback regulation through complex-dependent stability.","method":"Inducible overexpression, Western blot for steady-state protein levels","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function/gain-of-function with defined molecular readout, single lab, two orthogonal methods","pmids":["17355966"],"is_preprint":false},{"year":2012,"finding":"Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein directly interact with SETD1B. This interaction requires the Rbm15 SPOC domain and the SETD1B LSD motif. Overexpression of Rbm15-Mkl1 leads to cytokine-independent cell growth that requires an intact SPOC domain mediating interaction with SETD1B, implicating altered SETD1B complex function in AMKL leukemogenesis.","method":"Co-immunoprecipitation, deletion/domain mutagenesis, cytokine-independent proliferation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction established by Co-IP with domain mapping, functional consequence in proliferation assay, single lab","pmids":["22927943"],"is_preprint":false},{"year":2014,"finding":"In mice, Setd1b is dispensable until after gastrulation (embryos survive to E11.5 but are grossly retarded), whereas Setd1a is required at the epiblast stage. Overexpression of Setd1b cannot rescue the proliferation defects caused by loss of Setd1a in embryonic stem cells, demonstrating non-redundant and developmentally distinct roles for the two Set1 orthologs.","method":"Conditional knockout mouse genetics, embryo phenotyping, Setd1b overexpression rescue experiment in ESCs","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined developmental and cellular phenotypes, negative rescue experiment provides epistatic placement, replicated across multiple genetic strategies","pmids":["24550110"],"is_preprint":false},{"year":2017,"finding":"SETD1B activates iNOS (nos2) expression in tumor-induced myeloid-derived suppressor cells (MDSCs). ChIP revealed enrichment of H3K4me3 (the catalytic product of SETD1B) at the nos2 promoter in MDSCs; inhibition or silencing of SETD1B diminished iNOS expression, demonstrating that SETD1B-mediated H3K4me3 deposition at the nos2 promoter drives iNOS transcription in an IRF8-independent manner.","method":"Chromatin immunoprecipitation (ChIP), SETD1B silencing/inhibition, qRT-PCR/Western blot for iNOS","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP links H3K4me3 to nos2 promoter, loss-of-function confirms functional requirement, single lab, two orthogonal methods","pmids":["28381543"],"is_preprint":false},{"year":2018,"finding":"Conditional deletion of Setd1b in adult mice using ubiquitous and hematopoietic-specific strategies results in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis, and lethality. Transplantation experiments and expression profiling show Setd1b is autonomously required in hematopoietic lineages and regulates key lineage specification genes including Cebpa, Gata1, and Klf1.","method":"Conditional knockout mouse genetics, bone marrow transplantation, RNA expression profiling, hematopoietic phenotyping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple genetic strategies, transplantation establishes cell-autonomous requirement, gene expression profiling identifies downstream targets, multiple orthogonal methods","pmids":["29916805"],"is_preprint":false},{"year":2021,"finding":"SET1B (SETD1B) is recruited to HIF target gene loci by the HIF transcription factor complex in hypoxia. SET1B accumulates on chromatin under hypoxic conditions, and its loss selectively reduces H3K4me3 at HIF target loci, correlating with decreased promoter acetylation and gene expression. Genome-wide mutagenesis screen identified SET1B as required for HIF transcriptional activity.","method":"Genome-wide CRISPR mutagenesis screen, ChIP-seq for SET1B and H3K4me3, promoter acetylation analysis, xenograft tumor assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen plus ChIP-seq plus functional rescue in multiple cell systems, multiple orthogonal methods establishing mechanism of recruitment","pmids":["34155378"],"is_preprint":false},{"year":2021,"finding":"Postnatal SETD1B in excitatory neurons controls expression of a set of genes with broad H3K4me3 peaks at their promoters, enriched for neuron-specific genes linked to learning and memory. Conditional deletion of Setd1b in excitatory forebrain neurons leads to severe learning impairment. Comparative ChIP-seq and RNA-seq with Kmt2a and Kmt2b conditional knockouts show SETD1B plays a more pronounced role in regulating neuron-enriched, broad-H3K4me3-marked genes.","method":"Neuron-specific conditional knockout, ChIP-seq (H3K4me3), RNA-seq, behavioral learning tests","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq and RNA-seq, behavioral phenotyping, comparative analysis with paralogs; multiple orthogonal methods in one study","pmids":["34806773"],"is_preprint":false},{"year":2022,"finding":"Loss of SETD1B in oocytes (conditional KO) causes redistribution of H3K4me3: losses at active gene promoters associated with downregulated gene expression, and gains at DNA-hypomethylated, transcriptionally inactive, CpG-rich regions (hallmarks of MLL2/KMT2B targets). This reveals two complementary mechanisms of H3K4me3 targeting in oogenesis—SETD1B linked to gene expression and MLL2 to CpG content—and shows SETD1B normally suppresses MLL2-mediated methylation at these sites.","method":"Conditional knockout oocytes, ultra-low input ChIP-seq for H3K4me3, DNA methylation analysis, RNA-seq","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in defined cell type, genome-wide ChIP-seq plus DNA methylation plus RNA-seq, multiple orthogonal methods in one study","pmids":["35137160"],"is_preprint":false},{"year":2020,"finding":"SETD1B is required for mycolactone-induced cell death. CRISPR/Cas9 inactivation of SETD1B renders cells resistant to lethal doses of mycolactone. Mechanistically, SETD1B is required for mycolactone-selective upregulation of CHAC1 (a GSH-degrading enzyme), and SETD1B loss prevents mycolactone-induced glutathione depletion and apoptotic gene induction.","method":"Haploid genetic screen, CRISPR/Cas9 knockout, transcriptome comparison (RNA-seq), glutathione level measurement","journal":"PLoS neglected tropical diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — haploid screen plus CRISPR KO plus transcriptomics plus metabolite measurement; single lab, multiple orthogonal methods","pmids":["33006969"],"is_preprint":false},{"year":2024,"finding":"SETD1B mutations/deletions in B cell lymphoma confer resistance to the BCL2 inhibitor Venetoclax and an MCL-1 inhibitor. Mechanistically, SETD1B is required for expression of several proapoptotic BCL2 family proteins (including BIM and BIK). KDM5 histone H3K4 demethylase inhibitors restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. SETD1B cooperates with KMT2D loss in lymphoma development in vivo.","method":"Loss-of-function genetics (mutations/deletions), drug resistance assays, gene expression analysis, in vivo lymphoma model, KDM5 inhibitor combination treatment","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism (H3K4me3-dependent proapoptotic gene expression), pharmacological rescue, in vivo model, single lab","pmids":["39235528"],"is_preprint":false},{"year":2025,"finding":"SETD1B SET domain disruption (via CRISPR tiling) in MLL-rearranged AML cells causes depletion of AML cells and downregulation of MYC pathway genes. SETD1B SET domain loss results in decreased H3K4me3 breadth at gene loci; exogenous MYC expression or disruption of H3K4 demethylase KDM5C rescues growth defects, establishing SETD1B's catalytic domain as required for broad H3K4me3 and MYC expression.","method":"CRISPR-tiling screen, H3K4me3 ChIP-seq, MYC overexpression rescue, KDM5C genetic disruption rescue","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR tiling plus ChIP-seq plus genetic epistasis rescue, single lab, multiple orthogonal methods","pmids":["40341256"],"is_preprint":false},{"year":2026,"finding":"SET1B interacts with RNA polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains beyond its histone methyltransferase activity. In clear cell renal cell carcinoma (ccRCC), SET1B is required for sustained HIF activity, and SET1B depletion enhances the efficacy of HIF-2 inhibitors.","method":"Co-immunoprecipitation (SET1B–RNAPII interaction), SET1B depletion, HIF-2 inhibitor combination experiments, patient sample correlation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes RNAPII interaction, loss-of-function with defined HIF transcriptional readout, pharmacological synergy; single lab","pmids":["41941749"],"is_preprint":false},{"year":2025,"finding":"SETD1B promotes ferroptosis in ischemic stroke brain cells by increasing H3K4me3 enrichment at the Tfrc (transferrin receptor 1) promoter, upregulating TfR1 expression and driving iron accumulation and lipid peroxidation. SETD1B knockdown reduces H3K4me3 at the Tfrc promoter and reverses ferroptosis markers in OGD/R-treated HT22 cells and ischemic mouse brain.","method":"ChIP for H3K4me3 at Tfrc promoter, SETD1B siRNA knockdown, ferroptosis marker assays (iron, LPO, GPX4), OGD/R cell model and mouse stroke model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP links SETD1B activity to specific promoter, KD with defined molecular and cellular phenotype, orthogonal in vivo and in vitro validation; single lab","pmids":["40228655"],"is_preprint":false},{"year":2025,"finding":"USP15 deubiquitinates SETD1B, increasing its protein stability. In ischemic stroke cells, USP15 knockdown increases SETD1B ubiquitination and decreases SETD1B protein levels, thereby reducing H3K4me3 enrichment at the Nckap1l and Wasf2 promoters and attenuating disulfidptosis.","method":"Co-immunoprecipitation (USP15–SETD1B), ubiquitination assay, siRNA knockdown, ChIP for H3K4me3 at target promoters","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishes the PTM writer–substrate relationship, ChIP links to downstream gene regulation, single lab","pmids":["40609959"],"is_preprint":false},{"year":2024,"finding":"SETD1B promotes CXCR4 expression by increasing H3K4me3 levels at the CXCR4 promoter, thereby suppressing NLRP1/Caspase1-mediated neuronal pyroptosis. SETD1B overexpression mitigates sevoflurane-induced cognitive impairment in neonatal mice by this mechanism.","method":"ChIP for SETD1B and H3K4me1/2/3 at CXCR4 promoter, SETD1B overexpression (adenovirus), behavioral tests, pyroptosis marker assays","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP maps SETD1B to specific promoter, gain-of-function with behavioral and molecular phenotype, single lab","pmids":["38447691"],"is_preprint":false},{"year":2016,"finding":"In Xenopus, maternal Setd1b is required for organizer gene expression during dorsal axis development. Depletion of Setd1b impairs organizer gene activation, indicating that Setd1b-mediated H3K4 trimethylation is required downstream of the maternal Wnt/β-catenin pathway for proper organizer formation.","method":"Antisense morpholino depletion in Xenopus embryos, in situ hybridization, organizer gene expression analysis","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in Xenopus with defined developmental and molecular phenotype; ortholog study, single lab","pmids":["27519569"],"is_preprint":false},{"year":2026,"finding":"YTHDF2 physically interacts with SETD1B (but not SETD1A or CXXC1) in the cerebellum. Loss of Ythdf2 suppresses Setd1b-mediated H3K4me3 deposition and reduces chromatin accessibility at neuronal developmental gene loci. Setd1b knockdown rescues the neural self-renewal and differentiation defects caused by Ythdf2 deletion, placing SETD1B downstream of YTHDF2 in cerebellar development.","method":"Co-immunoprecipitation (YTHDF2–SETD1B), H3K4me3 ChIP analysis, ATAC-seq (chromatin accessibility), Setd1b knockdown rescue of Ythdf2 KO phenotype","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes specific interaction, genetic epistasis rescue places SETD1B downstream, ChIP links to H3K4me3; single lab, multiple orthogonal methods","pmids":["41933071"],"is_preprint":false},{"year":2025,"finding":"DamID-seq using SET1B-Dam fusion protein provided the first genome-wide DNA binding map for SET1B, revealing strong concordance between SET1B chromatin occupancy and HIF-1α ChIP-seq data at HIF target loci.","method":"DamID-seq (Dam methyltransferase tagging of SET1B), bioinformatic comparison with HIF-1α ChIP-seq","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide chromatin binding map by DamID validated against orthogonal ChIP-seq; single lab, novel method application","pmids":["41087863"],"is_preprint":false}],"current_model":"SETD1B (Set1B/KMT2G) is the catalytic subunit of an ~450 kDa H3K4 methyltransferase complex containing CFP1, Rbbp5, Ash2, Wdr5, and Wdr82, which produces H3K4me3 at active gene promoters; it is recruited to specific loci by interacting partners including the HIF complex and YTHDF2, and its catalytic SET domain is required for maintaining H3K4me3 breadth to sustain expression of target genes (including MYC pathway genes and proapoptotic BCL2 family members); its protein stability is regulated by USP15-mediated deubiquitination; and it plays non-redundant, cell-type-specific roles in hematopoiesis, oogenesis, neuronal learning, and hypoxia responses, with loss-of-function causing intellectual disability, epilepsy, and lymphoma drug resistance in humans."},"narrative":{"mechanistic_narrative":"SETD1B is the catalytic subunit of an ~450 kDa histone H3K4 methyltransferase complex that deposits H3K4me3 at active gene promoters to sustain target-gene expression [PMID:17355966]. It assembles with the non-catalytic subunits CFP1, Rbbp5, Ash2, Wdr5, and Wdr82 through a 123-amino-acid region upstream of its catalytic SET domain, and complex incorporation reciprocally stabilizes the catalytic protein [PMID:17355966]. SETD1B occupies a largely distinct set of euchromatic loci from its paralog SETD1A and performs non-redundant, developmentally and cell-type-specific functions: it is required after gastrulation in mouse development [PMID:24550110], cell-autonomously controls hematopoietic lineage genes such as Cebpa, Gata1, and Klf1 [PMID:29916805], and governs neuron-enriched genes marked by broad H3K4me3 peaks to support learning and memory [PMID:34806773]. A recurring theme is that SETD1B catalytic activity maintains H3K4me3 breadth at specific promoters, with its SET domain required for MYC pathway gene expression in MLL-rearranged AML [PMID:40341256] and for expression of proapoptotic BCL2 family genes including BIM and BIK, such that SETD1B loss confers Venetoclax resistance in B-cell lymphoma that is reversible by KDM5 demethylase inhibition [PMID:39235528]. Sequence-specific recruitment is achieved through interacting partners: the HIF transcription factor complex recruits SETD1B to hypoxia-responsive loci and SETD1B further engages RNA polymerase II to sustain HIF-driven transcription [PMID:34155378, PMID:41941749, PMID:41087863], while YTHDF2 directs SETD1B-dependent H3K4me3 at neuronal developmental genes in the cerebellum [PMID:41933071]. SETD1B protein stability is controlled by USP15-mediated deubiquitination [PMID:40609959]. Across oogenesis, SETD1B-linked, expression-coupled H3K4me3 is functionally distinct from and antagonistic to CpG-directed MLL2/KMT2B methylation [PMID:35137160].","teleology":[{"year":2007,"claim":"Establishing that SETD1B is the catalytic core of a defined multi-subunit H3K4 methyltransferase resolved what biochemical activity and partners define the protein and showed it targets loci distinct from its paralog.","evidence":"Co-IP/mass spectrometry, in vitro HMT assay, deletion mutagenesis, and confocal imaging of nuclear speckles","pmids":["17355966"],"confidence":"High","gaps":["Subunit stoichiometry and structural architecture of the complex not resolved","The basis for SETD1B vs SETD1A locus selectivity not identified","Direct genomic targets in vivo not mapped"]},{"year":2007,"claim":"Demonstrating that catalytic subunit levels depend on complex association revealed a feedback mechanism coupling SETD1B abundance to assembly with its non-catalytic partners.","evidence":"Inducible overexpression of SETD1A/B C-termini with Western blot readout of endogenous protein levels","pmids":["17355966"],"confidence":"Medium","gaps":["Degradation pathway mediating destabilization not identified","Whether free catalytic subunit is targeted for proteolysis directly unaddressed"]},{"year":2012,"claim":"Identifying a direct Rbm15/Rbm15-Mkl1 interaction with SETD1B linked altered complex function to leukemogenesis, providing a first disease-associated binding partner.","evidence":"Co-IP with SPOC/LSD domain mapping and cytokine-independent proliferation assay","pmids":["22927943"],"confidence":"Medium","gaps":["Effect of the fusion on SETD1B catalytic activity or genomic targeting not shown","In vivo relevance of the interaction not tested"]},{"year":2014,"claim":"Genetic comparison of Setd1a and Setd1b in mice and ESCs established that the two paralogs are non-redundant and act at distinct developmental stages.","evidence":"Conditional knockout embryo phenotyping plus negative Setd1b-overexpression rescue in ESCs","pmids":["24550110"],"confidence":"High","gaps":["Molecular basis of non-redundancy not defined","Specific genes driving the post-gastrulation requirement not identified"]},{"year":2016,"claim":"Maternal Setd1b requirement for organizer gene activation placed SETD1B-dependent H3K4me3 downstream of Wnt/β-catenin in axis formation.","evidence":"Morpholino depletion in Xenopus embryos with in situ analysis of organizer genes","pmids":["27519569"],"confidence":"Medium","gaps":["Direct genomic targets in organizer not mapped","Mechanism connecting Wnt signaling to SETD1B recruitment unknown"]},{"year":2018,"claim":"Conditional deletion in adult mice defined a cell-autonomous, non-redundant SETD1B role in hematopoiesis and identified downstream lineage-specification targets.","evidence":"Hematopoietic-specific conditional KO, bone marrow transplantation, and RNA expression profiling","pmids":["29916805"],"confidence":"High","gaps":["Whether Cebpa/Gata1/Klf1 are direct H3K4me3 targets not shown by ChIP","Mechanism of lineage-specific recruitment unaddressed"]},{"year":2021,"claim":"Identifying HIF-complex recruitment of SETD1B to hypoxia-responsive loci provided a sequence-specific targeting mechanism linking the methyltransferase to inducible transcription.","evidence":"Genome-wide CRISPR screen, SET1B and H3K4me3 ChIP-seq, promoter acetylation analysis, and xenografts","pmids":["34155378"],"confidence":"High","gaps":["Direct physical interface between SET1B and the HIF complex not mapped","How H3K4me3 feeds back to promoter acetylation not resolved"]},{"year":2021,"claim":"Neuron-specific deletion established that SETD1B preferentially controls broad-H3K4me3 neuronal genes underlying learning, distinguishing its role from Kmt2a/Kmt2b.","evidence":"Excitatory-neuron conditional KO with H3K4me3 ChIP-seq, RNA-seq, behavioral testing, and paralog comparison","pmids":["34806773"],"confidence":"High","gaps":["What confers preference for broad-peak loci not defined","Recruitment machinery in neurons not identified"]},{"year":2022,"claim":"Oocyte deletion revealed two complementary H3K4me3 targeting logics—expression-coupled SETD1B versus CpG-directed MLL2—and showed SETD1B suppresses ectopic MLL2 methylation.","evidence":"Conditional KO oocytes with ultra-low-input H3K4me3 ChIP-seq, DNA methylation analysis, and RNA-seq","pmids":["35137160"],"confidence":"High","gaps":["Mechanism by which SETD1B restrains MLL2 at CpG islands unknown","Direct competition vs indirect effect not distinguished"]},{"year":2024,"claim":"Linking SETD1B catalytic function to proapoptotic BCL2-family gene expression explained how its loss drives BCL2/MCL-1 inhibitor resistance and revealed a KDM5-inhibitor rescue strategy.","evidence":"Loss-of-function genetics, drug resistance assays, expression analysis, in vivo lymphoma model, and KDM5 inhibitor combination","pmids":["39235528"],"confidence":"Medium","gaps":["Whether BIM/BIK are direct SETD1B targets shown only at the expression level","Mechanism of cooperation with KMT2D loss not detailed"]},{"year":2025,"claim":"CRISPR-tiling of the SET domain in MLL-rearranged AML established that catalytic activity per se maintains H3K4me3 breadth and MYC pathway gene expression required for leukemic growth.","evidence":"CRISPR-tiling screen, H3K4me3 ChIP-seq, and MYC overexpression / KDM5C disruption epistasis rescue","pmids":["40341256"],"confidence":"Medium","gaps":["How breadth specifically controls MYC expression mechanistically unresolved","Whether SET-domain dependence generalizes beyond MLL-rearranged AML untested"]},{"year":2025,"claim":"Identifying USP15 as a deubiquitinase stabilizing SETD1B defined a post-translational control point governing its abundance and downstream H3K4me3 deposition.","evidence":"Co-IP, ubiquitination assay, siRNA knockdown, and ChIP at Nckap1l/Wasf2 promoters in ischemic stroke cells","pmids":["40609959"],"confidence":"Medium","gaps":["E3 ligase that ubiquitinates SETD1B not identified","Ubiquitination site(s) not mapped"]},{"year":2025,"claim":"ChIP-based studies in disease models extended SETD1B's promoter-specific H3K4me3 control to Tfrc-driven ferroptosis and CXCR4-mediated suppression of pyroptosis, illustrating context-specific target genes.","evidence":"ChIP for H3K4me3 at Tfrc/CXCR4 promoters, SETD1B knockdown/overexpression, and ferroptosis/pyroptosis and behavioral assays","pmids":["40228655","38447691"],"confidence":"Medium","gaps":["Recruitment mechanism to these loci not defined","Direct vs indirect promoter regulation not fully distinguished"]},{"year":2025,"claim":"A genome-wide SET1B DNA-binding map by DamID confirmed concordance of SET1B occupancy with HIF-1α sites, independently validating HIF-directed targeting.","evidence":"DamID-seq using SET1B-Dam fusion compared to HIF-1α ChIP-seq","pmids":["41087863"],"confidence":"Medium","gaps":["Non-HIF SET1B binding sites not characterized","DamID resolution limits precise promoter assignment"]},{"year":2026,"claim":"Demonstrating SET1B–RNA polymerase II interaction and YTHDF2-directed recruitment refined the recruitment logic, showing SETD1B uses partner interactions and non-catalytic domains to sustain transcription in specific contexts.","evidence":"Co-IP (SET1B–RNAPII; YTHDF2–SETD1B), depletion/knockdown, HIF-2 inhibitor synergy, ATAC-seq, and epistasis rescue","pmids":["41941749","41933071"],"confidence":"Medium","gaps":["Direct interaction interfaces not mapped","Relative contribution of catalytic vs non-catalytic functions not quantified"]},{"year":null,"claim":"How SETD1B achieves locus selectivity and broad-versus-narrow H3K4me3 deposition across cell types, and the structural basis of its partner interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the SETD1B complex or its partner interfaces","The determinant of broad-peak target selection unidentified","Full E3/DUB regulatory circuit controlling SETD1B abundance incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,8,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,7,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,16]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6]}],"complexes":["SETD1B/Set1B H3K4 methyltransferase complex (with CFP1, Rbbp5, Ash2, Wdr5, Wdr82)"],"partners":["CFP1","RBBP5","ASH2L","WDR5","WDR82","USP15","YTHDF2","RBM15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPS6","full_name":"Histone-lysine N-methyltransferase SETD1B","aliases":["Lysine N-methyltransferase 2G","SET domain-containing protein 1B","hSET1B"],"length_aa":1966,"mass_kda":212.8,"function":"Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism (PubMed:17355966, PubMed:25561738). Part of chromatin remodeling machinery, forms H3K4me1, H3K4me2 and H3K4me3 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:17355966, PubMed:25561738). Plays an essential role in regulating the transcriptional programming of multipotent hematopoietic progenitor cells and lymphoid lineage specification during hematopoiesis (By similarity)","subcellular_location":"Nucleus; Nucleus speckle; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UPS6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SETD1B","classification":"Not Classified","n_dependent_lines":216,"n_total_lines":1208,"dependency_fraction":0.17880794701986755},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SETD1B","total_profiled":1310},"omim":[{"mim_id":"619000","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEIZURES AND LANGUAGE DELAY; IDDSELD","url":"https://www.omim.org/entry/619000"},{"mim_id":"611055","title":"SET DOMAIN-CONTAINING PROTEIN 1B; SETD1B","url":"https://www.omim.org/entry/611055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SETD1B"},"hgnc":{"alias_symbol":["KIAA1076","Set1B","KMT2G"],"prev_symbol":[]},"alphafold":{"accession":"Q9UPS6","domains":[{"cath_id":"-","chopping":"30-65","consensus_level":"medium","plddt":63.9958,"start":30,"end":65},{"cath_id":"3.30.70.330","chopping":"101-206","consensus_level":"medium","plddt":89.5409,"start":101,"end":206},{"cath_id":"-","chopping":"1675-1717","consensus_level":"high","plddt":79.2605,"start":1675,"end":1717},{"cath_id":"2.170.270.10","chopping":"1824-1858_1900-1966","consensus_level":"medium","plddt":90.3889,"start":1824,"end":1966}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPS6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPS6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPS6-F1-predicted_aligned_error_v6.png","plddt_mean":45.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SETD1B","jax_strain_url":"https://www.jax.org/strain/search?query=SETD1B"},"sequence":{"accession":"Q9UPS6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPS6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPS6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPS6"}},"corpus_meta":[{"pmid":"17355966","id":"PMC_17355966","title":"Identification 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polycythemia vera patient with a novel SETD1B/GTF2H3 fusion gene.","date":"2014","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/24382738","citation_count":10,"is_preprint":false},{"pmid":"39235528","id":"PMC_39235528","title":"SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.","date":"2024","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39235528","citation_count":9,"is_preprint":false},{"pmid":"35196069","id":"PMC_35196069","title":"The methyltransferase enzymes KMT2D, SETD1B, and ASH1L are key mediators of both metabolic and epigenetic changes during cellular senescence.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35196069","citation_count":8,"is_preprint":false},{"pmid":"38447691","id":"PMC_38447691","title":"Epigenetic Mechanism of SETD1B-mediated Histone Methylation in Cognitive Impairment Induced by Sevoflurane Anesthesia 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In vitro assays demonstrate the complex produces H3K4me3. A 123-amino acid fragment upstream of the SET domain is required for interaction with CFP1, Ash2, Rbbp5, and Wdr5. Confocal microscopy reveals SETD1B localizes to a largely non-overlapping set of euchromatic nuclear speckles compared to SETD1A, suggesting non-redundant target gene binding.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, in vitro histone methyltransferase assay, deletion mutagenesis, confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro activity, complex defined by Co-IP + MS, mutagenesis of interaction domain, localization by direct imaging; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"17355966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SETD1B stability depends on its association with the methyltransferase complex: inducible expression of the carboxyl terminus of SETD1A or SETD1B decreases steady-state levels of both endogenous SETD1A and SETD1B protein without altering levels of the non-catalytic components, indicating feedback regulation through complex-dependent stability.\",\n      \"method\": \"Inducible overexpression, Western blot for steady-state protein levels\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function/gain-of-function with defined molecular readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"17355966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein directly interact with SETD1B. This interaction requires the Rbm15 SPOC domain and the SETD1B LSD motif. Overexpression of Rbm15-Mkl1 leads to cytokine-independent cell growth that requires an intact SPOC domain mediating interaction with SETD1B, implicating altered SETD1B complex function in AMKL leukemogenesis.\",\n      \"method\": \"Co-immunoprecipitation, deletion/domain mutagenesis, cytokine-independent proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction established by Co-IP with domain mapping, functional consequence in proliferation assay, single lab\",\n      \"pmids\": [\"22927943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In mice, Setd1b is dispensable until after gastrulation (embryos survive to E11.5 but are grossly retarded), whereas Setd1a is required at the epiblast stage. Overexpression of Setd1b cannot rescue the proliferation defects caused by loss of Setd1a in embryonic stem cells, demonstrating non-redundant and developmentally distinct roles for the two Set1 orthologs.\",\n      \"method\": \"Conditional knockout mouse genetics, embryo phenotyping, Setd1b overexpression rescue experiment in ESCs\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined developmental and cellular phenotypes, negative rescue experiment provides epistatic placement, replicated across multiple genetic strategies\",\n      \"pmids\": [\"24550110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SETD1B activates iNOS (nos2) expression in tumor-induced myeloid-derived suppressor cells (MDSCs). ChIP revealed enrichment of H3K4me3 (the catalytic product of SETD1B) at the nos2 promoter in MDSCs; inhibition or silencing of SETD1B diminished iNOS expression, demonstrating that SETD1B-mediated H3K4me3 deposition at the nos2 promoter drives iNOS transcription in an IRF8-independent manner.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), SETD1B silencing/inhibition, qRT-PCR/Western blot for iNOS\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP links H3K4me3 to nos2 promoter, loss-of-function confirms functional requirement, single lab, two orthogonal methods\",\n      \"pmids\": [\"28381543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional deletion of Setd1b in adult mice using ubiquitous and hematopoietic-specific strategies results in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis, and lethality. Transplantation experiments and expression profiling show Setd1b is autonomously required in hematopoietic lineages and regulates key lineage specification genes including Cebpa, Gata1, and Klf1.\",\n      \"method\": \"Conditional knockout mouse genetics, bone marrow transplantation, RNA expression profiling, hematopoietic phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple genetic strategies, transplantation establishes cell-autonomous requirement, gene expression profiling identifies downstream targets, multiple orthogonal methods\",\n      \"pmids\": [\"29916805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SET1B (SETD1B) is recruited to HIF target gene loci by the HIF transcription factor complex in hypoxia. SET1B accumulates on chromatin under hypoxic conditions, and its loss selectively reduces H3K4me3 at HIF target loci, correlating with decreased promoter acetylation and gene expression. Genome-wide mutagenesis screen identified SET1B as required for HIF transcriptional activity.\",\n      \"method\": \"Genome-wide CRISPR mutagenesis screen, ChIP-seq for SET1B and H3K4me3, promoter acetylation analysis, xenograft tumor assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen plus ChIP-seq plus functional rescue in multiple cell systems, multiple orthogonal methods establishing mechanism of recruitment\",\n      \"pmids\": [\"34155378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Postnatal SETD1B in excitatory neurons controls expression of a set of genes with broad H3K4me3 peaks at their promoters, enriched for neuron-specific genes linked to learning and memory. Conditional deletion of Setd1b in excitatory forebrain neurons leads to severe learning impairment. Comparative ChIP-seq and RNA-seq with Kmt2a and Kmt2b conditional knockouts show SETD1B plays a more pronounced role in regulating neuron-enriched, broad-H3K4me3-marked genes.\",\n      \"method\": \"Neuron-specific conditional knockout, ChIP-seq (H3K4me3), RNA-seq, behavioral learning tests\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq and RNA-seq, behavioral phenotyping, comparative analysis with paralogs; multiple orthogonal methods in one study\",\n      \"pmids\": [\"34806773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of SETD1B in oocytes (conditional KO) causes redistribution of H3K4me3: losses at active gene promoters associated with downregulated gene expression, and gains at DNA-hypomethylated, transcriptionally inactive, CpG-rich regions (hallmarks of MLL2/KMT2B targets). This reveals two complementary mechanisms of H3K4me3 targeting in oogenesis—SETD1B linked to gene expression and MLL2 to CpG content—and shows SETD1B normally suppresses MLL2-mediated methylation at these sites.\",\n      \"method\": \"Conditional knockout oocytes, ultra-low input ChIP-seq for H3K4me3, DNA methylation analysis, RNA-seq\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in defined cell type, genome-wide ChIP-seq plus DNA methylation plus RNA-seq, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35137160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD1B is required for mycolactone-induced cell death. CRISPR/Cas9 inactivation of SETD1B renders cells resistant to lethal doses of mycolactone. Mechanistically, SETD1B is required for mycolactone-selective upregulation of CHAC1 (a GSH-degrading enzyme), and SETD1B loss prevents mycolactone-induced glutathione depletion and apoptotic gene induction.\",\n      \"method\": \"Haploid genetic screen, CRISPR/Cas9 knockout, transcriptome comparison (RNA-seq), glutathione level measurement\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — haploid screen plus CRISPR KO plus transcriptomics plus metabolite measurement; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33006969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SETD1B mutations/deletions in B cell lymphoma confer resistance to the BCL2 inhibitor Venetoclax and an MCL-1 inhibitor. Mechanistically, SETD1B is required for expression of several proapoptotic BCL2 family proteins (including BIM and BIK). KDM5 histone H3K4 demethylase inhibitors restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. SETD1B cooperates with KMT2D loss in lymphoma development in vivo.\",\n      \"method\": \"Loss-of-function genetics (mutations/deletions), drug resistance assays, gene expression analysis, in vivo lymphoma model, KDM5 inhibitor combination treatment\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism (H3K4me3-dependent proapoptotic gene expression), pharmacological rescue, in vivo model, single lab\",\n      \"pmids\": [\"39235528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SETD1B SET domain disruption (via CRISPR tiling) in MLL-rearranged AML cells causes depletion of AML cells and downregulation of MYC pathway genes. SETD1B SET domain loss results in decreased H3K4me3 breadth at gene loci; exogenous MYC expression or disruption of H3K4 demethylase KDM5C rescues growth defects, establishing SETD1B's catalytic domain as required for broad H3K4me3 and MYC expression.\",\n      \"method\": \"CRISPR-tiling screen, H3K4me3 ChIP-seq, MYC overexpression rescue, KDM5C genetic disruption rescue\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR tiling plus ChIP-seq plus genetic epistasis rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40341256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SET1B interacts with RNA polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains beyond its histone methyltransferase activity. In clear cell renal cell carcinoma (ccRCC), SET1B is required for sustained HIF activity, and SET1B depletion enhances the efficacy of HIF-2 inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (SET1B–RNAPII interaction), SET1B depletion, HIF-2 inhibitor combination experiments, patient sample correlation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes RNAPII interaction, loss-of-function with defined HIF transcriptional readout, pharmacological synergy; single lab\",\n      \"pmids\": [\"41941749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SETD1B promotes ferroptosis in ischemic stroke brain cells by increasing H3K4me3 enrichment at the Tfrc (transferrin receptor 1) promoter, upregulating TfR1 expression and driving iron accumulation and lipid peroxidation. SETD1B knockdown reduces H3K4me3 at the Tfrc promoter and reverses ferroptosis markers in OGD/R-treated HT22 cells and ischemic mouse brain.\",\n      \"method\": \"ChIP for H3K4me3 at Tfrc promoter, SETD1B siRNA knockdown, ferroptosis marker assays (iron, LPO, GPX4), OGD/R cell model and mouse stroke model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP links SETD1B activity to specific promoter, KD with defined molecular and cellular phenotype, orthogonal in vivo and in vitro validation; single lab\",\n      \"pmids\": [\"40228655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP15 deubiquitinates SETD1B, increasing its protein stability. In ischemic stroke cells, USP15 knockdown increases SETD1B ubiquitination and decreases SETD1B protein levels, thereby reducing H3K4me3 enrichment at the Nckap1l and Wasf2 promoters and attenuating disulfidptosis.\",\n      \"method\": \"Co-immunoprecipitation (USP15–SETD1B), ubiquitination assay, siRNA knockdown, ChIP for H3K4me3 at target promoters\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishes the PTM writer–substrate relationship, ChIP links to downstream gene regulation, single lab\",\n      \"pmids\": [\"40609959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SETD1B promotes CXCR4 expression by increasing H3K4me3 levels at the CXCR4 promoter, thereby suppressing NLRP1/Caspase1-mediated neuronal pyroptosis. SETD1B overexpression mitigates sevoflurane-induced cognitive impairment in neonatal mice by this mechanism.\",\n      \"method\": \"ChIP for SETD1B and H3K4me1/2/3 at CXCR4 promoter, SETD1B overexpression (adenovirus), behavioral tests, pyroptosis marker assays\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP maps SETD1B to specific promoter, gain-of-function with behavioral and molecular phenotype, single lab\",\n      \"pmids\": [\"38447691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus, maternal Setd1b is required for organizer gene expression during dorsal axis development. Depletion of Setd1b impairs organizer gene activation, indicating that Setd1b-mediated H3K4 trimethylation is required downstream of the maternal Wnt/β-catenin pathway for proper organizer formation.\",\n      \"method\": \"Antisense morpholino depletion in Xenopus embryos, in situ hybridization, organizer gene expression analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in Xenopus with defined developmental and molecular phenotype; ortholog study, single lab\",\n      \"pmids\": [\"27519569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YTHDF2 physically interacts with SETD1B (but not SETD1A or CXXC1) in the cerebellum. Loss of Ythdf2 suppresses Setd1b-mediated H3K4me3 deposition and reduces chromatin accessibility at neuronal developmental gene loci. Setd1b knockdown rescues the neural self-renewal and differentiation defects caused by Ythdf2 deletion, placing SETD1B downstream of YTHDF2 in cerebellar development.\",\n      \"method\": \"Co-immunoprecipitation (YTHDF2–SETD1B), H3K4me3 ChIP analysis, ATAC-seq (chromatin accessibility), Setd1b knockdown rescue of Ythdf2 KO phenotype\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes specific interaction, genetic epistasis rescue places SETD1B downstream, ChIP links to H3K4me3; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41933071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DamID-seq using SET1B-Dam fusion protein provided the first genome-wide DNA binding map for SET1B, revealing strong concordance between SET1B chromatin occupancy and HIF-1α ChIP-seq data at HIF target loci.\",\n      \"method\": \"DamID-seq (Dam methyltransferase tagging of SET1B), bioinformatic comparison with HIF-1α ChIP-seq\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide chromatin binding map by DamID validated against orthogonal ChIP-seq; single lab, novel method application\",\n      \"pmids\": [\"41087863\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SETD1B (Set1B/KMT2G) is the catalytic subunit of an ~450 kDa H3K4 methyltransferase complex containing CFP1, Rbbp5, Ash2, Wdr5, and Wdr82, which produces H3K4me3 at active gene promoters; it is recruited to specific loci by interacting partners including the HIF complex and YTHDF2, and its catalytic SET domain is required for maintaining H3K4me3 breadth to sustain expression of target genes (including MYC pathway genes and proapoptotic BCL2 family members); its protein stability is regulated by USP15-mediated deubiquitination; and it plays non-redundant, cell-type-specific roles in hematopoiesis, oogenesis, neuronal learning, and hypoxia responses, with loss-of-function causing intellectual disability, epilepsy, and lymphoma drug resistance in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SETD1B is the catalytic subunit of an ~450 kDa histone H3K4 methyltransferase complex that deposits H3K4me3 at active gene promoters to sustain target-gene expression [#0]. It assembles with the non-catalytic subunits CFP1, Rbbp5, Ash2, Wdr5, and Wdr82 through a 123-amino-acid region upstream of its catalytic SET domain, and complex incorporation reciprocally stabilizes the catalytic protein [#0, #1]. SETD1B occupies a largely distinct set of euchromatic loci from its paralog SETD1A and performs non-redundant, developmentally and cell-type-specific functions: it is required after gastrulation in mouse development [#3], cell-autonomously controls hematopoietic lineage genes such as Cebpa, Gata1, and Klf1 [#5], and governs neuron-enriched genes marked by broad H3K4me3 peaks to support learning and memory [#7]. A recurring theme is that SETD1B catalytic activity maintains H3K4me3 breadth at specific promoters, with its SET domain required for MYC pathway gene expression in MLL-rearranged AML [#11] and for expression of proapoptotic BCL2 family genes including BIM and BIK, such that SETD1B loss confers Venetoclax resistance in B-cell lymphoma that is reversible by KDM5 demethylase inhibition [#10]. Sequence-specific recruitment is achieved through interacting partners: the HIF transcription factor complex recruits SETD1B to hypoxia-responsive loci and SETD1B further engages RNA polymerase II to sustain HIF-driven transcription [#6, #12, #18], while YTHDF2 directs SETD1B-dependent H3K4me3 at neuronal developmental genes in the cerebellum [#17]. SETD1B protein stability is controlled by USP15-mediated deubiquitination [#14]. Across oogenesis, SETD1B-linked, expression-coupled H3K4me3 is functionally distinct from and antagonistic to CpG-directed MLL2/KMT2B methylation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that SETD1B is the catalytic core of a defined multi-subunit H3K4 methyltransferase resolved what biochemical activity and partners define the protein and showed it targets loci distinct from its paralog.\",\n      \"evidence\": \"Co-IP/mass spectrometry, in vitro HMT assay, deletion mutagenesis, and confocal imaging of nuclear speckles\",\n      \"pmids\": [\"17355966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry and structural architecture of the complex not resolved\", \"The basis for SETD1B vs SETD1A locus selectivity not identified\", \"Direct genomic targets in vivo not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that catalytic subunit levels depend on complex association revealed a feedback mechanism coupling SETD1B abundance to assembly with its non-catalytic partners.\",\n      \"evidence\": \"Inducible overexpression of SETD1A/B C-termini with Western blot readout of endogenous protein levels\",\n      \"pmids\": [\"17355966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway mediating destabilization not identified\", \"Whether free catalytic subunit is targeted for proteolysis directly unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying a direct Rbm15/Rbm15-Mkl1 interaction with SETD1B linked altered complex function to leukemogenesis, providing a first disease-associated binding partner.\",\n      \"evidence\": \"Co-IP with SPOC/LSD domain mapping and cytokine-independent proliferation assay\",\n      \"pmids\": [\"22927943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of the fusion on SETD1B catalytic activity or genomic targeting not shown\", \"In vivo relevance of the interaction not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic comparison of Setd1a and Setd1b in mice and ESCs established that the two paralogs are non-redundant and act at distinct developmental stages.\",\n      \"evidence\": \"Conditional knockout embryo phenotyping plus negative Setd1b-overexpression rescue in ESCs\",\n      \"pmids\": [\"24550110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of non-redundancy not defined\", \"Specific genes driving the post-gastrulation requirement not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Maternal Setd1b requirement for organizer gene activation placed SETD1B-dependent H3K4me3 downstream of Wnt/β-catenin in axis formation.\",\n      \"evidence\": \"Morpholino depletion in Xenopus embryos with in situ analysis of organizer genes\",\n      \"pmids\": [\"27519569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct genomic targets in organizer not mapped\", \"Mechanism connecting Wnt signaling to SETD1B recruitment unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional deletion in adult mice defined a cell-autonomous, non-redundant SETD1B role in hematopoiesis and identified downstream lineage-specification targets.\",\n      \"evidence\": \"Hematopoietic-specific conditional KO, bone marrow transplantation, and RNA expression profiling\",\n      \"pmids\": [\"29916805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cebpa/Gata1/Klf1 are direct H3K4me3 targets not shown by ChIP\", \"Mechanism of lineage-specific recruitment unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying HIF-complex recruitment of SETD1B to hypoxia-responsive loci provided a sequence-specific targeting mechanism linking the methyltransferase to inducible transcription.\",\n      \"evidence\": \"Genome-wide CRISPR screen, SET1B and H3K4me3 ChIP-seq, promoter acetylation analysis, and xenografts\",\n      \"pmids\": [\"34155378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interface between SET1B and the HIF complex not mapped\", \"How H3K4me3 feeds back to promoter acetylation not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Neuron-specific deletion established that SETD1B preferentially controls broad-H3K4me3 neuronal genes underlying learning, distinguishing its role from Kmt2a/Kmt2b.\",\n      \"evidence\": \"Excitatory-neuron conditional KO with H3K4me3 ChIP-seq, RNA-seq, behavioral testing, and paralog comparison\",\n      \"pmids\": [\"34806773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What confers preference for broad-peak loci not defined\", \"Recruitment machinery in neurons not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Oocyte deletion revealed two complementary H3K4me3 targeting logics—expression-coupled SETD1B versus CpG-directed MLL2—and showed SETD1B suppresses ectopic MLL2 methylation.\",\n      \"evidence\": \"Conditional KO oocytes with ultra-low-input H3K4me3 ChIP-seq, DNA methylation analysis, and RNA-seq\",\n      \"pmids\": [\"35137160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SETD1B restrains MLL2 at CpG islands unknown\", \"Direct competition vs indirect effect not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking SETD1B catalytic function to proapoptotic BCL2-family gene expression explained how its loss drives BCL2/MCL-1 inhibitor resistance and revealed a KDM5-inhibitor rescue strategy.\",\n      \"evidence\": \"Loss-of-function genetics, drug resistance assays, expression analysis, in vivo lymphoma model, and KDM5 inhibitor combination\",\n      \"pmids\": [\"39235528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BIM/BIK are direct SETD1B targets shown only at the expression level\", \"Mechanism of cooperation with KMT2D loss not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR-tiling of the SET domain in MLL-rearranged AML established that catalytic activity per se maintains H3K4me3 breadth and MYC pathway gene expression required for leukemic growth.\",\n      \"evidence\": \"CRISPR-tiling screen, H3K4me3 ChIP-seq, and MYC overexpression / KDM5C disruption epistasis rescue\",\n      \"pmids\": [\"40341256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How breadth specifically controls MYC expression mechanistically unresolved\", \"Whether SET-domain dependence generalizes beyond MLL-rearranged AML untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying USP15 as a deubiquitinase stabilizing SETD1B defined a post-translational control point governing its abundance and downstream H3K4me3 deposition.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA knockdown, and ChIP at Nckap1l/Wasf2 promoters in ischemic stroke cells\",\n      \"pmids\": [\"40609959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase that ubiquitinates SETD1B not identified\", \"Ubiquitination site(s) not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ChIP-based studies in disease models extended SETD1B's promoter-specific H3K4me3 control to Tfrc-driven ferroptosis and CXCR4-mediated suppression of pyroptosis, illustrating context-specific target genes.\",\n      \"evidence\": \"ChIP for H3K4me3 at Tfrc/CXCR4 promoters, SETD1B knockdown/overexpression, and ferroptosis/pyroptosis and behavioral assays\",\n      \"pmids\": [\"40228655\", \"38447691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism to these loci not defined\", \"Direct vs indirect promoter regulation not fully distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A genome-wide SET1B DNA-binding map by DamID confirmed concordance of SET1B occupancy with HIF-1α sites, independently validating HIF-directed targeting.\",\n      \"evidence\": \"DamID-seq using SET1B-Dam fusion compared to HIF-1α ChIP-seq\",\n      \"pmids\": [\"41087863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-HIF SET1B binding sites not characterized\", \"DamID resolution limits precise promoter assignment\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating SET1B–RNA polymerase II interaction and YTHDF2-directed recruitment refined the recruitment logic, showing SETD1B uses partner interactions and non-catalytic domains to sustain transcription in specific contexts.\",\n      \"evidence\": \"Co-IP (SET1B–RNAPII; YTHDF2–SETD1B), depletion/knockdown, HIF-2 inhibitor synergy, ATAC-seq, and epistasis rescue\",\n      \"pmids\": [\"41941749\", \"41933071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction interfaces not mapped\", \"Relative contribution of catalytic vs non-catalytic functions not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SETD1B achieves locus selectivity and broad-versus-narrow H3K4me3 deposition across cell types, and the structural basis of its partner interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the SETD1B complex or its partner interfaces\", \"The determinant of broad-peak target selection unidentified\", \"Full E3/DUB regulatory circuit controlling SETD1B abundance incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 8, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 16]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"SETD1B/Set1B H3K4 methyltransferase complex (with CFP1, Rbbp5, Ash2, Wdr5, Wdr82)\"],\n    \"partners\": [\"CFP1\", \"RBBP5\", \"ASH2L\", \"WDR5\", \"WDR82\", \"USP15\", \"YTHDF2\", \"RBM15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}