Affinage

MIDEAS

Mitotic deacetylase-associated SANT domain protein · UniProt Q6PJG2

Round 2 corrected
Length
1045 aa
Mass
115.0 kDa
Annotated
2026-04-28
44 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    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

    PMID:21258344

    Open questions at the time
    • No structural information on how MIDEAS engages HDAC1/2
    • Biological function of MiDAC unknown
    • Stoichiometry and full subunit composition unresolved
  2. 2015 High

    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

    PMID:25653165

    Open questions at the time
    • Higher-order assembly of the full MiDAC tetramer unresolved
    • No functional phenotype yet linked to MiDAC loss
    • Genomic targets of MiDAC unknown
  3. 2020 High

    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

    PMID:32591534

    Open questions at the time
    • Specific genomic loci regulated by MiDAC in mitosis not identified
    • Mechanism of mitotic recruitment unknown
    • Postnatal cardiac role not explored
  4. 2024 Medium

    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

    PMID:38904247

    Open questions at the time
    • 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
  5. 2025 High

    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

    PMID:40588350

    Open questions at the time
    • Whether cardiac phenotype is due to HDAC-dependent deacetylation, nPDC inhibition, or both is unresolved
    • Rescue experiments with catalytically dead MiDAC not performed
  6. 2025 High

    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

    PMID:41290615

    Open questions at the time
    • 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
  7. 2025 High

    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

    PMID:40505660

    Open questions at the time
    • 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
  8. 2025 High

    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

    PMID:40768599

    Open questions at the time
    • Whether AHR–MIDEAS–MYC axis operates in non-hematopoietic tissues unknown
    • Direct ChIP of MiDAC at MYC loci not shown
  9. 2025 High

    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

    PMID:40966515

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1643685 Disease 1
Partners
AHRDNTTIP1HDAC1HDAC2PDHA1
Complex memberships
MiDAC

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Affinity capture mass spectrometry with HDAC inhibitor probes Nature biotechnology High 21258344
2015 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. Crystal structures of DNTTIP1 domains, co-immunoprecipitation, nucleosome-binding assays Nucleic acids research High 25653165
2020 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. CryoEM structure determination, MIDEAS/DNTTIP1 knockout mice, cancer cell line loss-of-function assays (chromosome alignment phenotype) Nature communications High 32591534
2025 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. CryoEM structure, patient fibroblast transcriptomics, rapid MiDAC degradation cell line comparison Nature communications High 41290615
2025 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. Phenotypic chemical screen, genome-wide CRISPR screen, proteomics, co-immunoprecipitation, in vivo xenograft models Cell metabolism High 40505660
2025 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. Functional CRISPR screen, ChIP, gene expression analysis, ELMSAN1 knockdown/overexpression in AML cell lines and patient-derived xenografts Science translational medicine High 40768599
2025 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. Structural comparison (MTA1:HDAC1 and MIDEAS:HDAC1 crystal structures), co-immunoprecipitation with HDAC1 surface mutants, mass spectrometry, HDAC1/2 double-KO rescue experiments Nucleic acids research High 40966515
2024 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. hiPSC ELMSAN1 knockdown/knockout, structural and functional cardiomyocyte assessment, ChIP for H3K27ac, transcriptome analysis Journal of the American Heart Association Medium 38904247
2025 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. αMHC-Cre cardiomyocyte-specific Elmsan1 knockout mice, echocardiography, RNA-seq, mitochondrial complex protein analysis, electron microscopy American journal of physiology. Heart and circulatory physiology High 40588350

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nature biotechnology 531 21258344
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2010 A human MAP kinase interactome. Nature methods 165 20936779
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2020 Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation. Cells 146 32344865
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
2018 Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function. EMBO reports 92 29467282
2003 The DNA sequence and analysis of human chromosome 14. Nature 80 12508121
2020 The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure. Nature communications 58 32591534
2015 Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting. Nucleic acids research 53 25653165
2017 Taxotere-induced elevated expression of IL8 in carcinoma-associated fibroblasts of breast invasive ductal cancer. Oncology letters 17 28454334
2008 BCL2 and BCL3 are recurrent translocation partners of the IGH locus. Cancer genetics and cytogenetics 14 18940474
2023 Long non-coding RNA MIDEAS-AS1 inhibits growth and metastasis of triple-negative breast cancer via transcriptionally activating NCALD. Breast cancer research : BCR 6 37770991
2025 Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming. Cell metabolism 4 40505660
2021 RNAmetasome network for macromolecule biogenesis in human cells. Communications biology 4 34912035
2025 Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation. Nucleic acids research 3 40966515
2025 DNA methylation in peripheral blood leukocytes in late onset Alzheimer's disease. Journal of Alzheimer's disease reports 2 40343304
2024 ELM2-SANT Domain-Containing Scaffolding Protein 1 Regulates Differentiation and Maturation of Cardiomyocytes Derived From Human-Induced Pluripotent Stem Cells. Journal of the American Heart Association 2 38904247
2025 Loss of Elmsan1 in cardiomyocytes leads to age-dependent cardiac dysfunction and reduced lifespan. American journal of physiology. Heart and circulatory physiology 1 40588350
2025 Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models. Science translational medicine 1 40768599
2025 Target compartmentalized metabolism to regulate epigenetics. Trends in endocrinology and metabolism: TEM 0 40935692
2025 A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome. Nature communications 0 41290615