{"gene":"ANKRD11","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2011,"finding":"ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete nuclear inclusions when neurons are depolarized, suggesting a role in neural plasticity.","method":"Subcellular localization by direct imaging in neurons with depolarization stimulus","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implication, single lab","pmids":["21782149"],"is_preprint":false},{"year":2008,"finding":"ANKRD11 is a p53-interacting protein that acts as a coactivator of p53 transcriptional activity; it associates with p53 acetyltransferases P/CAF and hADA3, enhances levels of acetylated p53, and increases p53 DNA-binding to the CDKN1A (p21) promoter, thereby upregulating p21 expression.","method":"Co-immunoprecipitation, shRNA knockdown, reporter assays, ChIP, exogenous expression in MCF-7 and MDA-MB-468 cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, KD) in single study with rigorous functional readouts","pmids":["18840648"],"is_preprint":false},{"year":2011,"finding":"ANKRD11 suppresses the oncogenic gain-of-function properties of mutant p53 by restoring a native conformation to mutant p53 protein and causing dissociation of the mutant p53–p63 complex, thereby alleviating mutant p53-driven centrosome amplification, mitotic defects, multinucleation, and invasion.","method":"Inducible expression, co-immunoprecipitation, conformational antibody assays, invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical and cellular methods establishing mechanism","pmids":["21986947"],"is_preprint":false},{"year":2014,"finding":"Ankrd11 functions as a chromatin regulator during neural development by associating with chromatin and colocalizing with HDAC3; it controls histone acetylation levels, and its loss causes decreased neural precursor proliferation, reduced neurogenesis, and aberrant neuronal positioning. The proliferation defect is rescued by inhibiting histone acetyltransferase activity or by expressing HDAC3.","method":"Knockdown in murine/human cortical neural precursors, Yoda point-mutant mouse (HDAC-binding domain mutation), chromatin association assay, co-localization with HDAC3, gene expression and histone acetylation analysis, epistasis rescue experiments","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, genetic mouse model, chromatin association, rescue epistasis) replicated across species","pmids":["25556659"],"is_preprint":false},{"year":2014,"finding":"The ANKRD11 C-terminus is required for proteasome-mediated degradation of the protein; wild-type ANKRD11 abundance is tightly regulated during the cell cycle, and all examined pathogenic truncating mutations in the C-terminal region result in aberrant accumulation of the mutant protein. D-box sequences (proteasome degradation signals) are present in the C-terminus.","method":"Cell cycle analysis of protein abundance, in silico D-box identification, functional comparison of 11 pathogenic ANKRD11 variants","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — cell-based protein-level analysis across multiple variants, single lab","pmids":["25413698"],"is_preprint":false},{"year":2017,"finding":"ANKRD11 regulates pyramidal neuron radial migration and dendritic differentiation in developing mouse cortex; its knockdown suppresses acetylation of p53 and histone H3, reduces mRNA levels of TrkB, BDNF, and neurite growth-related genes, and the TrkB promoter in ANKRD11-deficient neurons shows reduced acetylated H3 and p53 occupancy with increased MeCP2 and DNMT1 binding. Overexpression of TrkB rescues abnormal dendrite growth.","method":"In utero electroporation knockdown, histone/p53 acetylation assays, ChIP, qRT-PCR, TrkB overexpression rescue","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vivo KD, ChIP, rescue) in single rigorous study","pmids":["29274743"],"is_preprint":false},{"year":2019,"finding":"ANKRD11 (ANCO1) acts as a transcriptional repressor at AIB1/YAP-TEAD target genes in breast epithelial cells; it is recruited to chromatin by AIB1 and its loss reverses AIB1-YAP-dependent gene repression, increases cell size, and enhances YAP-driven aberrant 3D growth.","method":"ChIP-seq, sequential ChIP, gene expression analysis, shRNA knockdown, 3D culture assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq plus functional KD experiments, multiple orthogonal methods","pmids":["31788936"],"is_preprint":false},{"year":2022,"finding":"Pathogenic ANKRD11 missense variants cause KBG syndrome either by reducing ANKRD11 protein stability (6 of 10 tested variants) or by causing loss of transcriptional repression activity (one variant also decreased proteasome degradation); variants significantly cluster in repression domain 2 at the C-terminus.","method":"Cell-based stability assays, transcriptional reporter assays, in silico analysis, functional characterization of 10 missense variants","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based functional assays across multiple variants, single lab","pmids":["35833929"],"is_preprint":false},{"year":2023,"finding":"ANKRD11 interacts with HDAC3 and upregulates its deacetylase activity; in the context of aromatase inhibitor resistance in breast cancer, ANKRD11 acts downstream of SERPINA3 to promote resistance through this HDAC3 interaction.","method":"Co-immunoprecipitation, HDAC3 activity assays, knockdown/overexpression experiments","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional activity assay, single lab","pmids":["37414914"],"is_preprint":false},{"year":2023,"finding":"A bipartite nuclear localization signal (bNLS) between residues 53 and 87 of ANKRD11 mediates its nuclear import via two binding sites for Importin α1; this bNLS is necessary and sufficient for nuclear localization, and mutations within it provide a pathogenic mechanism for certain clinical ANKRD11 variants.","method":"Site-directed mutagenesis, biochemical binding assays, GFP-fusion nuclear import assays in HeLa cells, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 — mutagenesis combined with localization assay and biochemical binding, single lab","pmids":["37290286"],"is_preprint":false},{"year":2024,"finding":"The minor spliceosomal protein 65K/RNPC3 interacts with ANKRD11, and ANKRD11 acts as a bridging factor that facilitates co-binding of HDAC3 and 65K/RNPC3 to common chromatin loci. ANKRD11 knockdown simultaneously reduces HDAC3 and 65K chromatin binding and decreases H3K9 deacetylation at shared target genes, linking the minor spliceosome to histone deacetylation-mediated gene regulation.","method":"Affinity purification (Drosophila and human), CRISPR/Cas9 deletion mutants, CUT&Tag assays, knockdown experiments, histone modification analysis","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (affinity purification, CUT&Tag, genetic KO, KD) across two organisms","pmids":["38837887"],"is_preprint":false},{"year":2024,"finding":"Conditional knockout of Ankrd11 in embryonic neural crest cells leads to persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility due to aberrant cardiac neural crest cell organization and outflow tract septation failure; Ankrd11 knockout impairs expression of transcription factors, chromatin remodelers, and mTOR, BMP, and TGF-β signaling pathways in cardiac neural crest cells.","method":"Conditional neural crest-specific knockout mouse, cardiac morphology analysis, transcriptome analysis of cardiac neural crest cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular and molecular phenotype, multiple pathway readouts","pmids":["38951500"],"is_preprint":false},{"year":2021,"finding":"Ankrd11 is required for intramembranous ossification and palate development; conditional deletion of Ankrd11 in neural crest cells causes cleft palate, retrognathia, midfacial hypoplasia, reduced calvarial growth, failure of ossification center expansion/fusion, and reduced proliferation of palatal shelves. Ankrd11 expression is closely associated with developing bony structures in the craniofacial complex.","method":"Neural crest-specific conditional heterozygous and homozygous knockout mice, 3D imaging, histology, proliferation assays","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with specific cellular phenotypes (proliferation, ossification) and gene expression readouts","pmids":["33996804"],"is_preprint":false},{"year":2025,"finding":"ANKRD11 binds to the cohesin complex via a short N-terminal peptide fragment with high affinity; crystal structure of the ANKRD11 peptide–cohesin complex shows ANKRD11 competes with CTCF for cohesin binding. A single Y347A point mutation in ANKRD11 disrupts the ANKRD11–cohesin interaction, perturbs gene expression in mouse embryonic stem cells, and causes neural and craniofacial anomalies in knock-in mice mirroring KBG syndrome.","method":"Crystal structure determination, biochemical binding assays, site-directed mutagenesis (Y347A knock-in mice), gene expression analysis in mESCs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis, in vivo knock-in model, and gene expression readouts","pmids":["39847329"],"is_preprint":false},{"year":2025,"finding":"ANKRD11 promotes SETD5 expression by binding to the Setd5 promoter and recruiting WDR5, a component of the H3K4 methyltransferase complex; reduced H3K4 methylation at the Setd5 promoter in ANKRD11-deficient cells leads to decreased SETD5, reduced ribosomal RNA (rRNA) levels, and impaired translation. Overexpression of ANKRD11 or SETD5 rescues rRNA and translational defects.","method":"ChIP (promoter binding, H3K4 methylation), co-immunoprecipitation (ANKRD11-WDR5), rRNA quantification, translational activity assays, rescue by overexpression","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, functional rescue) establishing a mechanistic pathway","pmids":["40520101"],"is_preprint":false},{"year":2023,"finding":"Loss of ANCO1 (ANKRD11) in early-stage triple-negative breast cancer cells leads to global increase in H3K27Ac signals enriched at AP-1, TEAD, STAT3, and NFκB motifs, activating breast-cancer-specific enhancers and oncogenic PI3K-AKT, EMT, and senescence pathways; ANCO1 depletion causes aneuploidy and enhanced 3D invasion.","method":"ChIP-seq (H3K27Ac), shRNA knockdown, 3D invasion assays, xenograft mouse model","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq with functional KD and in vivo validation, multiple orthogonal methods","pmids":["37511268"],"is_preprint":false},{"year":2020,"finding":"ANKRD11 can enhance transactivation of the p21 (CDKN1A) promoter; two loss-of-function ANKRD11 variants (p.Lys1347del and p.Leu2143Val) failed to restore p21-promoter luciferase activity or endogenous p21 mRNA levels when re-introduced, demonstrating their functional impairment in this transcriptional activity.","method":"p21-promoter luciferase reporter assay, knockdown and rescue with wild-type vs. mutant ANKRD11 in cell lines","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay with mutant vs. WT rescue, single lab, single method","pmids":["33354850"],"is_preprint":false},{"year":2024,"finding":"A truncated ANKRD11 protein generated by a frameshift variant escapes nonsense-mediated decay, accumulates at higher levels than wild-type, localizes predominantly to the nucleus (whereas wild-type distributes between nucleus and cytoplasm), and significantly reduces CDKN1A/p21-promoter luciferase activity and endogenous p21 mRNA, suggesting a dominant-negative loss of transcriptional activation function.","method":"RT-PCR (NMD assessment), Western blot, immunofluorescence, p21-promoter luciferase reporter assay in HEK293 cells","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple cell-based methods but single lab; provides novel mechanistic insight into truncation mechanism","pmids":["38515699"],"is_preprint":false}],"current_model":"ANKRD11 is a large nuclear chromatin regulator that controls gene expression by modulating histone acetylation (via HDAC3 recruitment), binding the cohesin complex (competing with CTCF), acting as a p53 coactivator (associating with P/CAF and hADA3 to enhance p53 acetylation and CDKN1A transcription), promoting SETD5/rRNA expression via WDR5-mediated H3K4 methylation, and bridging HDAC3 with the minor spliceosome component 65K/RNPC3 at common chromatin targets; loss-of-function through haploinsufficiency impairs neural precursor proliferation, neuronal migration, dendritic differentiation, craniofacial bone development, and cardiac neural crest-mediated outflow tract septation."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that ANKRD11 directly participates in p53-mediated transcription resolved how a previously uncharacterized ankyrin-repeat protein could function as a transcriptional coactivator: it bridges p53 with acetyltransferases P/CAF and hADA3, enhances p53 acetylation and DNA binding at the CDKN1A promoter, and upregulates p21 expression.","evidence":"Co-IP, ChIP, shRNA knockdown, and reporter assays in MCF-7 and MDA-MB-468 breast cancer cells","pmids":["18840648"],"confidence":"High","gaps":["Whether the ANKRD11–P/CAF–hADA3 interaction is direct or requires additional scaffold factors","Whether ANKRD11 coactivates p53 targets beyond CDKN1A genome-wide","No structural information on the ANKRD11–p53 interface"]},{"year":2011,"claim":"Two studies expanded ANKRD11's functional scope: its nuclear localization in neurons with activity-dependent redistribution into nuclear inclusions suggested a role in neural plasticity, while its ability to restore native conformation to mutant p53 and dissociate the mutant-p53–p63 complex established a gain-of-function suppressor activity relevant to cancer.","evidence":"Subcellular imaging in depolarized neurons (PMID:21782149); inducible expression, conformational antibody assays, co-IP, and invasion assays (PMID:21986947)","pmids":["21782149","21986947"],"confidence":"High","gaps":["Mechanism by which depolarization drives ANKRD11 into nuclear inclusions","Whether conformational rescue of mutant p53 occurs in vivo","No identification of the ANKRD11 domain responsible for p53 conformational correction"]},{"year":2014,"claim":"Identification of ANKRD11 as a chromatin-associated HDAC3 partner that controls histone acetylation in neural precursors defined its core developmental mechanism: Ankrd11 loss increases histone acetylation, reduces precursor proliferation and neurogenesis, and these defects are rescued by HDAC3 overexpression or HAT inhibition, placing ANKRD11 upstream of histone acetylation balance during cortical development.","evidence":"Knockdown in murine/human cortical precursors, Yoda point-mutant mouse, chromatin association and HDAC3 co-localization assays, epistasis rescue (PMID:25556659); cell cycle protein-level analysis of pathogenic C-terminal truncation variants (PMID:25413698)","pmids":["25556659","25413698"],"confidence":"High","gaps":["Identity of specific ANKRD11 target genes regulated through HDAC3","Whether the C-terminal D-box-mediated proteasomal degradation is required for normal cell-cycle-dependent function in vivo","No genome-wide map of ANKRD11 chromatin binding sites in neural precursors"]},{"year":2017,"claim":"Demonstrating that ANKRD11 controls pyramidal neuron migration and dendritic differentiation through p53/histone H3 acetylation at the TrkB promoter linked the chromatin-regulatory and p53-coactivation arms into one pathway operating during cortical development.","evidence":"In utero electroporation knockdown, ChIP for acetylated H3 and p53 at TrkB promoter, TrkB overexpression rescue","pmids":["29274743"],"confidence":"High","gaps":["Whether the TrkB–BDNF axis fully accounts for ANKRD11-dependent dendritic phenotypes","Contribution of HDAC3 versus p53 arms at the TrkB locus not dissected"]},{"year":2019,"claim":"ChIP-seq in breast epithelial cells revealed a distinct repressor function: ANKRD11 (ANCO1) is recruited by AIB1 to YAP-TEAD target genes, where it represses transcription; its loss activates YAP-dependent programs driving aberrant 3D growth, establishing ANKRD11 as a context-dependent repressor beyond its coactivator role at p53 targets.","evidence":"ChIP-seq, sequential ChIP, shRNA knockdown, 3D culture assays in breast epithelial cells","pmids":["31788936"],"confidence":"High","gaps":["Whether ANKRD11 repression at YAP-TEAD targets operates through HDAC3 or an independent corepressor mechanism","Relevance of this repressor axis in non-epithelial contexts"]},{"year":2021,"claim":"Conditional deletion of Ankrd11 in neural crest cells established its requirement for intramembranous ossification and palate morphogenesis, extending the gene's developmental roles from brain to craniofacial skeleton and directly modeling KBG syndrome craniofacial features.","evidence":"Neural crest-specific conditional KO mice, 3D imaging, histology, and proliferation assays","pmids":["33996804"],"confidence":"High","gaps":["Downstream transcriptional targets of ANKRD11 in osteoprogenitors not identified","Whether the craniofacial phenotype depends on HDAC3 or cohesin interactions"]},{"year":2023,"claim":"Multiple 2023 studies deepened the chromatin and disease mechanism: ANKRD11 loss in triple-negative breast cancer globally elevated H3K27Ac at oncogenic enhancers (AP-1, TEAD, STAT3, NF-κB), ANKRD11 was shown to interact with and upregulate HDAC3 deacetylase activity, a bipartite NLS was mapped to residues 53–87 mediating Importin-α1-dependent nuclear import, and pathogenic missense variants were shown to reduce either protein stability or transcriptional repression activity.","evidence":"ChIP-seq/shRNA/xenograft (PMID:37511268); Co-IP and HDAC3 activity assays (PMID:37414914); mutagenesis and GFP-import assays (PMID:37290286); cell-based stability and reporter assays on 10 missense variants (PMID:35833929)","pmids":["37511268","37414914","37290286","35833929"],"confidence":"High","gaps":["Whether ANKRD11-dependent HDAC3 activation is allosteric or recruitment-based","Structural basis of the repression domain 2 clustering of pathogenic variants","Whether bipartite NLS mutations account for clinical cases beyond those tested"]},{"year":2024,"claim":"Two 2024 studies revealed new functional partnerships: ANKRD11 bridges HDAC3 and the minor spliceosome protein 65K/RNPC3 at shared chromatin loci to couple histone deacetylation with minor-intron gene regulation, and neural crest-specific Ankrd11 knockout causes persistent truncus arteriosus and impaired ventricular function through disrupted mTOR/BMP/TGF-β signaling in cardiac neural crest cells.","evidence":"Affinity purification, CUT&Tag, CRISPR KO in Drosophila and human cells (PMID:38837887); conditional neural crest KO mouse with cardiac phenotyping and transcriptomics (PMID:38951500); truncated variant NMD-escape and dominant-negative activity (PMID:38515699)","pmids":["38837887","38951500","38515699"],"confidence":"High","gaps":["Whether bridging of HDAC3–65K is required for minor intron splicing per se or only for transcriptional regulation of minor-intron-containing genes","Specific cardiac neural crest target genes directly bound by ANKRD11","Whether dominant-negative truncated ANKRD11 variants operate through the HDAC3 or cohesin arm"]},{"year":2025,"claim":"A crystal structure of an ANKRD11 N-terminal peptide bound to the cohesin complex demonstrated that ANKRD11 competes with CTCF for the same cohesin binding surface; a Y347A knock-in mouse disrupting this single interaction recapitulated neural and craniofacial KBG syndrome features, establishing cohesin binding as a major independent axis of ANKRD11 function. Separately, ANKRD11 was shown to recruit WDR5 to the Setd5 promoter, promoting H3K4 methylation and SETD5-dependent rRNA biogenesis and translation.","evidence":"Crystal structure, biochemical competition assays, Y347A knock-in mice, gene expression in mESCs (PMID:39847329); ChIP, Co-IP, rRNA quantification, translational assays, rescue experiments (PMID:40520101)","pmids":["39847329","40520101"],"confidence":"High","gaps":["Whether cohesin and HDAC3 interactions are coordinated at the same loci or operate at distinct gene sets","Global contribution of the SETD5–rRNA axis to KBG syndrome phenotypes","No full-length ANKRD11 structure to reveal inter-domain organization"]},{"year":null,"claim":"Key unresolved questions include how ANKRD11's multiple chromatin-regulatory arms (HDAC3 recruitment, cohesin binding, p53 coactivation, WDR5-mediated H3K4 methylation, minor spliceosome bridging) are coordinated or segregated at individual genomic loci, and which arm(s) are primarily responsible for each tissue-specific developmental phenotype in KBG syndrome.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrative multi-omic dataset mapping all ANKRD11 interaction arms genome-wide in a single cell type","Contribution of each mechanistic arm to specific KBG syndrome features (neurological vs. craniofacial vs. cardiac) not dissected","No full-length structural model of ANKRD11"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,5,6,7,15,16,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,5,10,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,17]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,6,10,13]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,5,10,14,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,6,7,14,15,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,11,12,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2,16]}],"complexes":[],"partners":["HDAC3","TP53","KAT2B","TADA3","CTCF","WDR5","RNPC3","NCOA3"],"other_free_text":[]},"mechanistic_narrative":"ANKRD11 is a nuclear chromatin regulator that controls gene expression during development and tumor suppression through multiple mechanistic arms: recruitment of histone deacetylase HDAC3 to modulate histone acetylation at target loci, coactivation of p53 via association with acetyltransferases P/CAF and hADA3 to drive CDKN1A/p21 transcription, competitive binding to the cohesin complex that displaces CTCF, and bridging HDAC3 with the minor spliceosome component 65K/RNPC3 at shared chromatin targets [PMID:25556659, PMID:18840648, PMID:39847329, PMID:38837887]. ANKRD11 additionally promotes SETD5 expression by recruiting WDR5 to the Setd5 promoter for H3K4 methylation, thereby sustaining rRNA levels and translation [PMID:40520101]. Loss of ANKRD11 function in neural crest and cortical precursor cells impairs proliferation, neuronal migration, dendritic differentiation, craniofacial ossification, and cardiac outflow tract septation, and haploinsufficiency causes KBG syndrome [PMID:25556659, PMID:33996804, PMID:38951500, PMID:39847329]. In breast epithelial cells, ANKRD11 acts as a transcriptional repressor at AIB1/YAP-TEAD target genes, and its loss activates oncogenic enhancers enriched for AP-1, TEAD, and NF-κB motifs, promoting invasion and aneuploidy [PMID:31788936, PMID:37511268]."},"prefetch_data":{"uniprot":{"accession":"Q6UB99","full_name":"Ankyrin repeat domain-containing protein 11","aliases":["Ankyrin repeat-containing cofactor 1"],"length_aa":2663,"mass_kda":297.9,"function":"Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells (By similarity). May recruit histone deacetylases (HDACs) to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation (PubMed:15184363). Has a role in proliferation and development of cortical neural precursors (PubMed:25556659). May also regulate bone homeostasis (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6UB99/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD11","classification":"Not Classified","n_dependent_lines":327,"n_total_lines":1208,"dependency_fraction":0.2706953642384106},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000167522","cell_line_id":"CID001385","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001385","total_profiled":1310},"omim":[{"mim_id":"616728","title":"CLEFT PALATE, PSYCHOMOTOR RETARDATION, AND DISTINCTIVE FACIAL FEATURES; CPRF","url":"https://www.omim.org/entry/616728"},{"mim_id":"611192","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 11; ANKRD11","url":"https://www.omim.org/entry/611192"},{"mim_id":"609757","title":"WILLIAMS-BEUREN REGION DUPLICATION SYNDROME","url":"https://www.omim.org/entry/609757"},{"mim_id":"609132","title":"LYSINE DEMETHYLASE 1A; 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36628575","citation_count":5,"is_preprint":false},{"pmid":"37511268","id":"PMC_37511268","title":"Loss of ANCO1 Expression Regulates Chromatin Accessibility and Drives Progression of Early-Stage Triple-Negative Breast Cancer.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37511268","citation_count":5,"is_preprint":false},{"pmid":"34247373","id":"PMC_34247373","title":"[Gender difference in clinical manifestations of KBG syndrome due to variants of ANKRD11 gene].","date":"2021","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34247373","citation_count":5,"is_preprint":false},{"pmid":"37064352","id":"PMC_37064352","title":"The clinical significance of computed tomography texture features of renal cell carcinoma in predicting pathological T1-3 staging.","date":"2023","source":"Quantitative imaging in medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/37064352","citation_count":5,"is_preprint":false},{"pmid":"29375862","id":"PMC_29375862","title":"The first antenatal diagnosis of KBG syndrome: a microdeletion at chromosome 16q24.2q24.3 containing multiple genes including ANKRD11 associated with the disorder.","date":"2017","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/29375862","citation_count":5,"is_preprint":false},{"pmid":"7327568","id":"PMC_7327568","title":"Proximal trisomy 13. A family with balanced reciprocal translocation t(8;13) in seven members and Robertsonian translocation t(13;14) in three members.","date":"1981","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7327568","citation_count":5,"is_preprint":false},{"pmid":"32575463","id":"PMC_32575463","title":"Transcriptome Analysis of High-NUE (T29) and Low-NUE (T13) Genotypes Identified Different Responsive Patterns Involved in Nitrogen Stress in Ramie (Boehmeria nivea (L.) Gaudich).","date":"2020","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32575463","citation_count":4,"is_preprint":false},{"pmid":"33653342","id":"PMC_33653342","title":"A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33653342","citation_count":4,"is_preprint":false},{"pmid":"37290286","id":"PMC_37290286","title":"Identification and functional characterization of a bipartite nuclear localization signal in ANKRD11.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37290286","citation_count":3,"is_preprint":false},{"pmid":"33052080","id":"PMC_33052080","title":"Cryptic t(15;17) acute promyelocytic leukemia with a karyotype of add(11)(p15) and t(13,20)- A case report with a literature review.","date":"2021","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33052080","citation_count":3,"is_preprint":false},{"pmid":"27698593","id":"PMC_27698593","title":"Hypofractionated accelerated radiotherapy in T1-3 N0 cancer of the larynx: A prospective cohort study with historical controls.","date":"2016","source":"Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27698593","citation_count":3,"is_preprint":false},{"pmid":"8908170","id":"PMC_8908170","title":"Unusual chromosome aberration, t(13;14)(q32;q32.3), in a case of essential thrombocythemia with extreme thrombocytosis.","date":"1996","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8908170","citation_count":3,"is_preprint":false},{"pmid":"39847329","id":"PMC_39847329","title":"ANKRD11 binding to cohesin suggests a connection between KBG syndrome and Cornelia de Lange syndrome.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39847329","citation_count":2,"is_preprint":false},{"pmid":"32081942","id":"PMC_32081942","title":"T-13 and T-26, the novel taxanes with improved oral bioavailability in rats.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32081942","citation_count":2,"is_preprint":false},{"pmid":"38515699","id":"PMC_38515699","title":"Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38515699","citation_count":2,"is_preprint":false},{"pmid":"37534006","id":"PMC_37534006","title":"Urothelial bladder afferents selectively project to L6/S1 levels and are more peptidergic than those projecting to the T13/L1 levels in female rats.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37534006","citation_count":2,"is_preprint":false},{"pmid":"40520101","id":"PMC_40520101","title":"KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40520101","citation_count":2,"is_preprint":false},{"pmid":"38689824","id":"PMC_38689824","title":"Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.","date":"2024","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/38689824","citation_count":2,"is_preprint":false},{"pmid":"40248734","id":"PMC_40248734","title":"ANKRD11 as a potential biomarker for brain metastasis from lung adenocarcinoma via cerebrospinal fluid liquid biopsy.","date":"2025","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40248734","citation_count":2,"is_preprint":false},{"pmid":"27382241","id":"PMC_27382241","title":"A rare balanced nonrobertsonian translocation involving acrocentric chromosomes: Chromosome abnormality of t(13;15)(p11.2;q22.1).","date":"2016","source":"Journal of human reproductive sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27382241","citation_count":2,"is_preprint":false},{"pmid":"10494096","id":"PMC_10494096","title":"Detection of a cryptic translocation t(13;20)(q34;p13) in an unexplained case of MCA/MR: value of FISH over high resolution banding.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10494096","citation_count":2,"is_preprint":false},{"pmid":"40004465","id":"PMC_40004465","title":"16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40004465","citation_count":1,"is_preprint":false},{"pmid":"40574944","id":"PMC_40574944","title":"A novel heterozygous mutation of ANKRD11 causes KBG syndrome in a preterm neonate: a case report and literature review.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40574944","citation_count":1,"is_preprint":false},{"pmid":"36584991","id":"PMC_36584991","title":"[Clinical and genetic analysis of three children with KBG syndrome due to novel variants of ANKRD11 gene].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36584991","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44517,"output_tokens":4369,"usd":0.099543},"stage2":{"model":"claude-opus-4-6","input_tokens":7841,"output_tokens":3526,"usd":0.191032},"total_usd":0.290575,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete nuclear inclusions when neurons are depolarized, suggesting a role in neural plasticity.\",\n      \"method\": \"Subcellular localization by direct imaging in neurons with depolarization stimulus\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implication, single lab\",\n      \"pmids\": [\"21782149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ANKRD11 is a p53-interacting protein that acts as a coactivator of p53 transcriptional activity; it associates with p53 acetyltransferases P/CAF and hADA3, enhances levels of acetylated p53, and increases p53 DNA-binding to the CDKN1A (p21) promoter, thereby upregulating p21 expression.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, reporter assays, ChIP, exogenous expression in MCF-7 and MDA-MB-468 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, KD) in single study with rigorous functional readouts\",\n      \"pmids\": [\"18840648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ANKRD11 suppresses the oncogenic gain-of-function properties of mutant p53 by restoring a native conformation to mutant p53 protein and causing dissociation of the mutant p53–p63 complex, thereby alleviating mutant p53-driven centrosome amplification, mitotic defects, multinucleation, and invasion.\",\n      \"method\": \"Inducible expression, co-immunoprecipitation, conformational antibody assays, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical and cellular methods establishing mechanism\",\n      \"pmids\": [\"21986947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ankrd11 functions as a chromatin regulator during neural development by associating with chromatin and colocalizing with HDAC3; it controls histone acetylation levels, and its loss causes decreased neural precursor proliferation, reduced neurogenesis, and aberrant neuronal positioning. The proliferation defect is rescued by inhibiting histone acetyltransferase activity or by expressing HDAC3.\",\n      \"method\": \"Knockdown in murine/human cortical neural precursors, Yoda point-mutant mouse (HDAC-binding domain mutation), chromatin association assay, co-localization with HDAC3, gene expression and histone acetylation analysis, epistasis rescue experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, genetic mouse model, chromatin association, rescue epistasis) replicated across species\",\n      \"pmids\": [\"25556659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The ANKRD11 C-terminus is required for proteasome-mediated degradation of the protein; wild-type ANKRD11 abundance is tightly regulated during the cell cycle, and all examined pathogenic truncating mutations in the C-terminal region result in aberrant accumulation of the mutant protein. D-box sequences (proteasome degradation signals) are present in the C-terminus.\",\n      \"method\": \"Cell cycle analysis of protein abundance, in silico D-box identification, functional comparison of 11 pathogenic ANKRD11 variants\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cell-based protein-level analysis across multiple variants, single lab\",\n      \"pmids\": [\"25413698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANKRD11 regulates pyramidal neuron radial migration and dendritic differentiation in developing mouse cortex; its knockdown suppresses acetylation of p53 and histone H3, reduces mRNA levels of TrkB, BDNF, and neurite growth-related genes, and the TrkB promoter in ANKRD11-deficient neurons shows reduced acetylated H3 and p53 occupancy with increased MeCP2 and DNMT1 binding. Overexpression of TrkB rescues abnormal dendrite growth.\",\n      \"method\": \"In utero electroporation knockdown, histone/p53 acetylation assays, ChIP, qRT-PCR, TrkB overexpression rescue\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vivo KD, ChIP, rescue) in single rigorous study\",\n      \"pmids\": [\"29274743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANKRD11 (ANCO1) acts as a transcriptional repressor at AIB1/YAP-TEAD target genes in breast epithelial cells; it is recruited to chromatin by AIB1 and its loss reverses AIB1-YAP-dependent gene repression, increases cell size, and enhances YAP-driven aberrant 3D growth.\",\n      \"method\": \"ChIP-seq, sequential ChIP, gene expression analysis, shRNA knockdown, 3D culture assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus functional KD experiments, multiple orthogonal methods\",\n      \"pmids\": [\"31788936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pathogenic ANKRD11 missense variants cause KBG syndrome either by reducing ANKRD11 protein stability (6 of 10 tested variants) or by causing loss of transcriptional repression activity (one variant also decreased proteasome degradation); variants significantly cluster in repression domain 2 at the C-terminus.\",\n      \"method\": \"Cell-based stability assays, transcriptional reporter assays, in silico analysis, functional characterization of 10 missense variants\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based functional assays across multiple variants, single lab\",\n      \"pmids\": [\"35833929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANKRD11 interacts with HDAC3 and upregulates its deacetylase activity; in the context of aromatase inhibitor resistance in breast cancer, ANKRD11 acts downstream of SERPINA3 to promote resistance through this HDAC3 interaction.\",\n      \"method\": \"Co-immunoprecipitation, HDAC3 activity assays, knockdown/overexpression experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional activity assay, single lab\",\n      \"pmids\": [\"37414914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A bipartite nuclear localization signal (bNLS) between residues 53 and 87 of ANKRD11 mediates its nuclear import via two binding sites for Importin α1; this bNLS is necessary and sufficient for nuclear localization, and mutations within it provide a pathogenic mechanism for certain clinical ANKRD11 variants.\",\n      \"method\": \"Site-directed mutagenesis, biochemical binding assays, GFP-fusion nuclear import assays in HeLa cells, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with localization assay and biochemical binding, single lab\",\n      \"pmids\": [\"37290286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The minor spliceosomal protein 65K/RNPC3 interacts with ANKRD11, and ANKRD11 acts as a bridging factor that facilitates co-binding of HDAC3 and 65K/RNPC3 to common chromatin loci. ANKRD11 knockdown simultaneously reduces HDAC3 and 65K chromatin binding and decreases H3K9 deacetylation at shared target genes, linking the minor spliceosome to histone deacetylation-mediated gene regulation.\",\n      \"method\": \"Affinity purification (Drosophila and human), CRISPR/Cas9 deletion mutants, CUT&Tag assays, knockdown experiments, histone modification analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (affinity purification, CUT&Tag, genetic KO, KD) across two organisms\",\n      \"pmids\": [\"38837887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockout of Ankrd11 in embryonic neural crest cells leads to persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility due to aberrant cardiac neural crest cell organization and outflow tract septation failure; Ankrd11 knockout impairs expression of transcription factors, chromatin remodelers, and mTOR, BMP, and TGF-β signaling pathways in cardiac neural crest cells.\",\n      \"method\": \"Conditional neural crest-specific knockout mouse, cardiac morphology analysis, transcriptome analysis of cardiac neural crest cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular and molecular phenotype, multiple pathway readouts\",\n      \"pmids\": [\"38951500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ankrd11 is required for intramembranous ossification and palate development; conditional deletion of Ankrd11 in neural crest cells causes cleft palate, retrognathia, midfacial hypoplasia, reduced calvarial growth, failure of ossification center expansion/fusion, and reduced proliferation of palatal shelves. Ankrd11 expression is closely associated with developing bony structures in the craniofacial complex.\",\n      \"method\": \"Neural crest-specific conditional heterozygous and homozygous knockout mice, 3D imaging, histology, proliferation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific cellular phenotypes (proliferation, ossification) and gene expression readouts\",\n      \"pmids\": [\"33996804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANKRD11 binds to the cohesin complex via a short N-terminal peptide fragment with high affinity; crystal structure of the ANKRD11 peptide–cohesin complex shows ANKRD11 competes with CTCF for cohesin binding. A single Y347A point mutation in ANKRD11 disrupts the ANKRD11–cohesin interaction, perturbs gene expression in mouse embryonic stem cells, and causes neural and craniofacial anomalies in knock-in mice mirroring KBG syndrome.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, site-directed mutagenesis (Y347A knock-in mice), gene expression analysis in mESCs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis, in vivo knock-in model, and gene expression readouts\",\n      \"pmids\": [\"39847329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANKRD11 promotes SETD5 expression by binding to the Setd5 promoter and recruiting WDR5, a component of the H3K4 methyltransferase complex; reduced H3K4 methylation at the Setd5 promoter in ANKRD11-deficient cells leads to decreased SETD5, reduced ribosomal RNA (rRNA) levels, and impaired translation. Overexpression of ANKRD11 or SETD5 rescues rRNA and translational defects.\",\n      \"method\": \"ChIP (promoter binding, H3K4 methylation), co-immunoprecipitation (ANKRD11-WDR5), rRNA quantification, translational activity assays, rescue by overexpression\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, functional rescue) establishing a mechanistic pathway\",\n      \"pmids\": [\"40520101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of ANCO1 (ANKRD11) in early-stage triple-negative breast cancer cells leads to global increase in H3K27Ac signals enriched at AP-1, TEAD, STAT3, and NFκB motifs, activating breast-cancer-specific enhancers and oncogenic PI3K-AKT, EMT, and senescence pathways; ANCO1 depletion causes aneuploidy and enhanced 3D invasion.\",\n      \"method\": \"ChIP-seq (H3K27Ac), shRNA knockdown, 3D invasion assays, xenograft mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq with functional KD and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37511268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANKRD11 can enhance transactivation of the p21 (CDKN1A) promoter; two loss-of-function ANKRD11 variants (p.Lys1347del and p.Leu2143Val) failed to restore p21-promoter luciferase activity or endogenous p21 mRNA levels when re-introduced, demonstrating their functional impairment in this transcriptional activity.\",\n      \"method\": \"p21-promoter luciferase reporter assay, knockdown and rescue with wild-type vs. mutant ANKRD11 in cell lines\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay with mutant vs. WT rescue, single lab, single method\",\n      \"pmids\": [\"33354850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A truncated ANKRD11 protein generated by a frameshift variant escapes nonsense-mediated decay, accumulates at higher levels than wild-type, localizes predominantly to the nucleus (whereas wild-type distributes between nucleus and cytoplasm), and significantly reduces CDKN1A/p21-promoter luciferase activity and endogenous p21 mRNA, suggesting a dominant-negative loss of transcriptional activation function.\",\n      \"method\": \"RT-PCR (NMD assessment), Western blot, immunofluorescence, p21-promoter luciferase reporter assay in HEK293 cells\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple cell-based methods but single lab; provides novel mechanistic insight into truncation mechanism\",\n      \"pmids\": [\"38515699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKRD11 is a large nuclear chromatin regulator that controls gene expression by modulating histone acetylation (via HDAC3 recruitment), binding the cohesin complex (competing with CTCF), acting as a p53 coactivator (associating with P/CAF and hADA3 to enhance p53 acetylation and CDKN1A transcription), promoting SETD5/rRNA expression via WDR5-mediated H3K4 methylation, and bridging HDAC3 with the minor spliceosome component 65K/RNPC3 at common chromatin targets; loss-of-function through haploinsufficiency impairs neural precursor proliferation, neuronal migration, dendritic differentiation, craniofacial bone development, and cardiac neural crest-mediated outflow tract septation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANKRD11 is a nuclear chromatin regulator that controls gene expression during development and tumor suppression through multiple mechanistic arms: recruitment of histone deacetylase HDAC3 to modulate histone acetylation at target loci, coactivation of p53 via association with acetyltransferases P/CAF and hADA3 to drive CDKN1A/p21 transcription, competitive binding to the cohesin complex that displaces CTCF, and bridging HDAC3 with the minor spliceosome component 65K/RNPC3 at shared chromatin targets [PMID:25556659, PMID:18840648, PMID:39847329, PMID:38837887]. ANKRD11 additionally promotes SETD5 expression by recruiting WDR5 to the Setd5 promoter for H3K4 methylation, thereby sustaining rRNA levels and translation [PMID:40520101]. Loss of ANKRD11 function in neural crest and cortical precursor cells impairs proliferation, neuronal migration, dendritic differentiation, craniofacial ossification, and cardiac outflow tract septation, and haploinsufficiency causes KBG syndrome [PMID:25556659, PMID:33996804, PMID:38951500, PMID:39847329]. In breast epithelial cells, ANKRD11 acts as a transcriptional repressor at AIB1/YAP-TEAD target genes, and its loss activates oncogenic enhancers enriched for AP-1, TEAD, and NF-κB motifs, promoting invasion and aneuploidy [PMID:31788936, PMID:37511268].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that ANKRD11 directly participates in p53-mediated transcription resolved how a previously uncharacterized ankyrin-repeat protein could function as a transcriptional coactivator: it bridges p53 with acetyltransferases P/CAF and hADA3, enhances p53 acetylation and DNA binding at the CDKN1A promoter, and upregulates p21 expression.\",\n      \"evidence\": \"Co-IP, ChIP, shRNA knockdown, and reporter assays in MCF-7 and MDA-MB-468 breast cancer cells\",\n      \"pmids\": [\"18840648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the ANKRD11–P/CAF–hADA3 interaction is direct or requires additional scaffold factors\", \"Whether ANKRD11 coactivates p53 targets beyond CDKN1A genome-wide\", \"No structural information on the ANKRD11–p53 interface\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies expanded ANKRD11's functional scope: its nuclear localization in neurons with activity-dependent redistribution into nuclear inclusions suggested a role in neural plasticity, while its ability to restore native conformation to mutant p53 and dissociate the mutant-p53–p63 complex established a gain-of-function suppressor activity relevant to cancer.\",\n      \"evidence\": \"Subcellular imaging in depolarized neurons (PMID:21782149); inducible expression, conformational antibody assays, co-IP, and invasion assays (PMID:21986947)\",\n      \"pmids\": [\"21782149\", \"21986947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which depolarization drives ANKRD11 into nuclear inclusions\", \"Whether conformational rescue of mutant p53 occurs in vivo\", \"No identification of the ANKRD11 domain responsible for p53 conformational correction\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of ANKRD11 as a chromatin-associated HDAC3 partner that controls histone acetylation in neural precursors defined its core developmental mechanism: Ankrd11 loss increases histone acetylation, reduces precursor proliferation and neurogenesis, and these defects are rescued by HDAC3 overexpression or HAT inhibition, placing ANKRD11 upstream of histone acetylation balance during cortical development.\",\n      \"evidence\": \"Knockdown in murine/human cortical precursors, Yoda point-mutant mouse, chromatin association and HDAC3 co-localization assays, epistasis rescue (PMID:25556659); cell cycle protein-level analysis of pathogenic C-terminal truncation variants (PMID:25413698)\",\n      \"pmids\": [\"25556659\", \"25413698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific ANKRD11 target genes regulated through HDAC3\", \"Whether the C-terminal D-box-mediated proteasomal degradation is required for normal cell-cycle-dependent function in vivo\", \"No genome-wide map of ANKRD11 chromatin binding sites in neural precursors\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that ANKRD11 controls pyramidal neuron migration and dendritic differentiation through p53/histone H3 acetylation at the TrkB promoter linked the chromatin-regulatory and p53-coactivation arms into one pathway operating during cortical development.\",\n      \"evidence\": \"In utero electroporation knockdown, ChIP for acetylated H3 and p53 at TrkB promoter, TrkB overexpression rescue\",\n      \"pmids\": [\"29274743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the TrkB–BDNF axis fully accounts for ANKRD11-dependent dendritic phenotypes\", \"Contribution of HDAC3 versus p53 arms at the TrkB locus not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP-seq in breast epithelial cells revealed a distinct repressor function: ANKRD11 (ANCO1) is recruited by AIB1 to YAP-TEAD target genes, where it represses transcription; its loss activates YAP-dependent programs driving aberrant 3D growth, establishing ANKRD11 as a context-dependent repressor beyond its coactivator role at p53 targets.\",\n      \"evidence\": \"ChIP-seq, sequential ChIP, shRNA knockdown, 3D culture assays in breast epithelial cells\",\n      \"pmids\": [\"31788936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANKRD11 repression at YAP-TEAD targets operates through HDAC3 or an independent corepressor mechanism\", \"Relevance of this repressor axis in non-epithelial contexts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conditional deletion of Ankrd11 in neural crest cells established its requirement for intramembranous ossification and palate morphogenesis, extending the gene's developmental roles from brain to craniofacial skeleton and directly modeling KBG syndrome craniofacial features.\",\n      \"evidence\": \"Neural crest-specific conditional KO mice, 3D imaging, histology, and proliferation assays\",\n      \"pmids\": [\"33996804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets of ANKRD11 in osteoprogenitors not identified\", \"Whether the craniofacial phenotype depends on HDAC3 or cohesin interactions\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple 2023 studies deepened the chromatin and disease mechanism: ANKRD11 loss in triple-negative breast cancer globally elevated H3K27Ac at oncogenic enhancers (AP-1, TEAD, STAT3, NF-κB), ANKRD11 was shown to interact with and upregulate HDAC3 deacetylase activity, a bipartite NLS was mapped to residues 53–87 mediating Importin-α1-dependent nuclear import, and pathogenic missense variants were shown to reduce either protein stability or transcriptional repression activity.\",\n      \"evidence\": \"ChIP-seq/shRNA/xenograft (PMID:37511268); Co-IP and HDAC3 activity assays (PMID:37414914); mutagenesis and GFP-import assays (PMID:37290286); cell-based stability and reporter assays on 10 missense variants (PMID:35833929)\",\n      \"pmids\": [\"37511268\", \"37414914\", \"37290286\", \"35833929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANKRD11-dependent HDAC3 activation is allosteric or recruitment-based\", \"Structural basis of the repression domain 2 clustering of pathogenic variants\", \"Whether bipartite NLS mutations account for clinical cases beyond those tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two 2024 studies revealed new functional partnerships: ANKRD11 bridges HDAC3 and the minor spliceosome protein 65K/RNPC3 at shared chromatin loci to couple histone deacetylation with minor-intron gene regulation, and neural crest-specific Ankrd11 knockout causes persistent truncus arteriosus and impaired ventricular function through disrupted mTOR/BMP/TGF-β signaling in cardiac neural crest cells.\",\n      \"evidence\": \"Affinity purification, CUT&Tag, CRISPR KO in Drosophila and human cells (PMID:38837887); conditional neural crest KO mouse with cardiac phenotyping and transcriptomics (PMID:38951500); truncated variant NMD-escape and dominant-negative activity (PMID:38515699)\",\n      \"pmids\": [\"38837887\", \"38951500\", \"38515699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether bridging of HDAC3–65K is required for minor intron splicing per se or only for transcriptional regulation of minor-intron-containing genes\", \"Specific cardiac neural crest target genes directly bound by ANKRD11\", \"Whether dominant-negative truncated ANKRD11 variants operate through the HDAC3 or cohesin arm\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A crystal structure of an ANKRD11 N-terminal peptide bound to the cohesin complex demonstrated that ANKRD11 competes with CTCF for the same cohesin binding surface; a Y347A knock-in mouse disrupting this single interaction recapitulated neural and craniofacial KBG syndrome features, establishing cohesin binding as a major independent axis of ANKRD11 function. Separately, ANKRD11 was shown to recruit WDR5 to the Setd5 promoter, promoting H3K4 methylation and SETD5-dependent rRNA biogenesis and translation.\",\n      \"evidence\": \"Crystal structure, biochemical competition assays, Y347A knock-in mice, gene expression in mESCs (PMID:39847329); ChIP, Co-IP, rRNA quantification, translational assays, rescue experiments (PMID:40520101)\",\n      \"pmids\": [\"39847329\", \"40520101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cohesin and HDAC3 interactions are coordinated at the same loci or operate at distinct gene sets\", \"Global contribution of the SETD5–rRNA axis to KBG syndrome phenotypes\", \"No full-length ANKRD11 structure to reveal inter-domain organization\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how ANKRD11's multiple chromatin-regulatory arms (HDAC3 recruitment, cohesin binding, p53 coactivation, WDR5-mediated H3K4 methylation, minor spliceosome bridging) are coordinated or segregated at individual genomic loci, and which arm(s) are primarily responsible for each tissue-specific developmental phenotype in KBG syndrome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrative multi-omic dataset mapping all ANKRD11 interaction arms genome-wide in a single cell type\", \"Contribution of each mechanistic arm to specific KBG syndrome features (neurological vs. craniofacial vs. cardiac) not dissected\", \"No full-length structural model of ANKRD11\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 5, 6, 7, 15, 16, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 5, 10, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 17]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 6, 10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 5, 10, 14, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 6, 7, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HDAC3\",\n      \"TP53\",\n      \"KAT2B\",\n      \"TADA3\",\n      \"CTCF\",\n      \"WDR5\",\n      \"RNPC3\",\n      \"NCOA3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}