{"gene":"KAT6B","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2008,"finding":"MORF (KAT6B) forms tetrameric complexes with ING5, EAF6, and BRPF1/2/3. BRPF1 bridges the association of MORF with ING5 and EAF6 via its N-terminal region (acetyltransferase domain interaction) and EPc homology domain (ING5/EAF6 interaction). Complex formation with BRPF1 and ING5 drastically stimulates MORF acetyltransferase activity on nucleosomal histone H3 and free histones H3 and H4. An 18-residue 'activation lid' at the C-terminal end of the catalytic domain is required for BRPF1 interaction.","method":"Reconstitution of tetrameric complexes, deletion mapping, in vitro HAT assays on nucleosomal and free histones, co-immunoprecipitation, reporter transcription assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted complexes in vitro, multiple orthogonal methods (pulldown, HAT assay, mutagenesis/deletion mapping, transcriptional assays), single rigorous study","pmids":["18794358"],"is_preprint":false},{"year":2002,"finding":"MORF (KAT6B) physically interacts with the Runt-domain transcription factor Runx2 (and Runx1/AML1) through its C-terminal SM (serine- and methionine-rich) domain, both in vitro and in vivo. The SM domain of MORF potentiates Runx2-dependent transcriptional activation, and endogenous MORF is required for transcriptional activation by Runx2. MORF does not acetylate Runx2. Runx2 negatively regulates the transcriptional activation potential of the SM domain.","method":"In vitro binding assay, co-immunoprecipitation (in vivo), reporter transcription assay, siRNA/dominant-negative knockdown","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro/in vivo binding and functional transcription assays in a single focused study with multiple orthogonal methods","pmids":["11965546"],"is_preprint":false},{"year":2000,"finding":"KAT6B (Querkopf/Qkf) is required for normal cerebral cortex development in mice. Homozygous querkopf mutants show a disproportionately small cortical plate, lack of large pyramidal cells in cortical layer V (reduced Otx1-positive neurons), and reduced GAD67-positive interneurons, establishing KAT6B as an essential regulator of cortical cell differentiation.","method":"Gene trap mouse mutagenesis, histological and immunostaining analysis of cortical layers","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse model with specific cellular phenotypic readouts, replicated in subsequent studies","pmids":["10821753"],"is_preprint":false},{"year":2006,"finding":"KAT6B (Qkf) is essential for adult neurogenesis. Qkf-deficient mice have fewer neural stem cells, fewer migrating neuroblasts in the rostral migratory stream, and declining numbers of olfactory bulb interneurons. Neural stem/progenitor cells from Qkf mutant mice show reduced self-renewal and reduced ability to produce differentiated neurons.","method":"Qkf hypomorphic mouse model, in vivo cell counting, neurosphere self-renewal assay, differentiation assays from isolated stem/progenitor cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function in vivo with specific cellular phenotype plus in vitro functional assays","pmids":["17079664"],"is_preprint":false},{"year":2011,"finding":"Haploinsufficiency of KAT6B (MYST4) in a patient with Noonan syndrome-like phenotype leads to reduced H3 acetylation and hyperactivation of the MAPK signaling pathway. ChIP and whole-genome expression studies in patient cells and siRNA knockdown cell lines showed that H3 acetylation by KAT6B specifically regulates the MAPK signaling pathway during neural, craniofacial, and skeletal morphogenesis.","method":"Chromosomal breakpoint mapping, H3 acetylation assays, ChIP, whole genome expression analysis, siRNA knockdown in cell lines, Myst4 querkopf mouse","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, expression profiling, patient cells, mouse model, siRNA knockdown) in a single study","pmids":["21804188"],"is_preprint":false},{"year":2012,"finding":"GPS-causing KAT6B truncating mutations result in reduced histone H3 and H4 acetylation in patient-derived cells, directly linking KAT6B loss-of-function to dysregulation of histone acetylation.","method":"Exome sequencing, Sanger sequencing, histone acetylation assays in patient-derived cells","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, patient-derived cells with acetylation assay, no mechanistic pathway dissection beyond histone modification","pmids":["22265017"],"is_preprint":false},{"year":2019,"finding":"The native MORF (KAT6B) complex is a histone H3K23-specific acetyltransferase. The DPF (double PHD finger) domain of MORF (MORFDPF) positively regulates MORF acetyltransferase function by recognizing crotonylated H3K14; crystal structure of MORFDPF-H3K14crotonyl complex reveals selectivity for lipophilic acyllysine substrates and DNA binding. ChIP data show that MORFDPF is required for MORF-dependent H3K23 acetylation of target genes. Mass spectrometry and genomic analyses demonstrate co-existence and co-occupancy of H3K23ac and H3K14ac marks.","method":"Native complex purification, in vitro HAT assay, crystal structure of DPF-H3K14 crotonyl peptide complex, mass spectrometry, ChIP-seq, biochemical binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis, native complex HAT assay, ChIP genomic validation, multiple orthogonal methods in a single rigorous study","pmids":["31624313"],"is_preprint":false},{"year":2017,"finding":"The DPF domain of MORF (KAT6B) recognizes many histone H3K14 acylation marks (including butyrylation). Crystal structure of the MORF DPF-H3K14butyryl complex provides insight into selectivity for lipophilic acyllysine substrates, supporting a mechanism by which MORF promotes spreading of histone acylation.","method":"Crystal structure determination, mass spectrometry, in vitro binding assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mass spectrometry and binding assays in a single focused study","pmids":["28286003"],"is_preprint":false},{"year":2012,"finding":"The tandem PHD1/2 fingers of MORF (KAT6B) recognize the N-terminal tail of histone H3; acetylation of H3K9 or H3K14 enhances binding 2-3 fold. Trimethylation of H3K4 inhibits the interaction. NMR, fluorescence spectroscopy, and mutagenesis identified key residues. Both PHD fingers are required for binding H3K14ac in vivo and for chromatin localization. H3K14ac interaction may promote MORF enzymatic activity in trans.","method":"NMR, fluorescence spectroscopy, mutagenesis, immunoprecipitation, fluorescence microscopy, in vitro HAT assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural analysis with mutagenesis, in vivo localization, and functional HAT assay in a single rigorous study","pmids":["23063713"],"is_preprint":false},{"year":2023,"finding":"MORF (KAT6B) and MOZ contain two structured winged helix (WH) domains (WH1 and WH2). WH1 specifically recognizes unmethylated CpG sequences and WH2 binds the dyad of the nucleosome. WHs bind DNA cooperatively and target MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation. WH1 recruits oncogenic fusions to HOXA genes. Cryo-EM, NMR, mass spectrometry, and mutagenesis provided mechanistic insight.","method":"Cryo-EM structure, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure, NMR, mutagenesis, and ChIP-seq genomic validation in a single rigorous multi-method study","pmids":["36754959"],"is_preprint":false},{"year":2024,"finding":"The first winged helix domain of MORF (MORFWH1) has dual binding activity: it recognizes the TAZ2 domain of p300 and CpG-rich DNA sequences through distinct binding sites. MORF/MOZWH1 co-localizes with H3K18ac (a product of p300 enzymatic activity) on CpG-rich promoters of target genes, suggesting functional cooperation of MORF and p300 acetyltransferases in transcriptional regulation.","method":"Structural analysis (biochemical), ChIP-seq genomic analysis, binding assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural/biochemical binding studies plus ChIP-seq validation, single lab","pmids":["38500836"],"is_preprint":false},{"year":2015,"finding":"KAT6B acts as a tumor suppressor in small cell lung cancer through histone H3 Lys23 acetyltransferase activity. Homozygous deletions of KAT6B are present in SCLC cell lines and primary tumors. Depletion of KAT6B enhances cancer cell growth in vitro and in vivo, while restoration induces tumor suppressor-like features.","method":"Genomic deletion analysis, KAT6B knockdown/restoration in cell lines and xenograft mouse models, in vitro HAT assay for H3K23","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function experiments in vitro and in vivo with enzymatic activity assay, single lab","pmids":["26208904"],"is_preprint":false},{"year":2019,"finding":"KAT6B (MORF) regulates chromatin organization and modulates binding of pluripotency transcription factors Oct4 and Nanog to chromatin in embryonic stem cells. Kat6b knockout (CRISPR/Cas9) ES cells show more compact chromatin organization (fluorescence correlation spectroscopy) and impaired Oct4/Nanog-chromatin interactions, and exhibit reduced efficiency of neural lineage differentiation. Kat6b is expressed in ES cells and is repressed during differentiation; its expression is regulated by Nanog and Oct4.","method":"CRISPR/Cas9 knockout ES cells, fluorescence correlation spectroscopy, neural differentiation assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with specific chromatin and differentiation readouts using fluorescence correlation spectroscopy, single lab","pmids":["30790630"],"is_preprint":false},{"year":2020,"finding":"KAT6B regulates hematopoietic stem cell (HSC) myeloid differentiation. Kat6b is highly expressed in long-term HSCs and decreases with aging. Knockdown of Kat6b in young LT-HSCs causes skewed myeloid production at the expense of erythroid cells in vitro and in vivo, with upregulation of aging/macrophage gene signatures and downregulation of self-renewal signatures.","method":"shRNA screen, in vitro and in vivo differentiation assays after knockdown, transcriptome analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — focused shRNA loss-of-function with in vivo reconstitution and transcriptome analysis, single lab","pmids":["32014431"],"is_preprint":false},{"year":2024,"finding":"KAT6B is essential for normal levels of histone H3 lysine 9 (H3K9) acetylation (but not H3K23 as previously proposed) in hematopoietic stem cells. Compound heterozygosity of Kat6b and Kat6a abolishes hematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promote transcription of hematopoiesis-regulating genes including Hoxa cluster, Pbx1, Meis1, Gata family, Erg, and Flt3.","method":"Germline deletion and overexpression mouse models, histone acetylation assays, bone marrow transplantation, transcriptome analysis, compound heterozygote analysis","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO, OE, compound heterozygote), in vivo functional assays, histone modification profiling, transcriptome; single lab but multiple orthogonal methods","pmids":["38518784"],"is_preprint":false},{"year":2024,"finding":"KAT6B deficiency causes reduction in histone H3 lysine 9 acetylation (H3K9ac) in human SBBYSS cells and mouse brain/blood. Treatment with HDAC inhibitor (valproic acid) or acetyl-carnitine (ALCAR) elevated histone acetylation levels and partially reversed gene expression changes in Kat6b+/- cortical neurons, improving sociability and restoring learning and memory in Kat6b+/- mice.","method":"Kat6b heterozygous mouse model, human SBBYSS patient cells, H3K9ac assays, HDAC inhibitor treatment, behavioral assays, cortical neuron transcriptome","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient cells and mouse model, histone modification readout, pharmacological rescue with behavioral validation; multiple orthogonal methods","pmids":["38557491"],"is_preprint":false},{"year":2025,"finding":"KAT6B loss of function in mesenchymal progenitor cells promotes transition toward an osteoblast-progenitor state with upregulation of RUNX2 gene targets and downregulation of SOX9. Compound heterozygosity at Kat6b and Runx2 loci partially rescues the ossification deficit of Runx2 heterozygous mice, placing KAT6B upstream of RUNX2 in limiting osteoblast differentiation. KAT6B loss causes premature ossification, shortened craniofacial elements, increased bone density, and shortened tibias.","method":"Germline Kat6b deletion mouse, compound heterozygote genetic epistasis (Kat6b x Runx2), histology, transcriptome analysis, immunostaining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double mutant rescue), in vivo phenotype, transcriptome, multiple orthogonal methods in a single rigorous study","pmids":["39832706"],"is_preprint":false},{"year":2025,"finding":"4-fold overexpression of Kat6b rescues all developmental defects in Kat6a homozygous null mice, including absence of hematopoietic stem cells. Kat6b overexpression restores H3K9 and H3K23 acetylation and reverses critical gene expression anomalies in Kat6a mutant mice, demonstrating functional overlap between KAT6B and KAT6A when KAT6B is expressed at sufficiently high levels.","method":"Transgenic Kat6b overexpression in Kat6a null mouse background, histone acetylation assays (H3K9ac, H3K23ac), transcriptome analysis, hematopoietic reconstitution assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment with histone modification assays and transcriptome, multiple orthogonal methods, single lab rigorous study","pmids":["40000651"],"is_preprint":false},{"year":2016,"finding":"Decreased KAT6B (MORF) expression in periodontitis-associated mesenchymal stem cells causes upregulation of PERK (a key UPR sensor), leading to persistent UPR activation and impaired osteogenic differentiation. KAT6B mediates PERK transcription; chronic inflammation suppresses KAT6B, thereby compromising UPR function through MORF-mediated PERK transcriptional regulation.","method":"Cell culture with proinflammatory cytokines, KAT6B knockdown/overexpression, in vivo periodontitis model, PERK and osteogenic differentiation assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain of function with specific pathway readout (PERK/UPR) in vitro and in vivo, single lab","pmids":["27447113"],"is_preprint":false},{"year":2017,"finding":"KAT6B promotes LPS-triggered IL-6 production in macrophages by increasing recruitment of H3K23 acetylation to the IL-6 gene promoter region. KAT6B knockdown suppressed LPS-induced IL-6 production; KAT6B overexpression promoted it. The effect was not mediated through changes in NF-κB p65 or MAPK activity.","method":"siRNA knockdown, overexpression, qRT-PCR, ELISA, ChIP (H3K23ac at IL-6 promoter), dual-luciferase reporter assay, Western blot","journal":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence plus functional gain/loss of function with multiple readouts, single lab","pmids":["29268844"],"is_preprint":false},{"year":2025,"finding":"KAT6B overexpression in mice causes aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression increases histone H3K9 acetylation and upregulates genes driving nervous system development and neuronal differentiation. KAT6B overexpression promotes neural stem cell proliferation and favors neuronal over astrocyte differentiation in vivo and in vitro.","method":"Transgenic Kat6b overexpression mouse, behavioral assays, H3K9ac assays, neural stem cell differentiation assays in vivo and in vitro, transcriptome","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function mouse model with multiple cellular phenotype readouts and histone modification assays, single lab","pmids":["40083716"],"is_preprint":false},{"year":2013,"finding":"KAT6B silencing in prostate cancer DU145 cells suppresses AKT signaling (PI3K-AKT pathway), reducing cell proliferation. DNA microarray and IPA analysis identified PI3K signaling among suppressed pathways upon KAT6B knockdown.","method":"RNAi screen, gene-specific siRNA knockdown, DNA microarray, Ingenuity Pathway Analysis, immunoblotting for AKT","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gene expression/pathway inference from knockdown without direct mechanistic dissection of KAT6B-AKT link","pmids":["24294372"],"is_preprint":false},{"year":2022,"finding":"KAT6B occupies the STAT3 promoter in glioma cells and promotes H3K23 acetylation (H3K23ac) and RNA polymerase II enrichment at the STAT3 promoter, thereby transcriptionally activating STAT3. KAT6B knockdown reduces H3K23ac and RNA pol II at the STAT3 promoter and downregulates STAT3, suppressing ferroptosis resistance.","method":"ChIP assay (H3K23ac and RNA pol II at STAT3 promoter), KAT6B knockdown/overexpression, cell viability and apoptosis assays","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP with functional rescue but limited mechanistic depth","pmids":["35432536"],"is_preprint":false},{"year":2007,"finding":"MYST4 (KAT6B) protein is expressed in specialized reproductive cells: in the ovary it is confined to oocytes, granulosa and theca cells, and vascular cells; in the testis it is restricted to elongating spermatids where it is exclusively nuclear. In oocytes and embryos, MYST4 protein localizes to both cytoplasm and nucleus.","method":"Immunohistochemistry on ovary and testis sections, subcellular localization by immunostaining in oocytes/embryos","journal":"BMC developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, localization data without direct functional consequence established","pmids":["17980037"],"is_preprint":false}],"current_model":"KAT6B (MORF/QKF/MYST4) is a MYST-family lysine acetyltransferase that functions as the catalytic subunit of a tetrameric complex with BRPF1/2/3, ING5, and EAF6; BRPF1 bridges complex assembly and dramatically stimulates KAT6B's acetyltransferase activity toward nucleosomal H3 and free histones H3/H4. Its primary histone substrates are H3K9 and H3K23, with H3K23 acetylation promoted by the DPF domain reading acylated H3K14 marks and by N-terminal winged helix domains (WH1/WH2) that cooperatively bind unmethylated CpG DNA to target the complex to gene promoters; WH1 also binds the TAZ2 domain of p300, suggesting functional cooperation with p300. KAT6B interacts with transcription factors Runx2/Runx1 through its C-terminal SM domain to coactivate their transcriptional programs. KAT6B is essential for cortical neurogenesis, adult neural stem cell self-renewal, and hematopoietic stem cell maintenance; it cooperates with the closely related KAT6A for full hematopoietic function, and its loss causes premature ossification by de-repressing RUNX2-driven osteoblast differentiation. Loss of KAT6B reduces H3K9 acetylation, dysregulates MAPK signaling, and causes intellectual disability syndromes (SBBYSS and genitopatellar syndrome) in humans."},"narrative":{"mechanistic_narrative":"KAT6B (MORF/QKF/MYST4) is a MYST-family lysine acetyltransferase that operates as the catalytic core of a tetrameric complex with BRPF1/2/3, ING5, and EAF6, in which BRPF1 bridges complex assembly and drastically stimulates acetyltransferase activity toward nucleosomal H3 and free histones H3 and H4 [PMID:18794358]. The native complex is an H3K23-specific acetyltransferase whose chromatin engagement is governed by reader and DNA-binding modules: the DPF (double PHD finger) domain recognizes lipophilic acyllysine marks such as crotonylated and butyrylated H3K14 to promote H3K23 acetylation of target genes [PMID:31624313, PMID:28286003], the tandem PHD fingers bind the H3 N-terminal tail (enhanced by H3K9/H3K14 acetylation, inhibited by H3K4me3) to direct chromatin localization [PMID:23063713], and tandem winged-helix domains WH1/WH2 bind unmethylated CpG DNA and the nucleosome dyad cooperatively to target promoters and stimulate transcription and H3K23 acetylation, with WH1 additionally engaging the p300 TAZ2 domain to coordinate with p300-driven H3K18 acetylation [PMID:36754959, PMID:38500836]. Through its C-terminal SM domain, KAT6B physically binds and coactivates the Runt-domain transcription factors Runx2 and Runx1 without acetylating them [PMID:11965546]. KAT6B is essential for cortical neurogenesis and adult neural stem cell self-renewal [PMID:10821753, PMID:17079664] and for hematopoietic stem cell function, where it sustains H3K9 acetylation and, in cooperation with the paralog KAT6A, drives transcription of hematopoietic regulators including the Hoxa cluster, Pbx1, Meis1, and Gata genes; sufficiently high KAT6B expression fully substitutes for KAT6A [PMID:38518784, PMID:40000651]. KAT6B loss de-represses RUNX2-driven osteoblast differentiation to cause premature ossification [PMID:39832706] and reduces H3K9 acetylation with dysregulated MAPK signaling [PMID:21804188]; human loss-of-function mutations cause genitopatellar and SBBYSS intellectual-disability syndromes, and elevating histone acetylation pharmacologically partially reverses neurological deficits in Kat6b-deficient mice [PMID:22265017, PMID:38557491].","teleology":[{"year":2000,"claim":"Established KAT6B as an essential developmental regulator by showing it is required for cerebral cortex differentiation, before any biochemical activity was assigned.","evidence":"Gene-trap mouse mutagenesis with histological and immunostaining analysis of cortical layers","pmids":["10821753"],"confidence":"High","gaps":["Did not define the molecular activity underlying the phenotype","No chromatin or substrate-level mechanism"]},{"year":2002,"claim":"Connected KAT6B to a transcriptional program by demonstrating its SM domain binds and coactivates Runx2/Runx1, defining a non-catalytic transcription-factor partnership.","evidence":"In vitro binding, co-IP, reporter assays, and knockdown in cells","pmids":["11965546"],"confidence":"High","gaps":["KAT6B does not acetylate Runx2, so the molecular basis of coactivation is unresolved","Did not connect to histone acetylation at Runx target genes"]},{"year":2006,"claim":"Extended the developmental role to adult tissue by showing KAT6B sustains neural stem cell self-renewal and neuroblast production.","evidence":"Hypomorphic mouse model, in vivo cell counting, neurosphere self-renewal and differentiation assays","pmids":["17079664"],"confidence":"High","gaps":["Did not identify direct target genes in neural stem cells","Molecular mechanism of self-renewal control unknown"]},{"year":2008,"claim":"Defined the biochemical core of KAT6B function by reconstituting the BRPF1/ING5/EAF6 tetramer and showing BRPF1 bridges assembly and drastically stimulates HAT activity on nucleosomes.","evidence":"Reconstituted complexes, deletion mapping, in vitro HAT assays, co-IP, reporter assays","pmids":["18794358"],"confidence":"High","gaps":["Did not pinpoint a single primary histone-lysine substrate","In vivo genomic targets of the complex not mapped"]},{"year":2011,"claim":"Linked KAT6B haploinsufficiency to a signaling defect, showing reduced H3 acetylation hyperactivates MAPK during morphogenesis.","evidence":"Breakpoint mapping, H3 acetylation assays, ChIP, expression profiling, siRNA, querkopf mouse","pmids":["21804188"],"confidence":"High","gaps":["Direct vs indirect control of MAPK genes not fully separated","Specific acetylated lysine not yet resolved"]},{"year":2012,"claim":"Resolved how the complex recognizes chromatin, showing tandem PHD fingers read the H3 tail with acetylation-enhanced and H3K4me3-inhibited binding required for localization.","evidence":"NMR, fluorescence spectroscopy, mutagenesis, IP, microscopy, in vitro HAT assay","pmids":["23063713"],"confidence":"High","gaps":["How PHD reading couples to catalytic stimulation in trans not fully defined"]},{"year":2012,"claim":"Confirmed human disease causality by tying GPS-causing truncating mutations to reduced H3/H4 acetylation in patient cells.","evidence":"Exome/Sanger sequencing and histone acetylation assays in patient-derived cells","pmids":["22265017"],"confidence":"Medium","gaps":["No pathway dissection beyond global histone modification","Genome-wide target consequences not mapped"]},{"year":2017,"claim":"Provided structural basis for acyl-mark reading, showing the DPF domain selects lipophilic H3K14 acylations (butyryl) to support spreading of acylation.","evidence":"Crystal structure of DPF-H3K14butyryl, mass spectrometry, binding assays","pmids":["28286003"],"confidence":"High","gaps":["Functional consequence of acyl reading on genomic targets shown later, not here"]},{"year":2019,"claim":"Established H3K23 as the principal substrate of the native complex and tied catalysis to DPF reading of crotonylated H3K14.","evidence":"Native complex HAT assay, DPF-H3K14cr crystal structure, mass spectrometry, ChIP-seq","pmids":["31624313"],"confidence":"High","gaps":["Relationship between H3K23ac and H3K9ac substrate preference across cell types unresolved"]},{"year":2019,"claim":"Connected KAT6B to chromatin architecture and pluripotency by showing its loss compacts chromatin and impairs Oct4/Nanog-chromatin binding in ES cells.","evidence":"CRISPR KO ES cells, fluorescence correlation spectroscopy, neural differentiation","pmids":["30790630"],"confidence":"Medium","gaps":["Direct vs indirect effect on Oct4/Nanog binding not separated","Histone substrate at affected loci not defined"]},{"year":2023,"claim":"Defined the DNA-targeting mechanism, showing tandem winged-helix domains cooperatively bind unmethylated CpG and the nucleosome dyad to direct the complex to promoters.","evidence":"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays","pmids":["36754959"],"confidence":"High","gaps":["How WH targeting integrates with PHD/DPF reading at native loci not fully reconstructed"]},{"year":2024,"claim":"Revealed coordination with a second acetyltransferase, showing WH1 binds the p300 TAZ2 domain and co-localizes with p300-deposited H3K18ac at CpG promoters.","evidence":"Biochemical structural analysis, ChIP-seq, binding assays","pmids":["38500836"],"confidence":"Medium","gaps":["Direct functional cooperation in vivo not demonstrated by epistasis","Single lab"]},{"year":2024,"claim":"Refined the hematopoietic substrate and revealed paralog redundancy, showing KAT6B maintains H3K9ac (not H3K23ac) in HSCs and cooperates with KAT6A to drive hematopoietic gene programs.","evidence":"KO/OE and compound-heterozygote mouse models, histone acetylation assays, transplantation, transcriptome","pmids":["38518784"],"confidence":"High","gaps":["Why substrate preference differs from H3K23ac in other systems unresolved","Direct vs indirect regulation of Hoxa/Meis1 not fully separated"]},{"year":2024,"claim":"Established a therapeutic rationale for the neurological syndrome, showing H3K9ac loss in SBBYSS cells/mice is partially reversed pharmacologically with behavioral rescue.","evidence":"Kat6b+/- mouse, human SBBYSS cells, H3K9ac assays, HDAC inhibitor/ALCAR treatment, behavior, transcriptome","pmids":["38557491"],"confidence":"High","gaps":["Direct target genes mediating behavioral rescue not pinpointed","Durability of rescue not addressed"]},{"year":2025,"claim":"Placed KAT6B upstream of RUNX2 in skeletal development by genetic epistasis, explaining premature ossification as RUNX2 de-repression.","evidence":"Germline Kat6b deletion mouse, Kat6b x Runx2 compound heterozygote rescue, histology, transcriptome","pmids":["39832706"],"confidence":"High","gaps":["Molecular step by which KAT6B restrains RUNX2 targets not defined","Relationship to the earlier SM-domain Runx2 coactivation not reconciled"]},{"year":2025,"claim":"Demonstrated full functional overlap with KAT6A, showing KAT6B overexpression rescues all defects of Kat6a-null mice including HSC loss and restores H3K9ac/H3K23ac.","evidence":"Transgenic Kat6b overexpression in Kat6a-null background, histone acetylation assays, transcriptome, reconstitution","pmids":["40000651"],"confidence":"High","gaps":["Endogenous division of labor between paralogs under physiological dosage not resolved"]},{"year":2025,"claim":"Showed dosage sensitivity in the nervous system, with KAT6B overexpression elevating H3K9ac, biasing neuronal differentiation, and producing behavioral/epileptic phenotypes.","evidence":"Transgenic Kat6b overexpression mouse, behavior, H3K9ac assays, NSC differentiation assays, transcriptome","pmids":["40083716"],"confidence":"Medium","gaps":["Direct target genes driving behavioral phenotypes not defined","Single lab"]},{"year":null,"claim":"How KAT6B's chromatin-reading and DNA-targeting modules integrate to select H3K9 versus H3K23 acetylation in a cell-type-specific manner, and how this dictates distinct neural, skeletal, and hematopoietic programs, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Determinants of H3K9ac vs H3K23ac substrate choice across tissues unknown","Unified model linking SM-domain TF coactivation, WH/PHD/DPF chromatin targeting, and disease phenotypes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,6,8,11,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,9,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6,7,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,9,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,23]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,9]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,9,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,16]}],"complexes":["KAT6B-BRPF1/2/3-ING5-EAF6 MYST acetyltransferase complex"],"partners":["BRPF1","ING5","EAF6","RUNX2","RUNX1","EP300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WYB5","full_name":"Histone acetyltransferase KAT6B","aliases":["Histone acetyltransferase MOZ2","MOZ, YBF2/SAS3, SAS2 and TIP60 protein 4","MYST-4","Monocytic leukemia zinc finger protein-related 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Required for RUNX2-dependent transcriptional activation. May be involved in cerebral cortex development. 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p300.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38500836","citation_count":5,"is_preprint":false},{"pmid":"36639835","id":"PMC_36639835","title":"XBP1-elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR-22/lncRNA/KAT6B-dependent NF-κB signalling.","date":"2023","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36639835","citation_count":5,"is_preprint":false},{"pmid":"37288707","id":"PMC_37288707","title":"Clinical features and underlying mechanisms of KAT6B disease in a Chinese boy.","date":"2023","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37288707","citation_count":4,"is_preprint":false},{"pmid":"39505971","id":"PMC_39505971","title":"ERα status of invasive ductal breast carcinoma as a result of regulatory interactions between lysine deacetylases KAT6A and KAT6B.","date":"2024","source":"Scientific 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Brassica napus.","date":"2024","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/38816808","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51267,"output_tokens":6680,"usd":0.127,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15434,"output_tokens":5061,"usd":0.101847,"stage2_stop_reason":"end_turn"},"total_usd":0.228847,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"MORF (KAT6B) forms tetrameric complexes with ING5, EAF6, and BRPF1/2/3. BRPF1 bridges the association of MORF with ING5 and EAF6 via its N-terminal region (acetyltransferase domain interaction) and EPc homology domain (ING5/EAF6 interaction). Complex formation with BRPF1 and ING5 drastically stimulates MORF acetyltransferase activity on nucleosomal histone H3 and free histones H3 and H4. An 18-residue 'activation lid' at the C-terminal end of the catalytic domain is required for BRPF1 interaction.\",\n      \"method\": \"Reconstitution of tetrameric complexes, deletion mapping, in vitro HAT assays on nucleosomal and free histones, co-immunoprecipitation, reporter transcription assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted complexes in vitro, multiple orthogonal methods (pulldown, HAT assay, mutagenesis/deletion mapping, transcriptional assays), single rigorous study\",\n      \"pmids\": [\"18794358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MORF (KAT6B) physically interacts with the Runt-domain transcription factor Runx2 (and Runx1/AML1) through its C-terminal SM (serine- and methionine-rich) domain, both in vitro and in vivo. The SM domain of MORF potentiates Runx2-dependent transcriptional activation, and endogenous MORF is required for transcriptional activation by Runx2. MORF does not acetylate Runx2. Runx2 negatively regulates the transcriptional activation potential of the SM domain.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation (in vivo), reporter transcription assay, siRNA/dominant-negative knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro/in vivo binding and functional transcription assays in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"11965546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KAT6B (Querkopf/Qkf) is required for normal cerebral cortex development in mice. Homozygous querkopf mutants show a disproportionately small cortical plate, lack of large pyramidal cells in cortical layer V (reduced Otx1-positive neurons), and reduced GAD67-positive interneurons, establishing KAT6B as an essential regulator of cortical cell differentiation.\",\n      \"method\": \"Gene trap mouse mutagenesis, histological and immunostaining analysis of cortical layers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse model with specific cellular phenotypic readouts, replicated in subsequent studies\",\n      \"pmids\": [\"10821753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KAT6B (Qkf) is essential for adult neurogenesis. Qkf-deficient mice have fewer neural stem cells, fewer migrating neuroblasts in the rostral migratory stream, and declining numbers of olfactory bulb interneurons. Neural stem/progenitor cells from Qkf mutant mice show reduced self-renewal and reduced ability to produce differentiated neurons.\",\n      \"method\": \"Qkf hypomorphic mouse model, in vivo cell counting, neurosphere self-renewal assay, differentiation assays from isolated stem/progenitor cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function in vivo with specific cellular phenotype plus in vitro functional assays\",\n      \"pmids\": [\"17079664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Haploinsufficiency of KAT6B (MYST4) in a patient with Noonan syndrome-like phenotype leads to reduced H3 acetylation and hyperactivation of the MAPK signaling pathway. ChIP and whole-genome expression studies in patient cells and siRNA knockdown cell lines showed that H3 acetylation by KAT6B specifically regulates the MAPK signaling pathway during neural, craniofacial, and skeletal morphogenesis.\",\n      \"method\": \"Chromosomal breakpoint mapping, H3 acetylation assays, ChIP, whole genome expression analysis, siRNA knockdown in cell lines, Myst4 querkopf mouse\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, expression profiling, patient cells, mouse model, siRNA knockdown) in a single study\",\n      \"pmids\": [\"21804188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GPS-causing KAT6B truncating mutations result in reduced histone H3 and H4 acetylation in patient-derived cells, directly linking KAT6B loss-of-function to dysregulation of histone acetylation.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, histone acetylation assays in patient-derived cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, patient-derived cells with acetylation assay, no mechanistic pathway dissection beyond histone modification\",\n      \"pmids\": [\"22265017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The native MORF (KAT6B) complex is a histone H3K23-specific acetyltransferase. The DPF (double PHD finger) domain of MORF (MORFDPF) positively regulates MORF acetyltransferase function by recognizing crotonylated H3K14; crystal structure of MORFDPF-H3K14crotonyl complex reveals selectivity for lipophilic acyllysine substrates and DNA binding. ChIP data show that MORFDPF is required for MORF-dependent H3K23 acetylation of target genes. Mass spectrometry and genomic analyses demonstrate co-existence and co-occupancy of H3K23ac and H3K14ac marks.\",\n      \"method\": \"Native complex purification, in vitro HAT assay, crystal structure of DPF-H3K14 crotonyl peptide complex, mass spectrometry, ChIP-seq, biochemical binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis, native complex HAT assay, ChIP genomic validation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31624313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The DPF domain of MORF (KAT6B) recognizes many histone H3K14 acylation marks (including butyrylation). Crystal structure of the MORF DPF-H3K14butyryl complex provides insight into selectivity for lipophilic acyllysine substrates, supporting a mechanism by which MORF promotes spreading of histone acylation.\",\n      \"method\": \"Crystal structure determination, mass spectrometry, in vitro binding assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mass spectrometry and binding assays in a single focused study\",\n      \"pmids\": [\"28286003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The tandem PHD1/2 fingers of MORF (KAT6B) recognize the N-terminal tail of histone H3; acetylation of H3K9 or H3K14 enhances binding 2-3 fold. Trimethylation of H3K4 inhibits the interaction. NMR, fluorescence spectroscopy, and mutagenesis identified key residues. Both PHD fingers are required for binding H3K14ac in vivo and for chromatin localization. H3K14ac interaction may promote MORF enzymatic activity in trans.\",\n      \"method\": \"NMR, fluorescence spectroscopy, mutagenesis, immunoprecipitation, fluorescence microscopy, in vitro HAT assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural analysis with mutagenesis, in vivo localization, and functional HAT assay in a single rigorous study\",\n      \"pmids\": [\"23063713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MORF (KAT6B) and MOZ contain two structured winged helix (WH) domains (WH1 and WH2). WH1 specifically recognizes unmethylated CpG sequences and WH2 binds the dyad of the nucleosome. WHs bind DNA cooperatively and target MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation. WH1 recruits oncogenic fusions to HOXA genes. Cryo-EM, NMR, mass spectrometry, and mutagenesis provided mechanistic insight.\",\n      \"method\": \"Cryo-EM structure, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure, NMR, mutagenesis, and ChIP-seq genomic validation in a single rigorous multi-method study\",\n      \"pmids\": [\"36754959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The first winged helix domain of MORF (MORFWH1) has dual binding activity: it recognizes the TAZ2 domain of p300 and CpG-rich DNA sequences through distinct binding sites. MORF/MOZWH1 co-localizes with H3K18ac (a product of p300 enzymatic activity) on CpG-rich promoters of target genes, suggesting functional cooperation of MORF and p300 acetyltransferases in transcriptional regulation.\",\n      \"method\": \"Structural analysis (biochemical), ChIP-seq genomic analysis, binding assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural/biochemical binding studies plus ChIP-seq validation, single lab\",\n      \"pmids\": [\"38500836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KAT6B acts as a tumor suppressor in small cell lung cancer through histone H3 Lys23 acetyltransferase activity. Homozygous deletions of KAT6B are present in SCLC cell lines and primary tumors. Depletion of KAT6B enhances cancer cell growth in vitro and in vivo, while restoration induces tumor suppressor-like features.\",\n      \"method\": \"Genomic deletion analysis, KAT6B knockdown/restoration in cell lines and xenograft mouse models, in vitro HAT assay for H3K23\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function experiments in vitro and in vivo with enzymatic activity assay, single lab\",\n      \"pmids\": [\"26208904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT6B (MORF) regulates chromatin organization and modulates binding of pluripotency transcription factors Oct4 and Nanog to chromatin in embryonic stem cells. Kat6b knockout (CRISPR/Cas9) ES cells show more compact chromatin organization (fluorescence correlation spectroscopy) and impaired Oct4/Nanog-chromatin interactions, and exhibit reduced efficiency of neural lineage differentiation. Kat6b is expressed in ES cells and is repressed during differentiation; its expression is regulated by Nanog and Oct4.\",\n      \"method\": \"CRISPR/Cas9 knockout ES cells, fluorescence correlation spectroscopy, neural differentiation assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with specific chromatin and differentiation readouts using fluorescence correlation spectroscopy, single lab\",\n      \"pmids\": [\"30790630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KAT6B regulates hematopoietic stem cell (HSC) myeloid differentiation. Kat6b is highly expressed in long-term HSCs and decreases with aging. Knockdown of Kat6b in young LT-HSCs causes skewed myeloid production at the expense of erythroid cells in vitro and in vivo, with upregulation of aging/macrophage gene signatures and downregulation of self-renewal signatures.\",\n      \"method\": \"shRNA screen, in vitro and in vivo differentiation assays after knockdown, transcriptome analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — focused shRNA loss-of-function with in vivo reconstitution and transcriptome analysis, single lab\",\n      \"pmids\": [\"32014431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT6B is essential for normal levels of histone H3 lysine 9 (H3K9) acetylation (but not H3K23 as previously proposed) in hematopoietic stem cells. Compound heterozygosity of Kat6b and Kat6a abolishes hematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promote transcription of hematopoiesis-regulating genes including Hoxa cluster, Pbx1, Meis1, Gata family, Erg, and Flt3.\",\n      \"method\": \"Germline deletion and overexpression mouse models, histone acetylation assays, bone marrow transplantation, transcriptome analysis, compound heterozygote analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO, OE, compound heterozygote), in vivo functional assays, histone modification profiling, transcriptome; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38518784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT6B deficiency causes reduction in histone H3 lysine 9 acetylation (H3K9ac) in human SBBYSS cells and mouse brain/blood. Treatment with HDAC inhibitor (valproic acid) or acetyl-carnitine (ALCAR) elevated histone acetylation levels and partially reversed gene expression changes in Kat6b+/- cortical neurons, improving sociability and restoring learning and memory in Kat6b+/- mice.\",\n      \"method\": \"Kat6b heterozygous mouse model, human SBBYSS patient cells, H3K9ac assays, HDAC inhibitor treatment, behavioral assays, cortical neuron transcriptome\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient cells and mouse model, histone modification readout, pharmacological rescue with behavioral validation; multiple orthogonal methods\",\n      \"pmids\": [\"38557491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT6B loss of function in mesenchymal progenitor cells promotes transition toward an osteoblast-progenitor state with upregulation of RUNX2 gene targets and downregulation of SOX9. Compound heterozygosity at Kat6b and Runx2 loci partially rescues the ossification deficit of Runx2 heterozygous mice, placing KAT6B upstream of RUNX2 in limiting osteoblast differentiation. KAT6B loss causes premature ossification, shortened craniofacial elements, increased bone density, and shortened tibias.\",\n      \"method\": \"Germline Kat6b deletion mouse, compound heterozygote genetic epistasis (Kat6b x Runx2), histology, transcriptome analysis, immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double mutant rescue), in vivo phenotype, transcriptome, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"39832706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"4-fold overexpression of Kat6b rescues all developmental defects in Kat6a homozygous null mice, including absence of hematopoietic stem cells. Kat6b overexpression restores H3K9 and H3K23 acetylation and reverses critical gene expression anomalies in Kat6a mutant mice, demonstrating functional overlap between KAT6B and KAT6A when KAT6B is expressed at sufficiently high levels.\",\n      \"method\": \"Transgenic Kat6b overexpression in Kat6a null mouse background, histone acetylation assays (H3K9ac, H3K23ac), transcriptome analysis, hematopoietic reconstitution assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment with histone modification assays and transcriptome, multiple orthogonal methods, single lab rigorous study\",\n      \"pmids\": [\"40000651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Decreased KAT6B (MORF) expression in periodontitis-associated mesenchymal stem cells causes upregulation of PERK (a key UPR sensor), leading to persistent UPR activation and impaired osteogenic differentiation. KAT6B mediates PERK transcription; chronic inflammation suppresses KAT6B, thereby compromising UPR function through MORF-mediated PERK transcriptional regulation.\",\n      \"method\": \"Cell culture with proinflammatory cytokines, KAT6B knockdown/overexpression, in vivo periodontitis model, PERK and osteogenic differentiation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain of function with specific pathway readout (PERK/UPR) in vitro and in vivo, single lab\",\n      \"pmids\": [\"27447113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KAT6B promotes LPS-triggered IL-6 production in macrophages by increasing recruitment of H3K23 acetylation to the IL-6 gene promoter region. KAT6B knockdown suppressed LPS-induced IL-6 production; KAT6B overexpression promoted it. The effect was not mediated through changes in NF-κB p65 or MAPK activity.\",\n      \"method\": \"siRNA knockdown, overexpression, qRT-PCR, ELISA, ChIP (H3K23ac at IL-6 promoter), dual-luciferase reporter assay, Western blot\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence plus functional gain/loss of function with multiple readouts, single lab\",\n      \"pmids\": [\"29268844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT6B overexpression in mice causes aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression increases histone H3K9 acetylation and upregulates genes driving nervous system development and neuronal differentiation. KAT6B overexpression promotes neural stem cell proliferation and favors neuronal over astrocyte differentiation in vivo and in vitro.\",\n      \"method\": \"Transgenic Kat6b overexpression mouse, behavioral assays, H3K9ac assays, neural stem cell differentiation assays in vivo and in vitro, transcriptome\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function mouse model with multiple cellular phenotype readouts and histone modification assays, single lab\",\n      \"pmids\": [\"40083716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KAT6B silencing in prostate cancer DU145 cells suppresses AKT signaling (PI3K-AKT pathway), reducing cell proliferation. DNA microarray and IPA analysis identified PI3K signaling among suppressed pathways upon KAT6B knockdown.\",\n      \"method\": \"RNAi screen, gene-specific siRNA knockdown, DNA microarray, Ingenuity Pathway Analysis, immunoblotting for AKT\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gene expression/pathway inference from knockdown without direct mechanistic dissection of KAT6B-AKT link\",\n      \"pmids\": [\"24294372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT6B occupies the STAT3 promoter in glioma cells and promotes H3K23 acetylation (H3K23ac) and RNA polymerase II enrichment at the STAT3 promoter, thereby transcriptionally activating STAT3. KAT6B knockdown reduces H3K23ac and RNA pol II at the STAT3 promoter and downregulates STAT3, suppressing ferroptosis resistance.\",\n      \"method\": \"ChIP assay (H3K23ac and RNA pol II at STAT3 promoter), KAT6B knockdown/overexpression, cell viability and apoptosis assays\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP with functional rescue but limited mechanistic depth\",\n      \"pmids\": [\"35432536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MYST4 (KAT6B) protein is expressed in specialized reproductive cells: in the ovary it is confined to oocytes, granulosa and theca cells, and vascular cells; in the testis it is restricted to elongating spermatids where it is exclusively nuclear. In oocytes and embryos, MYST4 protein localizes to both cytoplasm and nucleus.\",\n      \"method\": \"Immunohistochemistry on ovary and testis sections, subcellular localization by immunostaining in oocytes/embryos\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization data without direct functional consequence established\",\n      \"pmids\": [\"17980037\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT6B (MORF/QKF/MYST4) is a MYST-family lysine acetyltransferase that functions as the catalytic subunit of a tetrameric complex with BRPF1/2/3, ING5, and EAF6; BRPF1 bridges complex assembly and dramatically stimulates KAT6B's acetyltransferase activity toward nucleosomal H3 and free histones H3/H4. Its primary histone substrates are H3K9 and H3K23, with H3K23 acetylation promoted by the DPF domain reading acylated H3K14 marks and by N-terminal winged helix domains (WH1/WH2) that cooperatively bind unmethylated CpG DNA to target the complex to gene promoters; WH1 also binds the TAZ2 domain of p300, suggesting functional cooperation with p300. KAT6B interacts with transcription factors Runx2/Runx1 through its C-terminal SM domain to coactivate their transcriptional programs. KAT6B is essential for cortical neurogenesis, adult neural stem cell self-renewal, and hematopoietic stem cell maintenance; it cooperates with the closely related KAT6A for full hematopoietic function, and its loss causes premature ossification by de-repressing RUNX2-driven osteoblast differentiation. Loss of KAT6B reduces H3K9 acetylation, dysregulates MAPK signaling, and causes intellectual disability syndromes (SBBYSS and genitopatellar syndrome) in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAT6B (MORF/QKF/MYST4) is a MYST-family lysine acetyltransferase that operates as the catalytic core of a tetrameric complex with BRPF1/2/3, ING5, and EAF6, in which BRPF1 bridges complex assembly and drastically stimulates acetyltransferase activity toward nucleosomal H3 and free histones H3 and H4 [#0]. The native complex is an H3K23-specific acetyltransferase whose chromatin engagement is governed by reader and DNA-binding modules: the DPF (double PHD finger) domain recognizes lipophilic acyllysine marks such as crotonylated and butyrylated H3K14 to promote H3K23 acetylation of target genes [#6, #7], the tandem PHD fingers bind the H3 N-terminal tail (enhanced by H3K9/H3K14 acetylation, inhibited by H3K4me3) to direct chromatin localization [#8], and tandem winged-helix domains WH1/WH2 bind unmethylated CpG DNA and the nucleosome dyad cooperatively to target promoters and stimulate transcription and H3K23 acetylation, with WH1 additionally engaging the p300 TAZ2 domain to coordinate with p300-driven H3K18 acetylation [#9, #10]. Through its C-terminal SM domain, KAT6B physically binds and coactivates the Runt-domain transcription factors Runx2 and Runx1 without acetylating them [#1]. KAT6B is essential for cortical neurogenesis and adult neural stem cell self-renewal [#2, #3] and for hematopoietic stem cell function, where it sustains H3K9 acetylation and, in cooperation with the paralog KAT6A, drives transcription of hematopoietic regulators including the Hoxa cluster, Pbx1, Meis1, and Gata genes; sufficiently high KAT6B expression fully substitutes for KAT6A [#14, #17]. KAT6B loss de-represses RUNX2-driven osteoblast differentiation to cause premature ossification [#16] and reduces H3K9 acetylation with dysregulated MAPK signaling [#4]; human loss-of-function mutations cause genitopatellar and SBBYSS intellectual-disability syndromes, and elevating histone acetylation pharmacologically partially reverses neurological deficits in Kat6b-deficient mice [#5, #15].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established KAT6B as an essential developmental regulator by showing it is required for cerebral cortex differentiation, before any biochemical activity was assigned.\",\n      \"evidence\": \"Gene-trap mouse mutagenesis with histological and immunostaining analysis of cortical layers\",\n      \"pmids\": [\"10821753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity underlying the phenotype\", \"No chromatin or substrate-level mechanism\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected KAT6B to a transcriptional program by demonstrating its SM domain binds and coactivates Runx2/Runx1, defining a non-catalytic transcription-factor partnership.\",\n      \"evidence\": \"In vitro binding, co-IP, reporter assays, and knockdown in cells\",\n      \"pmids\": [\"11965546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KAT6B does not acetylate Runx2, so the molecular basis of coactivation is unresolved\", \"Did not connect to histone acetylation at Runx target genes\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended the developmental role to adult tissue by showing KAT6B sustains neural stem cell self-renewal and neuroblast production.\",\n      \"evidence\": \"Hypomorphic mouse model, in vivo cell counting, neurosphere self-renewal and differentiation assays\",\n      \"pmids\": [\"17079664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify direct target genes in neural stem cells\", \"Molecular mechanism of self-renewal control unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the biochemical core of KAT6B function by reconstituting the BRPF1/ING5/EAF6 tetramer and showing BRPF1 bridges assembly and drastically stimulates HAT activity on nucleosomes.\",\n      \"evidence\": \"Reconstituted complexes, deletion mapping, in vitro HAT assays, co-IP, reporter assays\",\n      \"pmids\": [\"18794358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint a single primary histone-lysine substrate\", \"In vivo genomic targets of the complex not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked KAT6B haploinsufficiency to a signaling defect, showing reduced H3 acetylation hyperactivates MAPK during morphogenesis.\",\n      \"evidence\": \"Breakpoint mapping, H3 acetylation assays, ChIP, expression profiling, siRNA, querkopf mouse\",\n      \"pmids\": [\"21804188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of MAPK genes not fully separated\", \"Specific acetylated lysine not yet resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how the complex recognizes chromatin, showing tandem PHD fingers read the H3 tail with acetylation-enhanced and H3K4me3-inhibited binding required for localization.\",\n      \"evidence\": \"NMR, fluorescence spectroscopy, mutagenesis, IP, microscopy, in vitro HAT assay\",\n      \"pmids\": [\"23063713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PHD reading couples to catalytic stimulation in trans not fully defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed human disease causality by tying GPS-causing truncating mutations to reduced H3/H4 acetylation in patient cells.\",\n      \"evidence\": \"Exome/Sanger sequencing and histone acetylation assays in patient-derived cells\",\n      \"pmids\": [\"22265017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No pathway dissection beyond global histone modification\", \"Genome-wide target consequences not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural basis for acyl-mark reading, showing the DPF domain selects lipophilic H3K14 acylations (butyryl) to support spreading of acylation.\",\n      \"evidence\": \"Crystal structure of DPF-H3K14butyryl, mass spectrometry, binding assays\",\n      \"pmids\": [\"28286003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of acyl reading on genomic targets shown later, not here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established H3K23 as the principal substrate of the native complex and tied catalysis to DPF reading of crotonylated H3K14.\",\n      \"evidence\": \"Native complex HAT assay, DPF-H3K14cr crystal structure, mass spectrometry, ChIP-seq\",\n      \"pmids\": [\"31624313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between H3K23ac and H3K9ac substrate preference across cell types unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected KAT6B to chromatin architecture and pluripotency by showing its loss compacts chromatin and impairs Oct4/Nanog-chromatin binding in ES cells.\",\n      \"evidence\": \"CRISPR KO ES cells, fluorescence correlation spectroscopy, neural differentiation\",\n      \"pmids\": [\"30790630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on Oct4/Nanog binding not separated\", \"Histone substrate at affected loci not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the DNA-targeting mechanism, showing tandem winged-helix domains cooperatively bind unmethylated CpG and the nucleosome dyad to direct the complex to promoters.\",\n      \"evidence\": \"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays\",\n      \"pmids\": [\"36754959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WH targeting integrates with PHD/DPF reading at native loci not fully reconstructed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed coordination with a second acetyltransferase, showing WH1 binds the p300 TAZ2 domain and co-localizes with p300-deposited H3K18ac at CpG promoters.\",\n      \"evidence\": \"Biochemical structural analysis, ChIP-seq, binding assays\",\n      \"pmids\": [\"38500836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional cooperation in vivo not demonstrated by epistasis\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the hematopoietic substrate and revealed paralog redundancy, showing KAT6B maintains H3K9ac (not H3K23ac) in HSCs and cooperates with KAT6A to drive hematopoietic gene programs.\",\n      \"evidence\": \"KO/OE and compound-heterozygote mouse models, histone acetylation assays, transplantation, transcriptome\",\n      \"pmids\": [\"38518784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why substrate preference differs from H3K23ac in other systems unresolved\", \"Direct vs indirect regulation of Hoxa/Meis1 not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a therapeutic rationale for the neurological syndrome, showing H3K9ac loss in SBBYSS cells/mice is partially reversed pharmacologically with behavioral rescue.\",\n      \"evidence\": \"Kat6b+/- mouse, human SBBYSS cells, H3K9ac assays, HDAC inhibitor/ALCAR treatment, behavior, transcriptome\",\n      \"pmids\": [\"38557491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating behavioral rescue not pinpointed\", \"Durability of rescue not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed KAT6B upstream of RUNX2 in skeletal development by genetic epistasis, explaining premature ossification as RUNX2 de-repression.\",\n      \"evidence\": \"Germline Kat6b deletion mouse, Kat6b x Runx2 compound heterozygote rescue, histology, transcriptome\",\n      \"pmids\": [\"39832706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step by which KAT6B restrains RUNX2 targets not defined\", \"Relationship to the earlier SM-domain Runx2 coactivation not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated full functional overlap with KAT6A, showing KAT6B overexpression rescues all defects of Kat6a-null mice including HSC loss and restores H3K9ac/H3K23ac.\",\n      \"evidence\": \"Transgenic Kat6b overexpression in Kat6a-null background, histone acetylation assays, transcriptome, reconstitution\",\n      \"pmids\": [\"40000651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous division of labor between paralogs under physiological dosage not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed dosage sensitivity in the nervous system, with KAT6B overexpression elevating H3K9ac, biasing neuronal differentiation, and producing behavioral/epileptic phenotypes.\",\n      \"evidence\": \"Transgenic Kat6b overexpression mouse, behavior, H3K9ac assays, NSC differentiation assays, transcriptome\",\n      \"pmids\": [\"40083716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target genes driving behavioral phenotypes not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KAT6B's chromatin-reading and DNA-targeting modules integrate to select H3K9 versus H3K23 acetylation in a cell-type-specific manner, and how this dictates distinct neural, skeletal, and hematopoietic programs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of H3K9ac vs H3K23ac substrate choice across tissues unknown\", \"Unified model linking SM-domain TF coactivation, WH/PHD/DPF chromatin targeting, and disease phenotypes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 6, 8, 11, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 9, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 9, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 23]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 16]}\n    ],\n    \"complexes\": [\"KAT6B-BRPF1/2/3-ING5-EAF6 MYST acetyltransferase complex\"],\n    \"partners\": [\"BRPF1\", \"ING5\", \"EAF6\", \"RUNX2\", \"RUNX1\", \"EP300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}