{"gene":"BAZ2A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2014,"finding":"BAZ2A (TIP5) directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis in prostate cancer cells.","method":"Co-immunoprecipitation / protein interaction assay in prostate cancer cells","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP reported, single lab, but finding is supported by genomic occupancy data in the same study","pmids":["25485837"],"is_preprint":false},{"year":2014,"finding":"The PHD zinc finger domain of TIP5 recognizes unmodified H3 histone tails as an independent structural module, while the bromodomain preferentially binds H3 and H4 acetylation marks followed by a key basic residue (KacXXR motif); together these modules mediate trans-histone tail recognition required for NoRC recruitment to chromatin and transcriptional repression of rDNA.","method":"X-ray crystallography of PHD and bromodomain in free and histone-bound forms; low-resolution SAXS of PHD-bromodomain module","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of multiple domain-histone complexes with functional validation, multiple orthogonal biophysical methods in one study","pmids":["25533489"],"is_preprint":false},{"year":2015,"finding":"The TAM domain of TIP5 adopts an extended MBD-like fold with unique C-terminal extensions that form a novel RNA-binding surface; mutation of critical residues on this surface abolishes RNA binding both in vitro and in vivo, explaining how NoRC is targeted to specific genomic loci via noncoding RNA.","method":"NMR structure determination; mutagenesis with in vitro RNA-binding assays and in vivo validation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis validated in vitro and in vivo in one study, multiple orthogonal methods","pmids":["25916849"],"is_preprint":false},{"year":2015,"finding":"GSK2801 acts as an acetyl-lysine competitive inhibitor of the BAZ2A bromodomain (KD ~257 nM for BAZ2A), binding in a canonical acetyl-lysine competitive mode as confirmed by crystal structure; cellular activity was demonstrated by FRAP showing displacement of GFP-BAZ2A from acetylated chromatin.","method":"Crystal structure of bromodomain–inhibitor complex; isothermal titration calorimetry / competition binding; FRAP in cells","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, biophysical binding assays, and cellular FRAP in one study with rigorous controls","pmids":["25799074"],"is_preprint":false},{"year":2015,"finding":"BAZ2-ICR occupies the BAZ2A bromodomain acetyl-lysine pocket through an intramolecular aromatic stacking interaction that efficiently fills the shallow binding site, as revealed by structure-based design.","method":"Structure-based drug design; X-ray crystallography of inhibitor–bromodomain complex","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional binding validation, single lab","pmids":["25719566"],"is_preprint":false},{"year":2013,"finding":"The TAM domain of Tip5 functions as the nucleolar localization and nuclear matrix targeting module, while AT-hooks are required for nucleolar targeting but do not mediate nuclear matrix association; Tip5 overexpression facilitates rDNA association with the nuclear matrix and increases DNase I inaccessibility, regulating large-scale rDNA chromatin organization.","method":"Domain deletion/mutation analysis; nuclear fractionation; DNase I accessibility assay; overexpression and localization imaging","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean domain dissection with multiple functional readouts, single lab","pmids":["23580549"],"is_preprint":false},{"year":2013,"finding":"NuRD complex directly binds to the TIP5 promoter and negatively regulates TIP5 expression, thereby limiting TIP5-mediated recruitment of DNA methyltransferase to rDNA promoters and maintaining their unmethylated state.","method":"ChIP at TIP5 promoter; knockdown of NuRD components with measurement of TIP5 expression and rDNA methylation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional KD experiments, single lab","pmids":["23796711"],"is_preprint":false},{"year":2018,"finding":"TIP5 physically interacts with TCF7L2 (identified by co-immunoprecipitation and GST pull-down) and enhances the interaction between β-catenin and TCF7L2, thereby activating Wnt/β-catenin signaling in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation; GST pull-down assay; reporter and functional cell assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal pulldown (Co-IP + GST), single lab, single study","pmids":["29620186"],"is_preprint":false},{"year":2020,"finding":"In ground-state embryonic stem cells, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A), and cohesin on chromatin; BAZ2A depletion increases chromatin accessibility at B compartments and dysregulates H3K27me3 genome occupancy in a TOP2A-dependent manner, demonstrating that BAZ2A limits invasion of active chromatin domains into repressive compartments.","method":"Co-immunoprecipitation; Hi-C genome architecture analysis; ATAC-seq; ChIP-seq; genetic depletion (BAZ2A KO/KD)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genome-wide and biochemical methods, clear mechanistic epistasis established","pmids":["33433018"],"is_preprint":false},{"year":2021,"finding":"BAZ2A bromodomain specifically binds H3K14ac-marked chromatin at inactive enhancers; BAZ2A-BRD mutations or pharmacological inhibition of the BAZ2A-BRD/H3K14ac interaction impairs prostate cancer stem cell features and Pten-loss-driven oncogenic transformation in organoids. BAZ2A-mediated repression at these enhancers is linked to EP300, which acetylates H3K14.","method":"ChIP-seq for BAZ2A and H3K14ac; bromodomain point mutations; BRD inhibitor treatment; organoid transformation assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, structure-function mutagenesis, pharmacological and genetic perturbations, and organoid functional assay in one study","pmids":["34403195"],"is_preprint":false},{"year":2021,"finding":"The BAZ2A TAM domain binds double-stranded DNA and double-stranded RNA in a sequence-nonspecific, backbone-dependent manner (distinct from canonical MBD methyl-CpG recognition), as established by EMSA, ITC, mutagenesis, and X-ray crystallography.","method":"EMSA; isothermal titration calorimetry; mutagenesis; X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with ITC, EMSA, and mutagenesis in one study; multiple orthogonal methods","pmids":["34715126"],"is_preprint":false},{"year":2023,"finding":"In prostate cancer, the BAZ2A TAM domain mediates interaction with TOP2A and KDM1A through an RNA-dependent mechanism; pharmacological inhibition of TOP2A or KDM1A upregulates BAZ2A-repressed genes controlled by inactive enhancers, whereas rRNA gene silencing is unaffected, revealing a distinct RNA-based gene repression mechanism separate from rDNA silencing.","method":"Co-immunoprecipitation; RNA-dependency experiments; pharmacological inhibition of TOP2A and KDM1A; ChIP-seq; RNA-seq","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pharmacological epistasis and genome-wide readouts, single lab","pmids":["37184661"],"is_preprint":false},{"year":2020,"finding":"TIP5 is required for the initiation of prostate cancer transformation of luminal cells driven by Pten-loss in organoids, but is dispensable once transformation is established, placing TIP5 upstream of Pten-loss-mediated oncogenesis in a defined cellular context.","method":"Mouse prostate organoid model; Pten knockdown; TIP5 depletion with defined temporal order; cross-species gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in organoid model with defined temporal order, single lab","pmids":["32024754"],"is_preprint":false}],"current_model":"BAZ2A (TIP5) is the large scaffolding subunit of the nucleolar remodeling complex (NoRC) that uses its PHD finger to bind unmodified H3 tails, its bromodomain to recognize acetylated histone marks (including H3K14ac at enhancers), and its TAM domain to bind dsDNA/dsRNA in a sequence-nonspecific manner, thereby recruiting NoRC to rDNA and other genomic loci; it represses rRNA genes and cancer-relevant target genes through interactions with SNF2H, EZH2, TOP2A, KDM1A, and cohesin, and its TAM domain anchors the complex to the nuclear matrix via a nucleolar localization function, collectively establishing BAZ2A as a multi-domain epigenetic reader-scaffold that coordinates chromatin remodeling, heterochromatin formation, and genome compartmentalization."},"narrative":{"mechanistic_narrative":"BAZ2A (TIP5) is a multi-domain chromatin reader-scaffold that recruits the nucleolar remodeling machinery to genomic loci to enforce transcriptional repression and heterochromatin organization [PMID:25533489, PMID:33433018]. It engages chromatin through distinct modules: a PHD finger that reads unmodified H3 tails and a bromodomain that recognizes acetylated histones via a KacXXR motif, with both modules cooperating in trans-histone recognition required for recruitment and rDNA repression [PMID:25533489]. The bromodomain specifically binds H3K14ac (deposited by EP300) at inactive enhancers, and disrupting this interaction by point mutation or small-molecule inhibition impairs prostate cancer stem cell features and Pten-loss-driven transformation [PMID:34403195]. Its TAM domain adopts an MBD-like fold that binds double-stranded DNA and RNA in a sequence-nonspecific, backbone-dependent manner, and also serves as the nucleolar localization and nuclear matrix targeting module that drives large-scale rDNA chromatin compaction [PMID:25916849, PMID:34715126, PMID:23580549]. Through these interactions BAZ2A partners with SNF2H, TOP2A, cohesin and KDM1A to constrain chromatin accessibility at repressive (B) compartments and to silence enhancer-controlled genes via an RNA-dependent mechanism distinct from rDNA silencing [PMID:33433018, PMID:37184661]. BAZ2A additionally maintains repressive epigenetic states with EZH2 in metastasis-related genes and is required for the initiation of Pten-loss prostate oncogenesis [PMID:25485837, PMID:32024754].","teleology":[{"year":2013,"claim":"Defined which BAZ2A module anchors rDNA chromatin to the nuclear scaffold, addressing how the complex organizes large-scale rDNA architecture.","evidence":"Domain deletion/mutation, nuclear fractionation, and DNase I accessibility assays on overexpressed Tip5","pmids":["23580549"],"confidence":"Medium","gaps":["Performed under overexpression conditions","Does not resolve TAM-domain ligand specificity for matrix association"]},{"year":2013,"claim":"Identified an upstream regulator of TIP5 expression, showing NuRD limits TIP5 levels to keep rDNA promoters unmethylated.","evidence":"ChIP at the TIP5 promoter plus knockdown of NuRD components measuring TIP5 expression and rDNA methylation","pmids":["23796711"],"confidence":"Medium","gaps":["Single lab","Direct DNA methyltransferase recruitment by TIP5 not structurally defined"]},{"year":2014,"claim":"Established a cancer-relevant repressive partnership by showing BAZ2A interacts with EZH2 to silence metastasis-suppressed genes.","evidence":"Co-immunoprecipitation with supporting genomic occupancy data in prostate cancer cells","pmids":["25485837"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation reported","Direct vs. complex-mediated interaction not separated"]},{"year":2014,"claim":"Defined the structural basis for histone-tail reading, showing the PHD finger and bromodomain act as cooperating modules for chromatin recruitment.","evidence":"X-ray crystallography of PHD and bromodomain in free and histone-bound forms plus SAXS of the combined module","pmids":["25533489"],"confidence":"High","gaps":["In vivo combinatorial readout at endogenous loci not mapped","Does not address TAM-domain contribution"]},{"year":2015,"claim":"Solved the TAM-domain fold and identified its nucleic-acid binding surface, explaining how noncoding RNA could target NoRC.","evidence":"NMR structure determination with mutagenesis validated in vitro and in vivo","pmids":["25916849"],"confidence":"High","gaps":["Sequence specificity of the RNA target not defined here","Genomic loci targeted by RNA binding not enumerated"]},{"year":2015,"claim":"Delivered chemical-probe inhibitors of the BAZ2A bromodomain, enabling pharmacological dissection of acetyl-lysine reading.","evidence":"Crystal structures of bromodomain-inhibitor complexes, ITC/competition binding, and cellular FRAP (GSK2801, BAZ2-ICR)","pmids":["25799074","25719566"],"confidence":"High","gaps":["Genome-wide consequences of bromodomain inhibition not assessed in these studies","Selectivity against the paralog bromodomain context"]},{"year":2020,"claim":"Revealed a genome-organization role, showing BAZ2A interacts with SNF2H, TOP2A and cohesin to prevent active chromatin invading repressive compartments.","evidence":"Co-IP, Hi-C, ATAC-seq, ChIP-seq and genetic depletion in ground-state embryonic stem cells","pmids":["33433018"],"confidence":"High","gaps":["Whether compartment maintenance requires the TAM or bromodomain not resolved","Mechanism of TOP2A-dependent H3K27me3 redistribution undefined"]},{"year":2020,"claim":"Placed TIP5 temporally upstream of Pten-loss oncogenesis, showing it is required for initiation but dispensable once transformation is established.","evidence":"Mouse prostate organoid model with Pten knockdown and temporally defined TIP5 depletion","pmids":["32024754"],"confidence":"Medium","gaps":["Molecular targets driving the initiation requirement not pinpointed","Single model system"]},{"year":2021,"claim":"Connected the bromodomain to a specific enhancer mark, showing H3K14ac (EP300-deposited) recognition drives repression and oncogenic transformation.","evidence":"ChIP-seq, bromodomain point mutations, BRD inhibitor treatment and organoid transformation assays","pmids":["34403195"],"confidence":"High","gaps":["How H3K14ac binding mediates repression mechanistically not fully resolved","Generality beyond prostate cells untested"]},{"year":2021,"claim":"Established the biochemical nature of TAM-domain nucleic-acid binding as sequence-nonspecific and backbone-dependent, distinguishing it from canonical methyl-CpG readers.","evidence":"EMSA, ITC, mutagenesis and X-ray crystallography","pmids":["34715126"],"confidence":"High","gaps":["How nonspecific binding achieves locus-specific targeting in vivo","Relative roles of dsDNA vs dsRNA binding"]},{"year":2023,"claim":"Distinguished an RNA-based enhancer-repression mechanism from rDNA silencing, showing the TAM domain recruits TOP2A and KDM1A in an RNA-dependent manner.","evidence":"Co-IP, RNA-dependency experiments, pharmacological inhibition of TOP2A/KDM1A, ChIP-seq and RNA-seq in prostate cancer","pmids":["37184661"],"confidence":"Medium","gaps":["Identity of the bridging RNA not defined","Direct vs. RNA-bridged contacts not structurally resolved"]},{"year":null,"claim":"How the sequence-nonspecific TAM domain and combinatorial histone reading are integrated to achieve locus-specific targeting across rDNA, enhancers, and genome compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified targeting model linking RNA, histone marks, and partner recruitment","Endogenous targeting RNAs unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,11]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,8,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,12]}],"complexes":["NoRC"],"partners":["EZH2","SNF2H","TOP2A","KDM1A","TCF7L2","EP300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIF9","full_name":"Bromodomain adjacent to zinc finger domain protein 2A","aliases":["Transcription termination factor I-interacting protein 5","TTF-I-interacting protein 5","Tip5","hWALp3"],"length_aa":1905,"mass_kda":211.2,"function":"Regulatory subunit of the ATP-dependent NoRC-1 and NoRC-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:28801535). Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). Directly stimulates the ATPase activity of SMARCA5 in the NoRC-5 ISWI chromatin remodeling complex (PubMed:28801535). The NoRC-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the NoRC-5 ISWI chromatin remodeling complex (PubMed:28801535). Within the NoRC-5 ISWI chromatin remodeling complex, mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing (By similarity). In the complex, it plays a central role by being recruited to rDNA and by targeting chromatin modifying enzymes such as HDAC1, leading to repress RNA polymerase I transcription (By similarity). Recruited to rDNA via its interaction with TTF1 and its ability to recognize and bind histone H4 acetylated on 'Lys-16' (H4K16ac), leading to deacetylation of H4K5ac, H4K8ac, H4K12ac but not H4K16ac (By similarity). Specifically binds pRNAs, 150-250 nucleotide RNAs that are complementary in sequence to the rDNA promoter; pRNA-binding is required for heterochromatin formation and rDNA silencing (By similarity)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9UIF9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAZ2A","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMARCA5","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BAZ2A","total_profiled":1310},"omim":[{"mim_id":"605682","title":"BROMODOMAIN ADJACENT TO ZINC FINGER DOMAIN, 2A; BAZ2A","url":"https://www.omim.org/entry/605682"},{"mim_id":"605680","title":"BROMODOMAIN ADJACENT TO ZINC FINGER DOMAIN, 1A; BAZ1A","url":"https://www.omim.org/entry/605680"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BAZ2A"},"hgnc":{"alias_symbol":["KIAA0314","TIP5","WALp3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIF9","domains":[{"cath_id":"3.30.890.10","chopping":"550-650","consensus_level":"high","plddt":87.8573,"start":550,"end":650},{"cath_id":"-","chopping":"1506-1618_1635-1677","consensus_level":"medium","plddt":84.0371,"start":1506,"end":1677},{"cath_id":"1.20.920.10","chopping":"1797-1902","consensus_level":"high","plddt":90.6378,"start":1797,"end":1902},{"cath_id":"1.20.58","chopping":"990-1027_1081-1113","consensus_level":"medium","plddt":88.3486,"start":990,"end":1113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIF9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIF9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIF9-F1-predicted_aligned_error_v6.png","plddt_mean":55.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAZ2A","jax_strain_url":"https://www.jax.org/strain/search?query=BAZ2A"},"sequence":{"accession":"Q9UIF9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIF9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIF9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIF9"}},"corpus_meta":[{"pmid":"25485837","id":"PMC_25485837","title":"BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25485837","citation_count":126,"is_preprint":false},{"pmid":"25799074","id":"PMC_25799074","title":"Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25799074","citation_count":107,"is_preprint":false},{"pmid":"25719566","id":"PMC_25719566","title":"Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25719566","citation_count":75,"is_preprint":false},{"pmid":"25533489","id":"PMC_25533489","title":"Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC.","date":"2014","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/25533489","citation_count":59,"is_preprint":false},{"pmid":"34403195","id":"PMC_34403195","title":"BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/34403195","citation_count":30,"is_preprint":false},{"pmid":"23580549","id":"PMC_23580549","title":"Large-scale organization of ribosomal DNA chromatin is regulated by Tip5.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23580549","citation_count":26,"is_preprint":false},{"pmid":"25916849","id":"PMC_25916849","title":"A novel RNA binding surface of the TAM domain of TIP5/BAZ2A mediates epigenetic regulation of rRNA genes.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25916849","citation_count":25,"is_preprint":false},{"pmid":"28837921","id":"PMC_28837921","title":"Discovery of BAZ2A bromodomain ligands.","date":"2017","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28837921","citation_count":23,"is_preprint":false},{"pmid":"16141224","id":"PMC_16141224","title":"Toutatis, a TIP5-related protein, positively regulates Pannier function during Drosophila neural development.","date":"2005","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16141224","citation_count":20,"is_preprint":false},{"pmid":"33433018","id":"PMC_33433018","title":"BAZ2A safeguards genome architecture of ground-state pluripotent stem cells.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33433018","citation_count":19,"is_preprint":false},{"pmid":"16643428","id":"PMC_16643428","title":"Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement.","date":"2006","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/16643428","citation_count":19,"is_preprint":false},{"pmid":"32024754","id":"PMC_32024754","title":"TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32024754","citation_count":16,"is_preprint":false},{"pmid":"29770599","id":"PMC_29770599","title":"Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains.","date":"2018","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/29770599","citation_count":14,"is_preprint":false},{"pmid":"23796711","id":"PMC_23796711","title":"CHD4/NuRD maintains demethylation state of rDNA promoters through inhibiting the expression of the 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alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37184661","citation_count":4,"is_preprint":false},{"pmid":"37574751","id":"PMC_37574751","title":"Reevaluation of bromodomain ligands targeting BAZ2A.","date":"2023","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/37574751","citation_count":4,"is_preprint":false},{"pmid":"27458840","id":"PMC_27458840","title":"Differential enrichment of TTF-I and Tip5 in the T-like promoter structures of the rDNA contribute to the epigenetic response of Cyprinus carpio during environmental adaptation.","date":"2016","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/27458840","citation_count":2,"is_preprint":false},{"pmid":"42233460","id":"PMC_42233460","title":"Unusual backfolded binding poses of BAZ2A bromodomain binders.","date":"2026","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/42233460","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11691,"output_tokens":2970,"usd":0.039811,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10480,"output_tokens":3482,"usd":0.069725,"stage2_stop_reason":"end_turn"},"total_usd":0.109536,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"BAZ2A (TIP5) directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation / protein interaction assay in prostate cancer cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP reported, single lab, but finding is supported by genomic occupancy data in the same study\",\n      \"pmids\": [\"25485837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The PHD zinc finger domain of TIP5 recognizes unmodified H3 histone tails as an independent structural module, while the bromodomain preferentially binds H3 and H4 acetylation marks followed by a key basic residue (KacXXR motif); together these modules mediate trans-histone tail recognition required for NoRC recruitment to chromatin and transcriptional repression of rDNA.\",\n      \"method\": \"X-ray crystallography of PHD and bromodomain in free and histone-bound forms; low-resolution SAXS of PHD-bromodomain module\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple domain-histone complexes with functional validation, multiple orthogonal biophysical methods in one study\",\n      \"pmids\": [\"25533489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The TAM domain of TIP5 adopts an extended MBD-like fold with unique C-terminal extensions that form a novel RNA-binding surface; mutation of critical residues on this surface abolishes RNA binding both in vitro and in vivo, explaining how NoRC is targeted to specific genomic loci via noncoding RNA.\",\n      \"method\": \"NMR structure determination; mutagenesis with in vitro RNA-binding assays and in vivo validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis validated in vitro and in vivo in one study, multiple orthogonal methods\",\n      \"pmids\": [\"25916849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GSK2801 acts as an acetyl-lysine competitive inhibitor of the BAZ2A bromodomain (KD ~257 nM for BAZ2A), binding in a canonical acetyl-lysine competitive mode as confirmed by crystal structure; cellular activity was demonstrated by FRAP showing displacement of GFP-BAZ2A from acetylated chromatin.\",\n      \"method\": \"Crystal structure of bromodomain–inhibitor complex; isothermal titration calorimetry / competition binding; FRAP in cells\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, biophysical binding assays, and cellular FRAP in one study with rigorous controls\",\n      \"pmids\": [\"25799074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAZ2-ICR occupies the BAZ2A bromodomain acetyl-lysine pocket through an intramolecular aromatic stacking interaction that efficiently fills the shallow binding site, as revealed by structure-based design.\",\n      \"method\": \"Structure-based drug design; X-ray crystallography of inhibitor–bromodomain complex\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional binding validation, single lab\",\n      \"pmids\": [\"25719566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TAM domain of Tip5 functions as the nucleolar localization and nuclear matrix targeting module, while AT-hooks are required for nucleolar targeting but do not mediate nuclear matrix association; Tip5 overexpression facilitates rDNA association with the nuclear matrix and increases DNase I inaccessibility, regulating large-scale rDNA chromatin organization.\",\n      \"method\": \"Domain deletion/mutation analysis; nuclear fractionation; DNase I accessibility assay; overexpression and localization imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean domain dissection with multiple functional readouts, single lab\",\n      \"pmids\": [\"23580549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NuRD complex directly binds to the TIP5 promoter and negatively regulates TIP5 expression, thereby limiting TIP5-mediated recruitment of DNA methyltransferase to rDNA promoters and maintaining their unmethylated state.\",\n      \"method\": \"ChIP at TIP5 promoter; knockdown of NuRD components with measurement of TIP5 expression and rDNA methylation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional KD experiments, single lab\",\n      \"pmids\": [\"23796711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIP5 physically interacts with TCF7L2 (identified by co-immunoprecipitation and GST pull-down) and enhances the interaction between β-catenin and TCF7L2, thereby activating Wnt/β-catenin signaling in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation; GST pull-down assay; reporter and functional cell assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal pulldown (Co-IP + GST), single lab, single study\",\n      \"pmids\": [\"29620186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In ground-state embryonic stem cells, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A), and cohesin on chromatin; BAZ2A depletion increases chromatin accessibility at B compartments and dysregulates H3K27me3 genome occupancy in a TOP2A-dependent manner, demonstrating that BAZ2A limits invasion of active chromatin domains into repressive compartments.\",\n      \"method\": \"Co-immunoprecipitation; Hi-C genome architecture analysis; ATAC-seq; ChIP-seq; genetic depletion (BAZ2A KO/KD)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genome-wide and biochemical methods, clear mechanistic epistasis established\",\n      \"pmids\": [\"33433018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAZ2A bromodomain specifically binds H3K14ac-marked chromatin at inactive enhancers; BAZ2A-BRD mutations or pharmacological inhibition of the BAZ2A-BRD/H3K14ac interaction impairs prostate cancer stem cell features and Pten-loss-driven oncogenic transformation in organoids. BAZ2A-mediated repression at these enhancers is linked to EP300, which acetylates H3K14.\",\n      \"method\": \"ChIP-seq for BAZ2A and H3K14ac; bromodomain point mutations; BRD inhibitor treatment; organoid transformation assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, structure-function mutagenesis, pharmacological and genetic perturbations, and organoid functional assay in one study\",\n      \"pmids\": [\"34403195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The BAZ2A TAM domain binds double-stranded DNA and double-stranded RNA in a sequence-nonspecific, backbone-dependent manner (distinct from canonical MBD methyl-CpG recognition), as established by EMSA, ITC, mutagenesis, and X-ray crystallography.\",\n      \"method\": \"EMSA; isothermal titration calorimetry; mutagenesis; X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with ITC, EMSA, and mutagenesis in one study; multiple orthogonal methods\",\n      \"pmids\": [\"34715126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In prostate cancer, the BAZ2A TAM domain mediates interaction with TOP2A and KDM1A through an RNA-dependent mechanism; pharmacological inhibition of TOP2A or KDM1A upregulates BAZ2A-repressed genes controlled by inactive enhancers, whereas rRNA gene silencing is unaffected, revealing a distinct RNA-based gene repression mechanism separate from rDNA silencing.\",\n      \"method\": \"Co-immunoprecipitation; RNA-dependency experiments; pharmacological inhibition of TOP2A and KDM1A; ChIP-seq; RNA-seq\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pharmacological epistasis and genome-wide readouts, single lab\",\n      \"pmids\": [\"37184661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TIP5 is required for the initiation of prostate cancer transformation of luminal cells driven by Pten-loss in organoids, but is dispensable once transformation is established, placing TIP5 upstream of Pten-loss-mediated oncogenesis in a defined cellular context.\",\n      \"method\": \"Mouse prostate organoid model; Pten knockdown; TIP5 depletion with defined temporal order; cross-species gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in organoid model with defined temporal order, single lab\",\n      \"pmids\": [\"32024754\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAZ2A (TIP5) is the large scaffolding subunit of the nucleolar remodeling complex (NoRC) that uses its PHD finger to bind unmodified H3 tails, its bromodomain to recognize acetylated histone marks (including H3K14ac at enhancers), and its TAM domain to bind dsDNA/dsRNA in a sequence-nonspecific manner, thereby recruiting NoRC to rDNA and other genomic loci; it represses rRNA genes and cancer-relevant target genes through interactions with SNF2H, EZH2, TOP2A, KDM1A, and cohesin, and its TAM domain anchors the complex to the nuclear matrix via a nucleolar localization function, collectively establishing BAZ2A as a multi-domain epigenetic reader-scaffold that coordinates chromatin remodeling, heterochromatin formation, and genome compartmentalization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BAZ2A (TIP5) is a multi-domain chromatin reader-scaffold that recruits the nucleolar remodeling machinery to genomic loci to enforce transcriptional repression and heterochromatin organization [#1, #8]. It engages chromatin through distinct modules: a PHD finger that reads unmodified H3 tails and a bromodomain that recognizes acetylated histones via a KacXXR motif, with both modules cooperating in trans-histone recognition required for recruitment and rDNA repression [#1]. The bromodomain specifically binds H3K14ac (deposited by EP300) at inactive enhancers, and disrupting this interaction by point mutation or small-molecule inhibition impairs prostate cancer stem cell features and Pten-loss-driven transformation [#9]. Its TAM domain adopts an MBD-like fold that binds double-stranded DNA and RNA in a sequence-nonspecific, backbone-dependent manner, and also serves as the nucleolar localization and nuclear matrix targeting module that drives large-scale rDNA chromatin compaction [#2, #10, #5]. Through these interactions BAZ2A partners with SNF2H, TOP2A, cohesin and KDM1A to constrain chromatin accessibility at repressive (B) compartments and to silence enhancer-controlled genes via an RNA-dependent mechanism distinct from rDNA silencing [#8, #11]. BAZ2A additionally maintains repressive epigenetic states with EZH2 in metastasis-related genes and is required for the initiation of Pten-loss prostate oncogenesis [#0, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined which BAZ2A module anchors rDNA chromatin to the nuclear scaffold, addressing how the complex organizes large-scale rDNA architecture.\",\n      \"evidence\": \"Domain deletion/mutation, nuclear fractionation, and DNase I accessibility assays on overexpressed Tip5\",\n      \"pmids\": [\"23580549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed under overexpression conditions\", \"Does not resolve TAM-domain ligand specificity for matrix association\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an upstream regulator of TIP5 expression, showing NuRD limits TIP5 levels to keep rDNA promoters unmethylated.\",\n      \"evidence\": \"ChIP at the TIP5 promoter plus knockdown of NuRD components measuring TIP5 expression and rDNA methylation\",\n      \"pmids\": [\"23796711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct DNA methyltransferase recruitment by TIP5 not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a cancer-relevant repressive partnership by showing BAZ2A interacts with EZH2 to silence metastasis-suppressed genes.\",\n      \"evidence\": \"Co-immunoprecipitation with supporting genomic occupancy data in prostate cancer cells\",\n      \"pmids\": [\"25485837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation reported\", \"Direct vs. complex-mediated interaction not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the structural basis for histone-tail reading, showing the PHD finger and bromodomain act as cooperating modules for chromatin recruitment.\",\n      \"evidence\": \"X-ray crystallography of PHD and bromodomain in free and histone-bound forms plus SAXS of the combined module\",\n      \"pmids\": [\"25533489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo combinatorial readout at endogenous loci not mapped\", \"Does not address TAM-domain contribution\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Solved the TAM-domain fold and identified its nucleic-acid binding surface, explaining how noncoding RNA could target NoRC.\",\n      \"evidence\": \"NMR structure determination with mutagenesis validated in vitro and in vivo\",\n      \"pmids\": [\"25916849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence specificity of the RNA target not defined here\", \"Genomic loci targeted by RNA binding not enumerated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Delivered chemical-probe inhibitors of the BAZ2A bromodomain, enabling pharmacological dissection of acetyl-lysine reading.\",\n      \"evidence\": \"Crystal structures of bromodomain-inhibitor complexes, ITC/competition binding, and cellular FRAP (GSK2801, BAZ2-ICR)\",\n      \"pmids\": [\"25799074\", \"25719566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide consequences of bromodomain inhibition not assessed in these studies\", \"Selectivity against the paralog bromodomain context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a genome-organization role, showing BAZ2A interacts with SNF2H, TOP2A and cohesin to prevent active chromatin invading repressive compartments.\",\n      \"evidence\": \"Co-IP, Hi-C, ATAC-seq, ChIP-seq and genetic depletion in ground-state embryonic stem cells\",\n      \"pmids\": [\"33433018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether compartment maintenance requires the TAM or bromodomain not resolved\", \"Mechanism of TOP2A-dependent H3K27me3 redistribution undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed TIP5 temporally upstream of Pten-loss oncogenesis, showing it is required for initiation but dispensable once transformation is established.\",\n      \"evidence\": \"Mouse prostate organoid model with Pten knockdown and temporally defined TIP5 depletion\",\n      \"pmids\": [\"32024754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets driving the initiation requirement not pinpointed\", \"Single model system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected the bromodomain to a specific enhancer mark, showing H3K14ac (EP300-deposited) recognition drives repression and oncogenic transformation.\",\n      \"evidence\": \"ChIP-seq, bromodomain point mutations, BRD inhibitor treatment and organoid transformation assays\",\n      \"pmids\": [\"34403195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3K14ac binding mediates repression mechanistically not fully resolved\", \"Generality beyond prostate cells untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the biochemical nature of TAM-domain nucleic-acid binding as sequence-nonspecific and backbone-dependent, distinguishing it from canonical methyl-CpG readers.\",\n      \"evidence\": \"EMSA, ITC, mutagenesis and X-ray crystallography\",\n      \"pmids\": [\"34715126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nonspecific binding achieves locus-specific targeting in vivo\", \"Relative roles of dsDNA vs dsRNA binding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished an RNA-based enhancer-repression mechanism from rDNA silencing, showing the TAM domain recruits TOP2A and KDM1A in an RNA-dependent manner.\",\n      \"evidence\": \"Co-IP, RNA-dependency experiments, pharmacological inhibition of TOP2A/KDM1A, ChIP-seq and RNA-seq in prostate cancer\",\n      \"pmids\": [\"37184661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the bridging RNA not defined\", \"Direct vs. RNA-bridged contacts not structurally resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the sequence-nonspecific TAM domain and combinatorial histone reading are integrated to achieve locus-specific targeting across rDNA, enhancers, and genome compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified targeting model linking RNA, histone marks, and partner recruitment\", \"Endogenous targeting RNAs unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"complexes\": [\"NoRC\"],\n    \"partners\": [\"EZH2\", \"SNF2H\", \"TOP2A\", \"KDM1A\", \"TCF7L2\", \"EP300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}