{"gene":"MIDEAS","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2011,"finding":"MIDEAS (as part of the MiDAC complex) was identified as a component of a novel mitotic deacetylase complex (MiDAC) through chemoproteomics profiling of HDAC inhibitors using affinity capture and quantitative mass spectrometry. MiDAC is scaffolded by an ELM-SANT domain subunit (MIDEAS) and associates with HDAC1/2.","method":"Affinity capture mass spectrometry with HDAC inhibitor probes","journal":"Nature biotechnology","confidence":"High","confidence_rationale":"Tier 2 — large-scale chemoproteomics with quantitative MS, independently followed up by multiple subsequent studies","pmids":["21258344"],"is_preprint":false},{"year":2015,"finding":"MIDEAS acts as a corepressor scaffold in the MiDAC complex: its ELM2-SANT domain mediates direct interaction with HDAC1, and DNTTIP1 (via its N-terminal dimerization domain) bridges MIDEAS and HDAC1. The C-terminal SKI/SNO/DAC-related domain of DNTTIP1 binds DNA and nucleosomes, positioning DNTTIP1 as a dimeric chromatin-targeting module within the HDAC1:MIDEAS complex.","method":"Crystal structures of DNTTIP1 domains, co-immunoprecipitation, nucleosome-binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — structural determination combined with biochemical binding assays","pmids":["25653165"],"is_preprint":false},{"year":2020,"finding":"MiDAC (containing MIDEAS and DNTTIP1) is essential for chromosome alignment during mitosis in cancer cell lines. Mice lacking MIDEAS die during late embryogenesis with heart malformation and haematopoietic failure due to gene expression perturbations. CryoEM structure of MiDAC reveals four copies of HDAC1 positioned at the periphery with outward-facing active sites, suggesting the complex targets multiple nucleosomes in a processive manner.","method":"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell line loss-of-function assays (chromosome alignment phenotype)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryoEM structure plus multiple genetic KO models with defined phenotypes","pmids":["32591534"],"is_preprint":false},{"year":2025,"finding":"A de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser) causes a multisystem neurodevelopmental disorder. CryoEM structure reveals Tyr654 resides in a conserved auto-inhibitory loop covering the HDAC active site; the variant is predicted to displace this loop, resulting in elevated MiDAC deacetylase activity. Patient fibroblasts show gene expression changes reciprocal to those from rapid MiDAC degradation, confirming gain-of-function hyperactivity.","method":"CryoEM structure, patient fibroblast transcriptomics, rapid MiDAC degradation cell line comparison","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryoEM structural data combined with patient fibroblast functional validation and reciprocal gene expression comparison","pmids":["41290615"],"is_preprint":false},{"year":2025,"finding":"ELMSAN1 (MIDEAS) directly interacts with and constitutively inhibits the nucleus-localized pyruvate dehydrogenase complex (nPDC), restricting nuclear acetyl-CoA production and histone acetylation. Pharmacologic disruption of the ELMSAN1-nPDC interaction derepresses nPDC activity, enhances nuclear acetyl-CoA generation, and reprograms cancer cells to a postmitotic state. Combination with HDAC1/2 inhibition synergistically inhibits tumor growth.","method":"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, co-immunoprecipitation, in vivo xenograft models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — convergent CRISPR screen, proteomics, and in vivo validation across multiple cancer models","pmids":["40505660"],"is_preprint":false},{"year":2025,"finding":"AHR activation directly upregulates ELMSAN1 (MIDEAS) transcription as a noncanonical AHR target gene. Elevated ELMSAN1 promotes histone deacetylation at MYC regulatory elements via MiDAC, repressing MYC expression and sensitizing AML cells to BET inhibitors. ELMSAN1 depletion abolishes AHR-induced MYC repression and BET inhibitor sensitization.","method":"Functional CRISPR screen, ChIP, gene expression analysis, ELMSAN1 knockdown/overexpression in AML cell lines and patient-derived xenografts","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — CRISPR screen plus orthogonal ChIP and genetic rescue experiments in multiple models","pmids":["40768599"],"is_preprint":false},{"year":2025,"finding":"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 complexes identified Y48 on HDAC1 as a critical contact residue for ELM2/SANT domain-containing proteins including MIDEAS. The HDAC1-Y48E mutation disrupts binding to all HDAC complexes except SIN3, demonstrating that MIDEAS (MiDAC) recruitment is dependent on HDAC1 surface residue Y48. E63R mutation markedly reduces NuRD and MiDAC binding but retains some CoREST binding.","method":"Structural comparison (MTA1:HDAC1 and MIDEAS:HDAC1 crystal structures), co-immunoprecipitation with HDAC1 surface mutants, mass spectrometry, HDAC1/2 double-KO rescue experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — structural analysis combined with mutagenesis and KO rescue experiments","pmids":["40966515"],"is_preprint":false},{"year":2024,"finding":"ELMSAN1 (MIDEAS) is required for differentiation and maturation of hiPSC-derived cardiomyocytes. ELMSAN1 depletion inhibits pluripotency deactivation, reduces expression of cardiac-specific markers, impairs sarcomere Z-line formation, decreases calcium handling, and disrupts electrophysiological properties. The cardiac role of ELMSAN1 is associated with regulation of histone H3K27 acetylation levels.","method":"hiPSC ELMSAN1 knockdown/knockout, structural and functional cardiomyocyte assessment, ChIP for H3K27ac, transcriptome analysis","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotypes and epigenetic readout, single lab","pmids":["38904247"],"is_preprint":false},{"year":2025,"finding":"Cardiomyocyte-specific Elmsan1 knockout mice develop progressive cardiac dysfunction with significantly reduced ejection fraction by 12 weeks and severe heart failure by 24 weeks, accompanied by cardiomyocyte hypertrophy, ventricular dilation, and shortened lifespan. RNA-seq of presymptomatic hearts revealed suppression of TCA cycle genes and key cardiac genes, and mitochondrial respiratory chain complex proteins were reduced with ultrastructural mitochondrial abnormalities and impaired calcium handling.","method":"αMHC-Cre cardiomyocyte-specific Elmsan1 knockout mice, echocardiography, RNA-seq, mitochondrial complex protein analysis, electron microscopy","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined functional, transcriptomic, and ultrastructural phenotypes","pmids":["40588350"],"is_preprint":false}],"current_model":"MIDEAS (ELMSAN1) is a scaffold protein that, via its ELM2-SANT domain, directly recruits HDAC1/2 into the tetrameric MiDAC complex together with DNTTIP1, which targets chromatin; the complex mediates processive histone deacetylation at nucleosomes, is essential for mitotic chromosome alignment and embryonic development (heart and haematopoiesis), regulates cardiac gene expression and cardiomyocyte maturation, represses MYC via histone deacetylation at MYC regulatory elements downstream of AHR signaling, and inhibits nuclear pyruvate dehydrogenase complex (nPDC) to restrict nuclear acetyl-CoA and histone acetylation; an auto-inhibitory loop in MIDEAS normally limits HDAC active-site access, and its disruption by the p.Tyr654Ser variant causes gain-of-function hyperdeacetylation and a neurodevelopmental syndrome."},"narrative":{"teleology":[{"year":2011,"claim":"Chemoproteomics identified a previously unknown mitotic HDAC complex (MiDAC) scaffolded by MIDEAS, establishing the first link between an ELM-SANT domain protein and a distinct class II HDAC1/2-containing assembly.","evidence":"Affinity capture with HDAC inhibitor probes and quantitative mass spectrometry in cell extracts","pmids":["21258344"],"confidence":"High","gaps":["No structural information on how MIDEAS engages HDAC1/2","Biological function of MiDAC unknown","Stoichiometry and full subunit composition unresolved"]},{"year":2015,"claim":"Crystal structures and binding assays revealed the molecular architecture of the MiDAC core: MIDEAS binds HDAC1 via its ELM2-SANT domain, while DNTTIP1 dimerizes and targets the complex to chromatin through its DNA/nucleosome-binding domain.","evidence":"Crystal structures of DNTTIP1 domains, co-immunoprecipitation, and nucleosome-binding assays","pmids":["25653165"],"confidence":"High","gaps":["Higher-order assembly of the full MiDAC tetramer unresolved","No functional phenotype yet linked to MiDAC loss","Genomic targets of MiDAC unknown"]},{"year":2020,"claim":"CryoEM structure of the full MiDAC complex and genetic knockout models demonstrated that four HDAC1 copies face outward for processive nucleosome deacetylation, and that MIDEAS is essential for mitotic chromosome alignment, embryonic heart development, and haematopoiesis.","evidence":"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell line loss-of-function assays","pmids":["32591534"],"confidence":"High","gaps":["Specific genomic loci regulated by MiDAC in mitosis not identified","Mechanism of mitotic recruitment unknown","Postnatal cardiac role not explored"]},{"year":2024,"claim":"Defining MIDEAS function in human cardiomyocyte differentiation showed it is required for pluripotency exit, sarcomere assembly, and calcium handling, linking MiDAC-dependent H3K27 deacetylation to cardiac gene regulation.","evidence":"ELMSAN1 knockdown/knockout in hiPSC-derived cardiomyocytes with structural, functional, and ChIP-based epigenetic assessment","pmids":["38904247"],"confidence":"Medium","gaps":["Single-lab observation; independent replication pending","Direct genomic targets in cardiomyocytes not mapped genome-wide","Unclear whether the cardiac role is MiDAC-specific or shared with other HDAC complexes"]},{"year":2025,"claim":"Cardiomyocyte-specific Elmsan1 knockout in mice confirmed an essential postnatal role: loss causes progressive heart failure with suppressed TCA-cycle gene expression, mitochondrial dysfunction, and premature death, solidifying MiDAC as a cardiac maintenance factor.","evidence":"αMHC-Cre cardiomyocyte-specific knockout mice, echocardiography, RNA-seq, electron microscopy","pmids":["40588350"],"confidence":"High","gaps":["Whether cardiac phenotype is due to HDAC-dependent deacetylation, nPDC inhibition, or both is unresolved","Rescue experiments with catalytically dead MiDAC not performed"]},{"year":2025,"claim":"Discovery that the p.Tyr654Ser variant disrupts a conserved auto-inhibitory loop covering the HDAC active site established a gain-of-function mechanism for MiDAC-associated neurodevelopmental disease, revealing an intrinsic regulatory feature of MIDEAS.","evidence":"CryoEM structure, patient fibroblast transcriptomics, reciprocal comparison with rapid MiDAC degradation","pmids":["41290615"],"confidence":"High","gaps":["Only one pathogenic variant characterized; genotype–phenotype spectrum unknown","Whether the auto-inhibitory loop is regulated physiologically (e.g., by post-translational modification) is untested"]},{"year":2025,"claim":"Identification of MIDEAS as a constitutive inhibitor of nuclear pyruvate dehydrogenase complex expanded its function beyond HDAC scaffolding, showing it restricts nuclear acetyl-CoA production and histone acetylation independently of MiDAC catalytic activity.","evidence":"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, co-immunoprecipitation, in vivo xenograft models","pmids":["40505660"],"confidence":"High","gaps":["Structural basis of the MIDEAS–nPDC interaction not determined","Whether nPDC inhibition is relevant in non-cancer contexts unknown","Relative contribution of HDAC scaffolding versus nPDC inhibition to MIDEAS cellular phenotypes not dissected"]},{"year":2025,"claim":"AHR was shown to directly transactivate MIDEAS, linking environmental/metabolic signaling to MiDAC-mediated MYC repression via histone deacetylation at MYC regulatory elements, with therapeutic relevance for AML sensitization to BET inhibitors.","evidence":"CRISPR screen, ChIP, gene expression analysis, knockdown/overexpression in AML cell lines and patient-derived xenografts","pmids":["40768599"],"confidence":"High","gaps":["Whether AHR–MIDEAS–MYC axis operates in non-hematopoietic tissues unknown","Direct ChIP of MiDAC at MYC loci not shown"]},{"year":2025,"claim":"Structural comparison and mutagenesis of the HDAC1 surface defined Y48 as the critical contact residue for MIDEAS (and other ELM2-SANT proteins), clarifying how HDAC1 discriminates between its multiple scaffolding partners.","evidence":"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 complexes, HDAC1 surface mutagenesis, co-IP, HDAC1/2 double-KO rescue","pmids":["40966515"],"confidence":"High","gaps":["Whether post-translational modifications of HDAC1-Y48 regulate complex switching in vivo is untested","Quantitative binding affinities of MIDEAS versus other ELM2-SANT proteins for HDAC1 not measured"]},{"year":null,"claim":"The relative contributions of MIDEAS's HDAC-scaffolding and nPDC-inhibitory functions to its developmental, cardiac, and disease phenotypes remain to be dissected, and the physiological regulation of the auto-inhibitory loop is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No separation-of-function mutants distinguishing HDAC scaffolding from nPDC inhibition","Whether the auto-inhibitory loop is dynamically regulated by signaling or modifications is untested","Genome-wide direct target maps for MiDAC across tissues are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,5,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3]}],"complexes":["MiDAC"],"partners":["HDAC1","HDAC2","DNTTIP1","PDHA1","AHR"],"other_free_text":[]},"mechanistic_narrative":"MIDEAS is a scaffold protein that nucleates the tetrameric MiDAC (mitotic deacetylase) complex by recruiting HDAC1/2 through its ELM2-SANT domain and partnering with the chromatin-targeting subunit DNTTIP1, thereby enabling processive histone deacetylation across nucleosomes [PMID:21258344, PMID:25653165, PMID:32591534]. MiDAC is essential for mitotic chromosome alignment, embryonic heart and haematopoietic development, and postnatal cardiomyocyte maturation; cardiomyocyte-specific loss causes progressive heart failure with mitochondrial dysfunction [PMID:32591534, PMID:38904247, PMID:40588350]. Beyond its HDAC-scaffolding role, MIDEAS constitutively inhibits the nuclear pyruvate dehydrogenase complex (nPDC), restricting nuclear acetyl-CoA supply and histone acetylation, and is transcriptionally induced by AHR signaling to repress MYC through MiDAC-mediated deacetylation at MYC regulatory elements [PMID:40505660, PMID:40768599]. A de novo heterozygous p.Tyr654Ser variant disrupts an auto-inhibitory loop that normally occludes the HDAC active site, producing gain-of-function hyperdeacetylation and a multisystem neurodevelopmental disorder [PMID:41290615]."},"prefetch_data":{"uniprot":{"accession":"Q6PJG2","full_name":"Mitotic deacetylase-associated SANT domain protein","aliases":["ELM2 and SANT domain-containing protein 1"],"length_aa":1045,"mass_kda":115.0,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6PJG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MIDEAS","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNTTIP1","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PTMA","stoichiometry":0.2},{"gene":"SNX12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MIDEAS","total_profiled":1310},"omim":[{"mim_id":"621074","title":"MITOTIC DEACETYLASE-ASSOCIATED SANT DOMAIN PROTEIN; MIDEAS","url":"https://www.omim.org/entry/621074"},{"mim_id":"611388","title":"DEOXYNUCLEOTIDYLTRANSFERASE, TERMINAL, INTERACTING PROTEIN 1; DNTTIP1","url":"https://www.omim.org/entry/611388"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MIDEAS"},"hgnc":{"alias_symbol":["LSR68"],"prev_symbol":["C14orf117","C14orf43","ELMSAN1"]},"alphafold":{"accession":"Q6PJG2","domains":[{"cath_id":"-","chopping":"750-830","consensus_level":"medium","plddt":85.5052,"start":750,"end":830},{"cath_id":"1.10.10.60","chopping":"831-896","consensus_level":"medium","plddt":86.1242,"start":831,"end":896}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJG2-F1-predicted_aligned_error_v6.png","plddt_mean":48.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MIDEAS","jax_strain_url":"https://www.jax.org/strain/search?query=MIDEAS"},"sequence":{"accession":"Q6PJG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PJG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PJG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJG2"}},"corpus_meta":[{"pmid":"32591534","id":"PMC_32591534","title":"The 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14.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12508121","citation_count":80,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8244,"output_tokens":2553,"usd":0.031513},"stage2":{"model":"claude-opus-4-6","input_tokens":5860,"output_tokens":2655,"usd":0.143512},"total_usd":0.37768,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":20018,"output_tokens":2527,"usd":0.04898},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6060,"output_tokens":2886,"usd":0.153675}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"MIDEAS forms a corepressor complex with HDAC1 and DNTTIP1. The amino-terminal dimerization domain of DNTTIP1 interacts with and mediates assembly of the HDAC1:MIDEAS complex, while the carboxy-terminal SKI/SNO/DAC-related domain of DNTTIP1 mediates interaction with DNA and nucleosomes, acting as a dimeric chromatin binding module.\",\n      \"method\": \"Crystal structure determination of DNTTIP1 domains, biochemical interaction assays, nucleosome binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination combined with biochemical interaction assays establishing complex assembly mechanism\",\n      \"pmids\": [\"25653165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MIDEAS is an essential scaffold subunit of the MiDAC histone deacetylase complex. CryoEM structure reveals a unique assembly where four copies of HDAC1 are positioned at the periphery with outward-facing active sites, suggesting a processive deacetylase function potentially targeting multiple nucleosomes. Mice lacking MIDEAS die during late embryogenesis with heart malformation and haematopoietic failure. In cancer cell lines, MiDAC is important for chromosome alignment during mitosis.\",\n      \"method\": \"CryoEM structure determination, MIDEAS knockout mice (loss-of-function), siRNA knockdown with mitotic chromosome alignment readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cryoEM structure plus genetic knockout with defined developmental phenotypes, replicated across cell lines and in vivo\",\n      \"pmids\": [\"32591534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo missense variant in MIDEAS (p.Tyr654Ser) is located in a conserved auto-inhibitory loop that covers the active site of the HDAC1 deacetylase. The variant is predicted to cause loop displacement leading to elevated (hyperactive) deacetylase activity. Patient fibroblasts show reciprocal gene expression changes compared to cells with rapid MiDAC degradation, consistent with gain-of-function hyperactivity.\",\n      \"method\": \"CryoEM structure of MiDAC complex, patient fibroblast transcriptomics, rapid MiDAC degradation cell line comparison\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cryoEM structure reveals mechanistic basis of variant effect, supported by gene expression data from patient cells and complementary degradation experiments\",\n      \"pmids\": [\"41290615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELMSAN1 (MIDEAS) directly interacts with the nuclear pyruvate dehydrogenase complex (nPDC) to constitutively inhibit its activity, thereby limiting nuclear acetyl-CoA generation and histone acetylation. Pharmacologic disruption of the ELMSAN1–nPDC interaction derepresses nPDC, increases nuclear acetyl-CoA, and reprograms cancer cells. This reprogramming is synergistically enhanced by HDAC1/2 inhibition.\",\n      \"method\": \"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, direct interaction assays (ELMSAN1–nPDC co-immunoprecipitation/pulldown), in vivo tumor models including PDX\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (CRISPR screen, proteomics, direct interaction, in vivo validation) in a single study establishing a direct inhibitory interaction\",\n      \"pmids\": [\"40505660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELMSAN1 is a component of the MiDAC HDAC complex and is directly upregulated by AHR (aryl hydrocarbon receptor). ELMSAN1 promotes histone deacetylation at MYC regulatory elements. ELMSAN1 depletion leads to MYC upregulation and impairs AHR signaling-induced BET inhibitor sensitization in AML.\",\n      \"method\": \"Functional CRISPR screen, ChIP (histone deacetylation at MYC loci), ELMSAN1 knockdown with MYC expression readout, patient-derived xenograft and murine leukemia models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen, ChIP, and in vivo xenograft models with defined molecular mechanism linking ELMSAN1 to histone deacetylation at MYC regulatory elements\",\n      \"pmids\": [\"40768599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Comparison of MTA1:HDAC1 and MIDEAS:HDAC1 crystal/cryo-EM structures identified residue Y48 on HDAC1 as critical for binding to ELM2/SANT domain-containing proteins including MIDEAS. The HDAC1-Y48E mutation disrupts binding to all HDAC complexes except SIN3. A second mutation, HDAC1-E63R, markedly reduces binding to NuRD and MiDAC complexes (including MIDEAS-containing MiDAC) but retains some CoREST binding.\",\n      \"method\": \"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 interfaces, co-immunoprecipitation, mass spectrometry, HDAC1/2 double-knockout rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural analysis combined with mutagenesis and KO rescue experiments defining the molecular determinants of MIDEAS–HDAC1 assembly\",\n      \"pmids\": [\"40966515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELMSAN1 (MIDEAS) is required for differentiation and maturation of human iPSC-derived cardiomyocytes. ELMSAN1 depletion inhibits pluripotency deactivation, reduces cardiac-specific marker expression, and impairs sarcomere formation, calcium handling, and electrophysiological maturation. The cardiac-specific role of ELMSAN1 is associated with regulation of histone H3K27 acetylation levels.\",\n      \"method\": \"ELMSAN1 knockdown and knockout in hiPSCs, cardiac differentiation assays, structural assessments (sarcomere Z-line), calcium imaging, electrophysiology, ChIP for H3K27ac, transcriptome analysis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays (electrophysiology, calcium handling, structural imaging, H3K27ac ChIP) in loss-of-function model\",\n      \"pmids\": [\"38904247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiomyocyte-specific deletion of Elmsan1 in mice leads to age-dependent cardiac dysfunction (reduced ejection fraction), cardiomyocyte hypertrophy, ventricular dilation, and shortened lifespan. Loss of Elmsan1 suppresses genes involved in the TCA cycle and calcium handling, reduces mitochondrial respiratory chain complex proteins, and causes ultrastructural mitochondrial abnormalities.\",\n      \"method\": \"Cardiomyocyte-specific Elmsan1 conditional knockout (αMHC-Cre), echocardiography, RNA-seq, electron microscopy, mitochondrial respiratory complex analysis, calcium handling measurements\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple orthogonal phenotypic and molecular readouts establishing specific cardiac role\",\n      \"pmids\": [\"40588350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELMSAN1 (MIDEAS) is identified as a core protein of the RNAmetasome network in human HEK293T cells, interacting with proteins involved in gene expression, splicing, ribosome biogenesis, chromatin remodeling, and cell cycle regulation, as determined by reciprocal immunoprecipitation.\",\n      \"method\": \"Reciprocal immunoprecipitation, knockdown experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single reciprocal IP identifying network membership without detailed mechanistic follow-up for ELMSAN1 specifically\",\n      \"pmids\": [\"34912035\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIDEAS (also known as ELMSAN1) is a scaffold protein that, together with DNTTIP1, assembles the MiDAC histone deacetylase complex containing four copies of HDAC1/2; it contacts HDAC1 through an ELM2/SANT domain interface (residue Y48 on HDAC1 is critical), contains an auto-inhibitory loop that normally restrains HDAC catalytic activity, and recruits the complex to chromatin where it promotes histone deacetylation at target loci (e.g., MYC regulatory elements), regulates chromosome alignment during mitosis, controls cardiac gene programs and cardiomyocyte maturation via H3K27 acetylation, and directly inhibits the nuclear pyruvate dehydrogenase complex to limit nuclear acetyl-CoA availability, with loss of MIDEAS causing embryonic lethality in mice and gain-of-function variants causing a human neurodevelopmental syndrome.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"MIDEAS (as part of the MiDAC complex) was identified as a component of a novel mitotic deacetylase complex (MiDAC) through chemoproteomics profiling of HDAC inhibitors using affinity capture and quantitative mass spectrometry. MiDAC is scaffolded by an ELM-SANT domain subunit (MIDEAS) and associates with HDAC1/2.\",\n      \"method\": \"Affinity capture mass spectrometry with HDAC inhibitor probes\",\n      \"journal\": \"Nature biotechnology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale chemoproteomics with quantitative MS, independently followed up by multiple subsequent studies\",\n      \"pmids\": [\"21258344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MIDEAS acts as a corepressor scaffold in the MiDAC complex: its ELM2-SANT domain mediates direct interaction with HDAC1, and DNTTIP1 (via its N-terminal dimerization domain) bridges MIDEAS and HDAC1. The C-terminal SKI/SNO/DAC-related domain of DNTTIP1 binds DNA and nucleosomes, positioning DNTTIP1 as a dimeric chromatin-targeting module within the HDAC1:MIDEAS complex.\",\n      \"method\": \"Crystal structures of DNTTIP1 domains, co-immunoprecipitation, nucleosome-binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination combined with biochemical binding assays\",\n      \"pmids\": [\"25653165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MiDAC (containing MIDEAS and DNTTIP1) is essential for chromosome alignment during mitosis in cancer cell lines. Mice lacking MIDEAS die during late embryogenesis with heart malformation and haematopoietic failure due to gene expression perturbations. CryoEM structure of MiDAC reveals four copies of HDAC1 positioned at the periphery with outward-facing active sites, suggesting the complex targets multiple nucleosomes in a processive manner.\",\n      \"method\": \"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell line loss-of-function assays (chromosome alignment phenotype)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryoEM structure plus multiple genetic KO models with defined phenotypes\",\n      \"pmids\": [\"32591534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser) causes a multisystem neurodevelopmental disorder. CryoEM structure reveals Tyr654 resides in a conserved auto-inhibitory loop covering the HDAC active site; the variant is predicted to displace this loop, resulting in elevated MiDAC deacetylase activity. Patient fibroblasts show gene expression changes reciprocal to those from rapid MiDAC degradation, confirming gain-of-function hyperactivity.\",\n      \"method\": \"CryoEM structure, patient fibroblast transcriptomics, rapid MiDAC degradation cell line comparison\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryoEM structural data combined with patient fibroblast functional validation and reciprocal gene expression comparison\",\n      \"pmids\": [\"41290615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELMSAN1 (MIDEAS) directly interacts with and constitutively inhibits the nucleus-localized pyruvate dehydrogenase complex (nPDC), restricting nuclear acetyl-CoA production and histone acetylation. Pharmacologic disruption of the ELMSAN1-nPDC interaction derepresses nPDC activity, enhances nuclear acetyl-CoA generation, and reprograms cancer cells to a postmitotic state. Combination with HDAC1/2 inhibition synergistically inhibits tumor growth.\",\n      \"method\": \"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, co-immunoprecipitation, in vivo xenograft models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — convergent CRISPR screen, proteomics, and in vivo validation across multiple cancer models\",\n      \"pmids\": [\"40505660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHR activation directly upregulates ELMSAN1 (MIDEAS) transcription as a noncanonical AHR target gene. Elevated ELMSAN1 promotes histone deacetylation at MYC regulatory elements via MiDAC, repressing MYC expression and sensitizing AML cells to BET inhibitors. ELMSAN1 depletion abolishes AHR-induced MYC repression and BET inhibitor sensitization.\",\n      \"method\": \"Functional CRISPR screen, ChIP, gene expression analysis, ELMSAN1 knockdown/overexpression in AML cell lines and patient-derived xenografts\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus orthogonal ChIP and genetic rescue experiments in multiple models\",\n      \"pmids\": [\"40768599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 complexes identified Y48 on HDAC1 as a critical contact residue for ELM2/SANT domain-containing proteins including MIDEAS. The HDAC1-Y48E mutation disrupts binding to all HDAC complexes except SIN3, demonstrating that MIDEAS (MiDAC) recruitment is dependent on HDAC1 surface residue Y48. E63R mutation markedly reduces NuRD and MiDAC binding but retains some CoREST binding.\",\n      \"method\": \"Structural comparison (MTA1:HDAC1 and MIDEAS:HDAC1 crystal structures), co-immunoprecipitation with HDAC1 surface mutants, mass spectrometry, HDAC1/2 double-KO rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural analysis combined with mutagenesis and KO rescue experiments\",\n      \"pmids\": [\"40966515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELMSAN1 (MIDEAS) is required for differentiation and maturation of hiPSC-derived cardiomyocytes. ELMSAN1 depletion inhibits pluripotency deactivation, reduces expression of cardiac-specific markers, impairs sarcomere Z-line formation, decreases calcium handling, and disrupts electrophysiological properties. The cardiac role of ELMSAN1 is associated with regulation of histone H3K27 acetylation levels.\",\n      \"method\": \"hiPSC ELMSAN1 knockdown/knockout, structural and functional cardiomyocyte assessment, ChIP for H3K27ac, transcriptome analysis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotypes and epigenetic readout, single lab\",\n      \"pmids\": [\"38904247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiomyocyte-specific Elmsan1 knockout mice develop progressive cardiac dysfunction with significantly reduced ejection fraction by 12 weeks and severe heart failure by 24 weeks, accompanied by cardiomyocyte hypertrophy, ventricular dilation, and shortened lifespan. RNA-seq of presymptomatic hearts revealed suppression of TCA cycle genes and key cardiac genes, and mitochondrial respiratory chain complex proteins were reduced with ultrastructural mitochondrial abnormalities and impaired calcium handling.\",\n      \"method\": \"αMHC-Cre cardiomyocyte-specific Elmsan1 knockout mice, echocardiography, RNA-seq, mitochondrial complex protein analysis, electron microscopy\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined functional, transcriptomic, and ultrastructural phenotypes\",\n      \"pmids\": [\"40588350\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIDEAS (ELMSAN1) is a scaffold protein that, via its ELM2-SANT domain, directly recruits HDAC1/2 into the tetrameric MiDAC complex together with DNTTIP1, which targets chromatin; the complex mediates processive histone deacetylation at nucleosomes, is essential for mitotic chromosome alignment and embryonic development (heart and haematopoiesis), regulates cardiac gene expression and cardiomyocyte maturation, represses MYC via histone deacetylation at MYC regulatory elements downstream of AHR signaling, and inhibits nuclear pyruvate dehydrogenase complex (nPDC) to restrict nuclear acetyl-CoA and histone acetylation; an auto-inhibitory loop in MIDEAS normally limits HDAC active-site access, and its disruption by the p.Tyr654Ser variant causes gain-of-function hyperdeacetylation and a neurodevelopmental syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MIDEAS (ELMSAN1) is a scaffold protein that nucleates the MiDAC histone deacetylase complex, organizing four copies of HDAC1 around a core formed with the chromatin-targeting subunit DNTTIP1, to direct processive histone deacetylation at specific genomic loci [PMID:25653165, PMID:32591534]. MIDEAS contacts HDAC1 through an ELM2/SANT domain interface dependent on HDAC1 residue Y48, and contains a conserved auto-inhibitory loop that restrains HDAC catalytic activity; a de novo gain-of-function missense variant (p.Tyr654Ser) in this loop causes a human neurodevelopmental syndrome by displacing auto-inhibition and hyperactivating deacetylase activity [PMID:41290615, PMID:40966515]. Beyond chromatin regulation, MIDEAS directly inhibits the nuclear pyruvate dehydrogenase complex to limit nuclear acetyl-CoA availability, linking metabolic control to histone acetylation [PMID:40505660]. MIDEAS is essential for embryonic development—knockout mice die with heart and hematopoietic defects—and is specifically required for cardiomyocyte maturation, mitotic chromosome alignment, and repression of MYC at its regulatory elements via H3K27 deacetylation [PMID:32591534, PMID:38904247, PMID:40768599].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The discovery that DNTTIP1 dimerizes and bridges HDAC1 and MIDEAS into a ternary complex, with its SKI/SNO/DAC domain binding nucleosomes, established the architectural basis for MiDAC assembly and chromatin targeting.\",\n      \"evidence\": \"Crystal structures of DNTTIP1 domains combined with biochemical and nucleosome-binding assays\",\n      \"pmids\": [\"25653165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and overall architecture of the full MiDAC complex were not resolved\",\n        \"No functional consequence of complex disruption was tested in cells or organisms\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CryoEM revealed the unique tetrameric HDAC1 architecture of MiDAC with outward-facing active sites, and genetic ablation of MIDEAS demonstrated its essential role in embryogenesis (heart and blood development) and mitotic chromosome alignment, establishing MiDAC as a functionally distinct HDAC complex.\",\n      \"evidence\": \"CryoEM structure determination; MIDEAS knockout mice with lethal cardiac and hematopoietic phenotypes; siRNA knockdown in cancer cell lines with mitotic readouts\",\n      \"pmids\": [\"32591534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genomic targets of MiDAC responsible for developmental phenotypes were not identified\",\n        \"Mechanism by which MiDAC promotes chromosome alignment was not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that ELMSAN1 depletion blocks iPSC-derived cardiomyocyte differentiation, sarcomere formation, calcium handling, and electrophysiological maturation—linked to H3K27ac dysregulation—established MIDEAS as a cardiac-specific epigenetic regulator.\",\n      \"evidence\": \"ELMSAN1 knockdown/knockout in hiPSCs with cardiac differentiation assays, ChIP for H3K27ac, calcium imaging, electrophysiology\",\n      \"pmids\": [\"38904247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct genomic targets in cardiomyocytes mediating the H3K27ac changes were not comprehensively mapped\",\n        \"Whether the cardiac phenotype is MiDAC-dependent or reflects an independent MIDEAS function was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a de novo MIDEAS p.Tyr654Ser variant in the auto-inhibitory loop that covers the HDAC1 active site, combined with reciprocal transcriptomic changes in patient fibroblasts versus MiDAC-degraded cells, established that gain-of-function MiDAC hyperactivity causes a human neurodevelopmental syndrome.\",\n      \"evidence\": \"CryoEM structure of MiDAC, patient fibroblast transcriptomics, rapid MiDAC degradation comparison\",\n      \"pmids\": [\"41290615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enzymatic hyperactivity of the Y654S variant has not been directly measured in vitro\",\n        \"Neural-specific targets of hyperactive MiDAC responsible for the neurodevelopmental phenotype are unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural comparison and mutagenesis pinpointed HDAC1 Y48 as critical for the ELM2/SANT-mediated interaction with MIDEAS, and HDAC1 E63R as selectively disrupting NuRD and MiDAC but not CoREST binding, defining the molecular determinants of MiDAC-specific HDAC1 recruitment.\",\n      \"evidence\": \"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 interfaces; co-IP, mass spectrometry, HDAC1/2 double-knockout rescue\",\n      \"pmids\": [\"40966515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether these interface determinants can be exploited for complex-selective pharmacology is untested\",\n        \"Full atomic-resolution structure of the MIDEAS ELM2/SANT:HDAC1 interface is not yet available\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that MIDEAS directly binds and inhibits the nuclear pyruvate dehydrogenase complex to restrict nuclear acetyl-CoA availability revealed a non-canonical, deacetylase-independent metabolic function that cooperates with HDAC activity to control histone acetylation.\",\n      \"evidence\": \"Phenotypic chemical screen, CRISPR screen, co-IP/pulldown of ELMSAN1–nPDC, in vivo tumor models including PDX\",\n      \"pmids\": [\"40505660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The binding interface between MIDEAS and PDC subunits has not been structurally resolved\",\n        \"Whether nPDC inhibition operates in non-cancer contexts (e.g., cardiac cells) is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that MIDEAS is a direct AHR target that promotes histone deacetylation at MYC regulatory elements identified a specific transcriptional circuit through which MiDAC represses MYC in AML.\",\n      \"evidence\": \"CRISPR screen, ChIP at MYC loci, ELMSAN1 knockdown with MYC expression readout, patient-derived xenograft and murine leukemia models\",\n      \"pmids\": [\"40768599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MiDAC is recruited to MYC elements directly or via AHR-dependent chromatin targeting is not resolved\",\n        \"Genome-wide catalog of MiDAC-deacetylated loci in AML is incomplete\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cardiomyocyte-specific Elmsan1 deletion in mice recapitulated age-dependent cardiac dysfunction with suppression of TCA cycle genes, mitochondrial respiratory defects, and calcium handling impairment, extending the cardiac role from an in vitro differentiation model to an in vivo adult cardiac maintenance function.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional KO (αMHC-Cre), echocardiography, RNA-seq, electron microscopy, respiratory complex analysis\",\n      \"pmids\": [\"40588350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the mitochondrial phenotype is a direct consequence of histone deacetylation changes or secondary metabolic adaptation is unclear\",\n        \"Contribution of nPDC inhibition versus HDAC-dependent deacetylation to the cardiac phenotype has not been dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the MIDEAS–nPDC interaction, the relative contributions of HDAC-dependent versus HDAC-independent MIDEAS functions across tissues, and the neural targets responsible for the neurodevelopmental syndrome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the MIDEAS–nPDC interface exists\",\n        \"Tissue-specific partitioning of MIDEAS between HDAC-dependent and metabolic functions is uncharacterized\",\n        \"Neural cell-type-specific MiDAC targets are unmapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"MiDAC (MIDEAS-DNTTIP1-HDAC1/2)\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"DNTTIP1\",\n      \"HDAC2\",\n      \"PDHA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MIDEAS is a scaffold protein that nucleates the tetrameric MiDAC (mitotic deacetylase) complex by recruiting HDAC1/2 through its ELM2-SANT domain and partnering with the chromatin-targeting subunit DNTTIP1, thereby enabling processive histone deacetylation across nucleosomes [PMID:21258344, PMID:25653165, PMID:32591534]. MiDAC is essential for mitotic chromosome alignment, embryonic heart and haematopoietic development, and postnatal cardiomyocyte maturation; cardiomyocyte-specific loss causes progressive heart failure with mitochondrial dysfunction [PMID:32591534, PMID:38904247, PMID:40588350]. Beyond its HDAC-scaffolding role, MIDEAS constitutively inhibits the nuclear pyruvate dehydrogenase complex (nPDC), restricting nuclear acetyl-CoA supply and histone acetylation, and is transcriptionally induced by AHR signaling to repress MYC through MiDAC-mediated deacetylation at MYC regulatory elements [PMID:40505660, PMID:40768599]. A de novo heterozygous p.Tyr654Ser variant disrupts an auto-inhibitory loop that normally occludes the HDAC active site, producing gain-of-function hyperdeacetylation and a multisystem neurodevelopmental disorder [PMID:41290615].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Chemoproteomics identified a previously unknown mitotic HDAC complex (MiDAC) scaffolded by MIDEAS, establishing the first link between an ELM-SANT domain protein and a distinct class II HDAC1/2-containing assembly.\",\n      \"evidence\": \"Affinity capture with HDAC inhibitor probes and quantitative mass spectrometry in cell extracts\",\n      \"pmids\": [\"21258344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information on how MIDEAS engages HDAC1/2\",\n        \"Biological function of MiDAC unknown\",\n        \"Stoichiometry and full subunit composition unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures and binding assays revealed the molecular architecture of the MiDAC core: MIDEAS binds HDAC1 via its ELM2-SANT domain, while DNTTIP1 dimerizes and targets the complex to chromatin through its DNA/nucleosome-binding domain.\",\n      \"evidence\": \"Crystal structures of DNTTIP1 domains, co-immunoprecipitation, and nucleosome-binding assays\",\n      \"pmids\": [\"25653165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Higher-order assembly of the full MiDAC tetramer unresolved\",\n        \"No functional phenotype yet linked to MiDAC loss\",\n        \"Genomic targets of MiDAC unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CryoEM structure of the full MiDAC complex and genetic knockout models demonstrated that four HDAC1 copies face outward for processive nucleosome deacetylation, and that MIDEAS is essential for mitotic chromosome alignment, embryonic heart development, and haematopoiesis.\",\n      \"evidence\": \"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell line loss-of-function assays\",\n      \"pmids\": [\"32591534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific genomic loci regulated by MiDAC in mitosis not identified\",\n        \"Mechanism of mitotic recruitment unknown\",\n        \"Postnatal cardiac role not explored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining MIDEAS function in human cardiomyocyte differentiation showed it is required for pluripotency exit, sarcomere assembly, and calcium handling, linking MiDAC-dependent H3K27 deacetylation to cardiac gene regulation.\",\n      \"evidence\": \"ELMSAN1 knockdown/knockout in hiPSC-derived cardiomyocytes with structural, functional, and ChIP-based epigenetic assessment\",\n      \"pmids\": [\"38904247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab observation; independent replication pending\",\n        \"Direct genomic targets in cardiomyocytes not mapped genome-wide\",\n        \"Unclear whether the cardiac role is MiDAC-specific or shared with other HDAC complexes\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cardiomyocyte-specific Elmsan1 knockout in mice confirmed an essential postnatal role: loss causes progressive heart failure with suppressed TCA-cycle gene expression, mitochondrial dysfunction, and premature death, solidifying MiDAC as a cardiac maintenance factor.\",\n      \"evidence\": \"αMHC-Cre cardiomyocyte-specific knockout mice, echocardiography, RNA-seq, electron microscopy\",\n      \"pmids\": [\"40588350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether cardiac phenotype is due to HDAC-dependent deacetylation, nPDC inhibition, or both is unresolved\",\n        \"Rescue experiments with catalytically dead MiDAC not performed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that the p.Tyr654Ser variant disrupts a conserved auto-inhibitory loop covering the HDAC active site established a gain-of-function mechanism for MiDAC-associated neurodevelopmental disease, revealing an intrinsic regulatory feature of MIDEAS.\",\n      \"evidence\": \"CryoEM structure, patient fibroblast transcriptomics, reciprocal comparison with rapid MiDAC degradation\",\n      \"pmids\": [\"41290615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Only one pathogenic variant characterized; genotype–phenotype spectrum unknown\",\n        \"Whether the auto-inhibitory loop is regulated physiologically (e.g., by post-translational modification) is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of MIDEAS as a constitutive inhibitor of nuclear pyruvate dehydrogenase complex expanded its function beyond HDAC scaffolding, showing it restricts nuclear acetyl-CoA production and histone acetylation independently of MiDAC catalytic activity.\",\n      \"evidence\": \"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, co-immunoprecipitation, in vivo xenograft models\",\n      \"pmids\": [\"40505660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the MIDEAS–nPDC interaction not determined\",\n        \"Whether nPDC inhibition is relevant in non-cancer contexts unknown\",\n        \"Relative contribution of HDAC scaffolding versus nPDC inhibition to MIDEAS cellular phenotypes not dissected\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"AHR was shown to directly transactivate MIDEAS, linking environmental/metabolic signaling to MiDAC-mediated MYC repression via histone deacetylation at MYC regulatory elements, with therapeutic relevance for AML sensitization to BET inhibitors.\",\n      \"evidence\": \"CRISPR screen, ChIP, gene expression analysis, knockdown/overexpression in AML cell lines and patient-derived xenografts\",\n      \"pmids\": [\"40768599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AHR–MIDEAS–MYC axis operates in non-hematopoietic tissues unknown\",\n        \"Direct ChIP of MiDAC at MYC loci not shown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural comparison and mutagenesis of the HDAC1 surface defined Y48 as the critical contact residue for MIDEAS (and other ELM2-SANT proteins), clarifying how HDAC1 discriminates between its multiple scaffolding partners.\",\n      \"evidence\": \"Structural comparison of MTA1:HDAC1 and MIDEAS:HDAC1 complexes, HDAC1 surface mutagenesis, co-IP, HDAC1/2 double-KO rescue\",\n      \"pmids\": [\"40966515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether post-translational modifications of HDAC1-Y48 regulate complex switching in vivo is untested\",\n        \"Quantitative binding affinities of MIDEAS versus other ELM2-SANT proteins for HDAC1 not measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relative contributions of MIDEAS's HDAC-scaffolding and nPDC-inhibitory functions to its developmental, cardiac, and disease phenotypes remain to be dissected, and the physiological regulation of the auto-inhibitory loop is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants distinguishing HDAC scaffolding from nPDC inhibition\",\n        \"Whether the auto-inhibitory loop is dynamically regulated by signaling or modifications is untested\",\n        \"Genome-wide direct target maps for MiDAC across tissues are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 5, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"MiDAC\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"HDAC2\",\n      \"DNTTIP1\",\n      \"PDHA1\",\n      \"AHR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}