{"gene":"MIDEAS","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"MIDEAS forms part of a histone deacetylase complex with HDAC1/2 and DNTTIP1. The amino-terminal dimerization domain of DNTTIP1 interacts with and mediates assembly of the HDAC1:MIDEAS complex; the carboxy-terminal SKI/SNO/DAC-related domain of DNTTIP1 mediates interaction with DNA and nucleosomes, acting as a dimeric chromatin-binding module within the complex.","method":"Crystal structures of DNTTIP1 domains, co-immunoprecipitation, nucleosome-binding assays","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with binding assays and functional validation in a single rigorous study","pmids":["25653165"],"is_preprint":false},{"year":2020,"finding":"MIDEAS is an essential scaffold protein of the MiDAC histone deacetylase complex. CryoEM structure shows MiDAC assembles with a unique multivalent architecture in which four copies of HDAC1 are positioned at the periphery with outward-facing active sites, suggesting processive deacetylation of multiple nucleosomes. Loss of MIDEAS in mice causes embryonic lethality with heart malformation and haematopoietic failure identical to loss of DNTTIP1, indicating a unique, non-redundant function. MIDEAS loss also impairs chromosome alignment during mitosis in cancer cell lines.","method":"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell-line knockdown with mitotic phenotype readout","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cryoEM structure plus in vivo KO with defined phenotypes, replicated across two KO lines (MIDEAS and DNTTIP1)","pmids":["32591534"],"is_preprint":false},{"year":2025,"finding":"A de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser) causes a neurodevelopmental syndrome. CryoEM structure of MiDAC shows Tyr654 resides in a conserved auto-inhibitory loop covering the HDAC active site; the Y654S substitution is proposed to displace this loop, resulting in elevated deacetylase activity. Reciprocal gene expression changes in patient fibroblasts versus a MiDAC-degraded cell line support hyperactivation of MiDAC as the pathogenic mechanism.","method":"CryoEM structure of MiDAC with variant mapping, patient fibroblast transcriptomics, comparison with rapid-degradation cell line","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — cryoEM structural localization of variant plus functional gene-expression evidence in patient cells, single lab but multiple orthogonal methods","pmids":["41290615"],"is_preprint":false},{"year":2025,"finding":"ELMSAN1/MIDEAS directly interacts with the nuclear pyruvate dehydrogenase complex (nPDC), constitutively inhibiting its activity. Pharmacological disruption of the ELMSAN1–nPDC interaction derepresses nPDC, increasing nuclear acetyl-CoA production and reprogramming cancer cells toward a postmitotic state; this effect is synergistically enhanced by HDAC1/2 inhibition.","method":"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, and direct protein interaction studies identifying ELMSAN1–nPDC binding","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal screens (CRISPR, chemical, proteomics) converging on the same interaction, with in vivo tumor growth validation","pmids":["40505660"],"is_preprint":false},{"year":2025,"finding":"AHR directly up-regulates ELMSAN1 transcription (a non-canonical AHR target). ELMSAN1, as a MiDAC component, then promotes histone deacetylation at MYC regulatory elements, repressing MYC expression. ELMSAN1 depletion abolishes AHR-mediated BET inhibitor sensitization and MYC repression in AML models.","method":"Functional CRISPR screen, ChIP, ELMSAN1 knockdown/depletion with MYC expression and BET inhibitor sensitivity readouts, patient-derived xenografts","journal":"Science Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic CRISPR screen plus ChIP and KD rescue, single lab, in vivo validation","pmids":["40768599"],"is_preprint":false},{"year":2025,"finding":"A single surface mutation in HDAC1 (Y48E) disrupts binding to MIDEAS (and all other ELM2/SANT-domain-containing partners) but not SIN3, indicating that Tyr48 on HDAC1 is a critical contact residue for MIDEAS:HDAC1 complex assembly. Comparative structural analysis of MTA1:HDAC1 and MIDEAS:HDAC1 confirmed differential HDAC1 recruitment mechanisms.","method":"Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry, HDAC1-Y48E/E63R mutant rescue experiments in HDAC1/2 double-KO cells, comparative structural analysis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structure-guided mutagenesis, Co-IP/MS, and KO rescue experiments with gene expression/histone acetylation readouts in a single rigorous study","pmids":["40966515"],"is_preprint":false},{"year":2024,"finding":"ELMSAN1 is required for differentiation and maturation of human iPSC-derived cardiomyocytes. ELMSAN1 depletion inhibits pluripotency deactivation, reduces cardiac-specific marker expression, 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":"ELMSAN1 knockdown and CRISPR knockout in hiPSCs, cardiac differentiation assays, structural (sarcomere imaging) and functional (calcium imaging, electrophysiology) assessments, transcriptome analysis","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with multiple orthogonal functional readouts, single lab, no direct biochemical reconstitution of MIDEAS–histone axis","pmids":["38904247"],"is_preprint":false},{"year":2025,"finding":"Cardiomyocyte-specific deletion of Elmsan1 in mice causes age-dependent progressive cardiac dysfunction (reduced ejection fraction by 12 weeks in males) with cardiomyocyte hypertrophy, ventricular dilation, shortened lifespan, mitochondrial ultrastructural abnormalities, decreased mitochondrial respiratory chain complex proteins, and impaired calcium handling. RNA-seq identified suppression of TCA cycle and key cardiac genes as early molecular changes.","method":"Cardiomyocyte-specific Elmsan1 conditional KO (αMHC-Cre), echocardiography, histology, RNA-seq, electron microscopy, calcium imaging","journal":"American Journal of Physiology. Heart and Circulatory Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal phenotypic and molecular readouts, single lab","pmids":["40588350"],"is_preprint":false}],"current_model":"MIDEAS/ELMSAN1 is an essential scaffold protein of the MiDAC histone deacetylase complex that, together with DNTTIP1, mediates assembly of a distinctive multivalent complex containing four peripherally positioned HDAC1/2 molecules; an auto-inhibitory loop in MIDEAS normally restrains HDAC activity, and its disruption causes neurodevelopmental disease, while MIDEAS also directly inhibits the nuclear pyruvate dehydrogenase complex to control nuclear acetyl-CoA levels, and acts downstream of AHR to deacetylate MYC regulatory chromatin, collectively regulating gene expression programs critical for mitosis, embryogenesis, cardiac development, and cancer cell identity."},"narrative":{"mechanistic_narrative":"MIDEAS (ELMSAN1) is an essential scaffold protein of the MiDAC histone deacetylase complex that organizes chromatin-directed deacetylation programs governing mitosis, embryogenesis, cardiac development, and cancer cell identity [PMID:32591534]. Together with DNTTIP1, whose amino-terminal dimerization domain nucleates assembly and whose carboxy-terminal SKI/SNO/DAC-related domain provides dimeric DNA- and nucleosome-binding, MIDEAS builds a multivalent complex that positions four peripheral HDAC1/2 molecules with outward-facing active sites for processive deacetylation of multiple nucleosomes [PMID:25653165, PMID:32591534]. HDAC1 recruitment into the complex depends on a specific contact residue (HDAC1 Tyr48) that distinguishes MIDEAS-type ELM2/SANT recruitment from other deacetylase assemblies [PMID:40966515]. A conserved auto-inhibitory loop in MIDEAS normally covers the HDAC active site, and a de novo p.Tyr654Ser variant displacing this loop hyperactivates MiDAC to cause a neurodevelopmental syndrome [PMID:41290615]. Through this complex MIDEAS controls gene expression at the chromatin level — acting downstream of AHR to deacetylate MYC regulatory elements and repress MYC [PMID:40768599] and regulating H3K27 acetylation during cardiomyocyte differentiation and maturation [PMID:38904247]. Independently of its chromatin role, MIDEAS directly binds and constitutively inhibits the nuclear pyruvate dehydrogenase complex, restraining nuclear acetyl-CoA production; disrupting this interaction reprograms cancer cells toward a postmitotic state, synergizing with HDAC1/2 inhibition [PMID:40505660]. Loss of MIDEAS causes embryonic lethality with heart malformation and haematopoietic failure in mice and progressive cardiac dysfunction with mitochondrial and metabolic defects upon cardiomyocyte-specific deletion [PMID:32591534, PMID:40588350].","teleology":[{"year":2015,"claim":"Established that MIDEAS is a constituent of an HDAC1/2 deacetylase complex and defined how DNTTIP1 bridges MIDEAS to HDAC1 while tethering the complex to nucleosomes, answering how the complex assembles and engages chromatin.","evidence":"Crystal structures of DNTTIP1 domains with co-immunoprecipitation and nucleosome-binding assays","pmids":["25653165"],"confidence":"High","gaps":["Did not resolve the full complex architecture or HDAC stoichiometry","MIDEAS-specific structural contributions not defined","No in vivo functional consequence established"]},{"year":2020,"claim":"Resolved the unique multivalent MiDAC architecture with four peripheral HDAC1 molecules and demonstrated that MIDEAS is a non-redundant scaffold essential for embryogenesis, hematopoiesis, and mitotic chromosome alignment.","evidence":"CryoEM structure plus MIDEAS and DNTTIP1 knockout mice and cancer cell-line knockdown with mitotic readouts","pmids":["32591534"],"confidence":"High","gaps":["Mechanistic basis of mitotic chromosome alignment defect not defined","Direct nucleosome substrate specificity in vivo not mapped","Tissue-specific gene programs controlled by MiDAC not enumerated"]},{"year":2024,"claim":"Demonstrated that MIDEAS is required for cardiomyocyte differentiation and maturation and linked its function to H3K27 acetylation control, connecting the complex to a defined developmental gene program.","evidence":"ELMSAN1 knockdown and CRISPR knockout in hiPSCs with cardiac differentiation, sarcomere imaging, calcium imaging, electrophysiology, and transcriptomics","pmids":["38904247"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of the MIDEAS-histone axis","Specific H3K27ac target loci not defined","Single model system"]},{"year":2025,"claim":"Pinpointed an auto-inhibitory loop residue (Tyr654) whose mutation hyperactivates MiDAC, establishing gain of deacetylase activity as the pathogenic mechanism of a neurodevelopmental syndrome.","evidence":"CryoEM structure with variant mapping, patient fibroblast transcriptomics, and comparison to a MiDAC-degraded cell line","pmids":["41290615"],"confidence":"High","gaps":["Direct enzymatic measurement of activity gain not shown","Affected neurodevelopmental gene targets not defined","Single patient/variant"]},{"year":2025,"claim":"Identified a chromatin-independent function: MIDEAS directly binds and constitutively inhibits the nuclear pyruvate dehydrogenase complex to limit nuclear acetyl-CoA, defining a metabolic node exploitable in cancer.","evidence":"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, and direct interaction studies with in vivo tumor validation","pmids":["40505660"],"confidence":"High","gaps":["Structural basis of the ELMSAN1-nPDC interaction not resolved","How chromatin-bound versus nPDC-bound pools are partitioned unknown","Relationship between acetyl-CoA pool and MiDAC deacetylase output not directly tested"]},{"year":2025,"claim":"Placed ELMSAN1 downstream of AHR transcriptional control as an effector that deacetylates MYC regulatory chromatin, linking a signaling input to MYC repression and BET inhibitor sensitivity in AML.","evidence":"Functional CRISPR screen, ChIP, ELMSAN1 depletion with MYC and BET inhibitor readouts, and patient-derived xenografts","pmids":["40768599"],"confidence":"Medium","gaps":["Direct demonstration of MiDAC-mediated histone deacetylation at MYC loci limited","Generalizability beyond AML not established","AHR-to-ELMSAN1 promoter mechanism not fully mapped"]},{"year":2025,"claim":"Defined HDAC1 Tyr48 as the contact residue distinguishing MIDEAS-type ELM2/SANT recruitment from SIN3 and MTA1 recruitment, explaining specificity of complex assembly.","evidence":"HDAC1-Flag Co-IP/MS, HDAC1 Y48E/E63R mutant rescue in HDAC1/2 double-KO cells, and comparative structural analysis","pmids":["40966515"],"confidence":"High","gaps":["Functional consequence of selectively disrupting MIDEAS recruitment in vivo not tested","Whether other complex members compete for the same surface unresolved"]},{"year":2025,"claim":"Showed that cardiomyocyte-specific Elmsan1 loss causes progressive cardiac dysfunction with mitochondrial and TCA-cycle gene suppression, tying MIDEAS to adult cardiac metabolic homeostasis.","evidence":"Cardiomyocyte-specific conditional KO mice with echocardiography, histology, RNA-seq, electron microscopy, and calcium imaging","pmids":["40588350"],"confidence":"Medium","gaps":["Direct chromatin targets driving TCA/mitochondrial gene suppression not defined","Link to the nPDC/acetyl-CoA function not tested in heart","Single model and sex-dependent timing"]},{"year":null,"claim":"How MIDEAS partitions between its chromatin-deacetylation scaffold role and its nuclear PDC-inhibitory role, and how these jointly control nuclear acetyl-CoA and tissue-specific gene programs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking acetyl-CoA supply to MiDAC deacetylase output","Substrate/locus selectivity of MiDAC across tissues unmapped","Structural basis of the nPDC interaction unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,7]}],"complexes":["MiDAC histone deacetylase complex"],"partners":["DNTTIP1","HDAC1","HDAC2","AHR"],"other_free_text":[]}},"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 MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32591534","citation_count":62,"is_preprint":false},{"pmid":"25653165","id":"PMC_25653165","title":"Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25653165","citation_count":53,"is_preprint":false},{"pmid":"28454334","id":"PMC_28454334","title":"Taxotere-induced elevated expression of IL8 in carcinoma-associated fibroblasts of breast invasive ductal cancer.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28454334","citation_count":17,"is_preprint":false},{"pmid":"18940474","id":"PMC_18940474","title":"BCL2 and BCL3 are recurrent translocation partners of the IGH locus.","date":"2008","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/18940474","citation_count":15,"is_preprint":false},{"pmid":"37770991","id":"PMC_37770991","title":"Long non-coding RNA MIDEAS-AS1 inhibits growth and metastasis of triple-negative breast cancer via transcriptionally activating NCALD.","date":"2023","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/37770991","citation_count":6,"is_preprint":false},{"pmid":"40505660","id":"PMC_40505660","title":"Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.","date":"2025","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40505660","citation_count":6,"is_preprint":false},{"pmid":"34912035","id":"PMC_34912035","title":"RNAmetasome network for macromolecule biogenesis in human cells.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34912035","citation_count":4,"is_preprint":false},{"pmid":"40768599","id":"PMC_40768599","title":"Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40768599","citation_count":3,"is_preprint":false},{"pmid":"40966515","id":"PMC_40966515","title":"Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40966515","citation_count":3,"is_preprint":false},{"pmid":"38904247","id":"PMC_38904247","title":"ELM2-SANT Domain-Containing Scaffolding Protein 1 Regulates Differentiation and Maturation of Cardiomyocytes Derived From Human-Induced Pluripotent Stem Cells.","date":"2024","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/38904247","citation_count":3,"is_preprint":false},{"pmid":"40343304","id":"PMC_40343304","title":"DNA methylation in peripheral blood leukocytes in late onset Alzheimer's disease.","date":"2025","source":"Journal of Alzheimer's disease reports","url":"https://pubmed.ncbi.nlm.nih.gov/40343304","citation_count":3,"is_preprint":false},{"pmid":"40588350","id":"PMC_40588350","title":"Loss of Elmsan1 in cardiomyocytes leads to age-dependent cardiac dysfunction and reduced lifespan.","date":"2025","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40588350","citation_count":1,"is_preprint":false},{"pmid":"40935692","id":"PMC_40935692","title":"Target compartmentalized metabolism to regulate epigenetics.","date":"2025","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/40935692","citation_count":1,"is_preprint":false},{"pmid":"41290615","id":"PMC_41290615","title":"A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41290615","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9016,"output_tokens":2330,"usd":0.030999,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9571,"output_tokens":3562,"usd":0.068452,"stage2_stop_reason":"end_turn"},"total_usd":0.099451,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"MIDEAS forms part of a histone deacetylase complex with HDAC1/2 and DNTTIP1. The amino-terminal dimerization domain of DNTTIP1 interacts with and mediates assembly of the HDAC1:MIDEAS complex; the carboxy-terminal SKI/SNO/DAC-related domain of DNTTIP1 mediates interaction with DNA and nucleosomes, acting as a dimeric chromatin-binding module within the 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 / Strong — crystal structures combined with binding assays and functional validation in a single rigorous study\",\n      \"pmids\": [\"25653165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MIDEAS is an essential scaffold protein of the MiDAC histone deacetylase complex. CryoEM structure shows MiDAC assembles with a unique multivalent architecture in which four copies of HDAC1 are positioned at the periphery with outward-facing active sites, suggesting processive deacetylation of multiple nucleosomes. Loss of MIDEAS in mice causes embryonic lethality with heart malformation and haematopoietic failure identical to loss of DNTTIP1, indicating a unique, non-redundant function. MIDEAS loss also impairs chromosome alignment during mitosis in cancer cell lines.\",\n      \"method\": \"CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell-line knockdown with mitotic phenotype readout\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cryoEM structure plus in vivo KO with defined phenotypes, replicated across two KO lines (MIDEAS and DNTTIP1)\",\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 neurodevelopmental syndrome. CryoEM structure of MiDAC shows Tyr654 resides in a conserved auto-inhibitory loop covering the HDAC active site; the Y654S substitution is proposed to displace this loop, resulting in elevated deacetylase activity. Reciprocal gene expression changes in patient fibroblasts versus a MiDAC-degraded cell line support hyperactivation of MiDAC as the pathogenic mechanism.\",\n      \"method\": \"CryoEM structure of MiDAC with variant mapping, patient fibroblast transcriptomics, comparison with rapid-degradation cell line\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cryoEM structural localization of variant plus functional gene-expression evidence in patient cells, single lab but multiple orthogonal methods\",\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), constitutively inhibiting its activity. Pharmacological disruption of the ELMSAN1–nPDC interaction derepresses nPDC, increasing nuclear acetyl-CoA production and reprogramming cancer cells toward a postmitotic state; this effect is synergistically enhanced by HDAC1/2 inhibition.\",\n      \"method\": \"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, and direct protein interaction studies identifying ELMSAN1–nPDC binding\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal screens (CRISPR, chemical, proteomics) converging on the same interaction, with in vivo tumor growth validation\",\n      \"pmids\": [\"40505660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHR directly up-regulates ELMSAN1 transcription (a non-canonical AHR target). ELMSAN1, as a MiDAC component, then promotes histone deacetylation at MYC regulatory elements, repressing MYC expression. ELMSAN1 depletion abolishes AHR-mediated BET inhibitor sensitization and MYC repression in AML models.\",\n      \"method\": \"Functional CRISPR screen, ChIP, ELMSAN1 knockdown/depletion with MYC expression and BET inhibitor sensitivity readouts, patient-derived xenografts\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic CRISPR screen plus ChIP and KD rescue, single lab, in vivo validation\",\n      \"pmids\": [\"40768599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A single surface mutation in HDAC1 (Y48E) disrupts binding to MIDEAS (and all other ELM2/SANT-domain-containing partners) but not SIN3, indicating that Tyr48 on HDAC1 is a critical contact residue for MIDEAS:HDAC1 complex assembly. Comparative structural analysis of MTA1:HDAC1 and MIDEAS:HDAC1 confirmed differential HDAC1 recruitment mechanisms.\",\n      \"method\": \"Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry, HDAC1-Y48E/E63R mutant rescue experiments in HDAC1/2 double-KO cells, comparative structural analysis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-guided mutagenesis, Co-IP/MS, and KO rescue experiments with gene expression/histone acetylation readouts in a single rigorous study\",\n      \"pmids\": [\"40966515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELMSAN1 is required for differentiation and maturation of human iPSC-derived cardiomyocytes. ELMSAN1 depletion inhibits pluripotency deactivation, reduces cardiac-specific marker expression, 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\": \"ELMSAN1 knockdown and CRISPR knockout in hiPSCs, cardiac differentiation assays, structural (sarcomere imaging) and functional (calcium imaging, electrophysiology) assessments, transcriptome analysis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with multiple orthogonal functional readouts, single lab, no direct biochemical reconstitution of MIDEAS–histone axis\",\n      \"pmids\": [\"38904247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiomyocyte-specific deletion of Elmsan1 in mice causes age-dependent progressive cardiac dysfunction (reduced ejection fraction by 12 weeks in males) with cardiomyocyte hypertrophy, ventricular dilation, shortened lifespan, mitochondrial ultrastructural abnormalities, decreased mitochondrial respiratory chain complex proteins, and impaired calcium handling. RNA-seq identified suppression of TCA cycle and key cardiac genes as early molecular changes.\",\n      \"method\": \"Cardiomyocyte-specific Elmsan1 conditional KO (αMHC-Cre), echocardiography, histology, RNA-seq, electron microscopy, calcium imaging\",\n      \"journal\": \"American Journal of Physiology. Heart and Circulatory Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"40588350\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIDEAS/ELMSAN1 is an essential scaffold protein of the MiDAC histone deacetylase complex that, together with DNTTIP1, mediates assembly of a distinctive multivalent complex containing four peripherally positioned HDAC1/2 molecules; an auto-inhibitory loop in MIDEAS normally restrains HDAC activity, and its disruption causes neurodevelopmental disease, while MIDEAS also directly inhibits the nuclear pyruvate dehydrogenase complex to control nuclear acetyl-CoA levels, and acts downstream of AHR to deacetylate MYC regulatory chromatin, collectively regulating gene expression programs critical for mitosis, embryogenesis, cardiac development, and cancer cell identity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MIDEAS (ELMSAN1) is an essential scaffold protein of the MiDAC histone deacetylase complex that organizes chromatin-directed deacetylation programs governing mitosis, embryogenesis, cardiac development, and cancer cell identity [#1]. Together with DNTTIP1, whose amino-terminal dimerization domain nucleates assembly and whose carboxy-terminal SKI/SNO/DAC-related domain provides dimeric DNA- and nucleosome-binding, MIDEAS builds a multivalent complex that positions four peripheral HDAC1/2 molecules with outward-facing active sites for processive deacetylation of multiple nucleosomes [#0, #1]. HDAC1 recruitment into the complex depends on a specific contact residue (HDAC1 Tyr48) that distinguishes MIDEAS-type ELM2/SANT recruitment from other deacetylase assemblies [#5]. A conserved auto-inhibitory loop in MIDEAS normally covers the HDAC active site, and a de novo p.Tyr654Ser variant displacing this loop hyperactivates MiDAC to cause a neurodevelopmental syndrome [#2]. Through this complex MIDEAS controls gene expression at the chromatin level — acting downstream of AHR to deacetylate MYC regulatory elements and repress MYC [#4] and regulating H3K27 acetylation during cardiomyocyte differentiation and maturation [#6]. Independently of its chromatin role, MIDEAS directly binds and constitutively inhibits the nuclear pyruvate dehydrogenase complex, restraining nuclear acetyl-CoA production; disrupting this interaction reprograms cancer cells toward a postmitotic state, synergizing with HDAC1/2 inhibition [#3]. Loss of MIDEAS causes embryonic lethality with heart malformation and haematopoietic failure in mice and progressive cardiac dysfunction with mitochondrial and metabolic defects upon cardiomyocyte-specific deletion [#1, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that MIDEAS is a constituent of an HDAC1/2 deacetylase complex and defined how DNTTIP1 bridges MIDEAS to HDAC1 while tethering the complex to nucleosomes, answering how the complex assembles and engages chromatin.\",\n      \"evidence\": \"Crystal structures of DNTTIP1 domains with co-immunoprecipitation and nucleosome-binding assays\",\n      \"pmids\": [\"25653165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full complex architecture or HDAC stoichiometry\", \"MIDEAS-specific structural contributions not defined\", \"No in vivo functional consequence established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the unique multivalent MiDAC architecture with four peripheral HDAC1 molecules and demonstrated that MIDEAS is a non-redundant scaffold essential for embryogenesis, hematopoiesis, and mitotic chromosome alignment.\",\n      \"evidence\": \"CryoEM structure plus MIDEAS and DNTTIP1 knockout mice and cancer cell-line knockdown with mitotic readouts\",\n      \"pmids\": [\"32591534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of mitotic chromosome alignment defect not defined\", \"Direct nucleosome substrate specificity in vivo not mapped\", \"Tissue-specific gene programs controlled by MiDAC not enumerated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that MIDEAS is required for cardiomyocyte differentiation and maturation and linked its function to H3K27 acetylation control, connecting the complex to a defined developmental gene program.\",\n      \"evidence\": \"ELMSAN1 knockdown and CRISPR knockout in hiPSCs with cardiac differentiation, sarcomere imaging, calcium imaging, electrophysiology, and transcriptomics\",\n      \"pmids\": [\"38904247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of the MIDEAS-histone axis\", \"Specific H3K27ac target loci not defined\", \"Single model system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pinpointed an auto-inhibitory loop residue (Tyr654) whose mutation hyperactivates MiDAC, establishing gain of deacetylase activity as the pathogenic mechanism of a neurodevelopmental syndrome.\",\n      \"evidence\": \"CryoEM structure with variant mapping, patient fibroblast transcriptomics, and comparison to a MiDAC-degraded cell line\",\n      \"pmids\": [\"41290615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic measurement of activity gain not shown\", \"Affected neurodevelopmental gene targets not defined\", \"Single patient/variant\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a chromatin-independent function: MIDEAS directly binds and constitutively inhibits the nuclear pyruvate dehydrogenase complex to limit nuclear acetyl-CoA, defining a metabolic node exploitable in cancer.\",\n      \"evidence\": \"Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, and direct interaction studies with in vivo tumor validation\",\n      \"pmids\": [\"40505660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ELMSAN1-nPDC interaction not resolved\", \"How chromatin-bound versus nPDC-bound pools are partitioned unknown\", \"Relationship between acetyl-CoA pool and MiDAC deacetylase output not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ELMSAN1 downstream of AHR transcriptional control as an effector that deacetylates MYC regulatory chromatin, linking a signaling input to MYC repression and BET inhibitor sensitivity in AML.\",\n      \"evidence\": \"Functional CRISPR screen, ChIP, ELMSAN1 depletion with MYC and BET inhibitor readouts, and patient-derived xenografts\",\n      \"pmids\": [\"40768599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of MiDAC-mediated histone deacetylation at MYC loci limited\", \"Generalizability beyond AML not established\", \"AHR-to-ELMSAN1 promoter mechanism not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined HDAC1 Tyr48 as the contact residue distinguishing MIDEAS-type ELM2/SANT recruitment from SIN3 and MTA1 recruitment, explaining specificity of complex assembly.\",\n      \"evidence\": \"HDAC1-Flag Co-IP/MS, HDAC1 Y48E/E63R mutant rescue in HDAC1/2 double-KO cells, and comparative structural analysis\",\n      \"pmids\": [\"40966515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of selectively disrupting MIDEAS recruitment in vivo not tested\", \"Whether other complex members compete for the same surface unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that cardiomyocyte-specific Elmsan1 loss causes progressive cardiac dysfunction with mitochondrial and TCA-cycle gene suppression, tying MIDEAS to adult cardiac metabolic homeostasis.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional KO mice with echocardiography, histology, RNA-seq, electron microscopy, and calcium imaging\",\n      \"pmids\": [\"40588350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets driving TCA/mitochondrial gene suppression not defined\", \"Link to the nPDC/acetyl-CoA function not tested in heart\", \"Single model and sex-dependent timing\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MIDEAS partitions between its chromatin-deacetylation scaffold role and its nuclear PDC-inhibitory role, and how these jointly control nuclear acetyl-CoA and tissue-specific gene programs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking acetyl-CoA supply to MiDAC deacetylase output\", \"Substrate/locus selectivity of MiDAC across tissues unmapped\", \"Structural basis of the nPDC interaction unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [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-1430728\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"MiDAC histone deacetylase complex\"],\n    \"partners\": [\"DNTTIP1\", \"HDAC1\", \"HDAC2\", \"AHR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}