{"gene":"MIER2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2017,"finding":"MIER2 localizes predominantly to the nucleus but a substantial proportion (~32%) is also found in the cytoplasm, as determined by confocal microscopy.","method":"Confocal microscopy/immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, single lab, single method","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"MIER2 recruits HDAC1 and HDAC2 in a cell-line-dependent manner (HDAC1 and HDAC2 in HEK293 cells; HDAC1 only in MCF7 and HeLa cells), demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP across multiple cell lines, single lab","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"MIER2 complexes possess histone deacetylase enzymatic activity, confirmed by in vitro HDAC assay.","method":"Histone deacetylase activity assay (in vitro)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic assay, single lab, orthogonal to Co-IP results","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"HDAC recruitment by MIER2 occurs through its ELM2 domain, established by deletion analysis.","method":"Deletion mutagenesis combined with co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mapping with functional co-IP readout, single lab","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"Tryptophan 228 (W228) in the ELM2 domain of MIER2 is a critical residue for HDAC recruitment, shown by site-directed mutagenesis.","method":"Site-directed mutagenesis combined with co-immunoprecipitation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with functional validation, single lab, two orthogonal methods (mutagenesis + Co-IP + HDAC assay)","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"MIER2 does not dimerize with MIER1 or MIER3, as shown by co-immunoprecipitation (negative result establishing specificity of interactions).","method":"Co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, single lab, replicated across multiple cell lines","pmids":["28046085"],"is_preprint":false},{"year":2017,"finding":"Addition of D-myo-inositol-1,4,5,6-tetrakisphosphate (IP4) had no effect on MIER2-associated deacetylase activity (negative result), in contrast to what is reported for some other ELM2-SANT associated HDACs.","method":"Histone deacetylase activity assay in the presence of IP4","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct enzymatic assay, single lab, single experiment","pmids":["28046085"],"is_preprint":false},{"year":2024,"finding":"MIER2 facilitates P53 deacetylation by binding to HDAC1; deacetylation of P53 reduces its DNA-binding stability and transcriptional activity, thereby suppressing transcription of PGC1A and leading to intracellular lipid accumulation in renal cell carcinoma.","method":"Chromatin immunoprecipitation (ChIP), western blot, co-immunoprecipitation, cell line and animal models","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP with functional readouts in cell and animal models, single lab","pmids":["38702028"],"is_preprint":false},{"year":2023,"finding":"MIER2 is targeted for proteasomal degradation by the Cul3-KBTBD4 E3 ligase complex in the presence of the small molecule UM171; critical recognition elements for this degradation reside within the ELM2 domain of MIER2, and conserved amino acid sites in the N-terminus of the ELM2 domain are essential for UM171-mediated degradation.","method":"Global quantitative proteomics, mutational analysis of ELM2 domain residues","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification followed by mutational validation, single lab","pmids":["36997086"],"is_preprint":false},{"year":2026,"finding":"MIER2 forms a stable complex with HDAC1 (referred to as HDAC1:MIER2:MHAP1 complex) along with the novel protein MHAP1 (C16orf87); integrative structural modeling combining crosslinking mass spectrometry data with computational tools revealed IDR-driven assembly involving the ELM2 domain of MIER2.","method":"Crosslinking mass spectrometry, integrative structural modeling (I-TASSER, HADDOCK, AlphaFold)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, integrative modeling with experimental crosslinking, single lab, limited direct biochemical validation described in abstract","pmids":["41928988"],"is_preprint":true}],"current_model":"MIER2 is a predominantly nuclear ELM2-SANT domain-containing transcriptional repressor that recruits HDAC1 (and HDAC2 in some cell lines) through a critical tryptophan residue (W228) in its ELM2 domain to form active deacetylase complexes; it promotes P53 deacetylation via HDAC1, suppressing PGC1A transcription and driving lipid metabolic reprogramming, while its ELM2 domain also serves as a degron recognized by the Cul3-KBTBD4 ubiquitin ligase for UM171-induced proteasomal degradation."},"narrative":{"mechanistic_narrative":"MIER2 is a predominantly nuclear ELM2-SANT domain transcriptional corepressor that assembles catalytically active histone deacetylase complexes [PMID:28046085]. It recruits HDAC1, and in a cell-line-dependent manner HDAC2, through its ELM2 domain, with tryptophan 228 (W228) serving as a critical residue for this interaction [PMID:28046085]; the resulting complexes possess intrinsic deacetylase activity that, unlike some other ELM2-SANT-associated HDACs, is unresponsive to IP4 [PMID:28046085]. Functionally, MIER2-bound HDAC1 deacetylates P53, reducing its DNA-binding stability and transcriptional activity, thereby suppressing PGC1A transcription and driving intracellular lipid accumulation in renal cell carcinoma [PMID:38702028]. The ELM2 domain additionally functions as a degron: conserved N-terminal residues within it are recognized by the Cul3-KBTBD4 E3 ubiquitin ligase to mediate UM171-induced proteasomal degradation of MIER2 [PMID:36997086]. MIER2 does not heterodimerize with its paralogs MIER1 or MIER3 [PMID:28046085].","teleology":[{"year":2017,"claim":"Established that MIER2 is a nuclear corepressor that nucleates an enzymatically active HDAC complex and mapped the structural determinant of recruitment, defining its core molecular function.","evidence":"Confocal microscopy, reciprocal co-immunoprecipitation across HEK293/MCF7/HeLa, in vitro HDAC activity assay, and deletion plus site-directed mutagenesis of the ELM2 domain","pmids":["28046085"],"confidence":"High","gaps":["Genomic loci and target genes bound by the MIER2-HDAC complex were not identified","Cell-line dependence of HDAC1 vs HDAC2 recruitment was not mechanistically explained","Structural basis for W228-mediated HDAC contact not resolved"]},{"year":2023,"claim":"Answered how MIER2 protein levels are controlled, showing the ELM2 domain doubles as a degron for a specific E3 ligase under small-molecule induction.","evidence":"Global quantitative proteomics and mutational analysis of ELM2 N-terminal residues identifying Cul3-KBTBD4-mediated, UM171-induced degradation","pmids":["36997086"],"confidence":"Medium","gaps":["Endogenous (UM171-independent) regulation of MIER2 stability not addressed","Direct ubiquitination sites on MIER2 not mapped","Functional consequence of MIER2 degradation on its HDAC complexes not tested"]},{"year":2024,"claim":"Connected the MIER2-HDAC1 module to a defined downstream pathway, showing it deacetylates P53 to repress PGC1A and reprogram lipid metabolism in cancer.","evidence":"ChIP, western blot, co-immunoprecipitation, and cell-line plus animal models in renal cell carcinoma","pmids":["38702028"],"confidence":"Medium","gaps":["Whether MIER2 directly binds chromatin at PGC1A or acts solely through P53 not fully resolved","Generality of the P53/PGC1A axis beyond renal cell carcinoma unknown","Single-lab functional model awaiting independent confirmation"]},{"year":2026,"claim":"Began resolving the architecture of the MIER2 corepressor complex, identifying an additional subunit and IDR-driven assembly.","evidence":"Crosslinking mass spectrometry with integrative structural modeling (I-TASSER, HADDOCK, AlphaFold) defining an HDAC1:MIER2:MHAP1 (C16orf87) complex (preprint)","pmids":["41928988"],"confidence":"Low","gaps":["Preprint with limited direct biochemical validation of the modeled complex","Functional role of MHAP1/C16orf87 within the complex not established","Stoichiometry and physiological relevance of the IDR-driven assembly untested"]},{"year":null,"claim":"The genome-wide target landscape and the physiological contexts that regulate endogenous MIER2 corepressor activity remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide chromatin occupancy map for MIER2","No structure of the W228-HDAC interface","Roles outside renal cell carcinoma and beyond the P53/PGC1A axis uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,3]}],"complexes":["HDAC1:MIER2:MHAP1 complex","Cul3-KBTBD4 E3 ligase complex"],"partners":["HDAC1","HDAC2","KBTBD4","CUL3","MHAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N344","full_name":"Mesoderm induction early response protein 2","aliases":[],"length_aa":545,"mass_kda":59.9,"function":"Transcriptional repressor","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8N344/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MIER2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MIER2","total_profiled":1310},"omim":[{"mim_id":"620100","title":"MIER FAMILY, MEMBER 3; MIER3","url":"https://www.omim.org/entry/620100"},{"mim_id":"620092","title":"MIER FAMILY, MEMBER 2; MIER2","url":"https://www.omim.org/entry/620092"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MIER2"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA1193"]},"alphafold":{"accession":"Q8N344","domains":[{"cath_id":"1.10.10.60","chopping":"305-360","consensus_level":"high","plddt":91.1045,"start":305,"end":360},{"cath_id":"1.10.8","chopping":"236-293","consensus_level":"high","plddt":77.0093,"start":236,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N344","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N344-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N344-F1-predicted_aligned_error_v6.png","plddt_mean":57.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MIER2","jax_strain_url":"https://www.jax.org/strain/search?query=MIER2"},"sequence":{"accession":"Q8N344","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N344.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N344/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N344"}},"corpus_meta":[{"pmid":"10574462","id":"PMC_10574462","title":"Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.","date":"1999","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/10574462","citation_count":111,"is_preprint":false},{"pmid":"28046085","id":"PMC_28046085","title":"Differential HDAC1 and 2 Recruitment by Members of the MIER Family.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28046085","citation_count":26,"is_preprint":false},{"pmid":"38702028","id":"PMC_38702028","title":"MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38702028","citation_count":16,"is_preprint":false},{"pmid":"36997086","id":"PMC_36997086","title":"The stem cell-supporting small molecule UM171 triggers Cul3-KBTBD4-mediated degradation of ELM2 domain-harboring proteins.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36997086","citation_count":8,"is_preprint":false},{"pmid":"39761802","id":"PMC_39761802","title":"Hsa_circ_0002005 aggravates osteosarcoma by increasing cell proliferation, migration, and invasion.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39761802","citation_count":3,"is_preprint":false},{"pmid":"41928988","id":"PMC_41928988","title":"Integrative Structural Modeling of Intrinsically Disordered Regions in a Human HDAC2 Chromatin Remodeling Complex.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41928988","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5357,"output_tokens":1967,"usd":0.022788,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8795,"output_tokens":2231,"usd":0.049875,"stage2_stop_reason":"end_turn"},"total_usd":0.072663,"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\": 2017,\n      \"finding\": \"MIER2 localizes predominantly to the nucleus but a substantial proportion (~32%) is also found in the cytoplasm, as determined by confocal microscopy.\",\n      \"method\": \"Confocal microscopy/immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, single lab, single method\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MIER2 recruits HDAC1 and HDAC2 in a cell-line-dependent manner (HDAC1 and HDAC2 in HEK293 cells; HDAC1 only in MCF7 and HeLa cells), demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP across multiple cell lines, single lab\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MIER2 complexes possess histone deacetylase enzymatic activity, confirmed by in vitro HDAC assay.\",\n      \"method\": \"Histone deacetylase activity assay (in vitro)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic assay, single lab, orthogonal to Co-IP results\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC recruitment by MIER2 occurs through its ELM2 domain, established by deletion analysis.\",\n      \"method\": \"Deletion mutagenesis combined with co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mapping with functional co-IP readout, single lab\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tryptophan 228 (W228) in the ELM2 domain of MIER2 is a critical residue for HDAC recruitment, shown by site-directed mutagenesis.\",\n      \"method\": \"Site-directed mutagenesis combined with co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with functional validation, single lab, two orthogonal methods (mutagenesis + Co-IP + HDAC assay)\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MIER2 does not dimerize with MIER1 or MIER3, as shown by co-immunoprecipitation (negative result establishing specificity of interactions).\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, single lab, replicated across multiple cell lines\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Addition of D-myo-inositol-1,4,5,6-tetrakisphosphate (IP4) had no effect on MIER2-associated deacetylase activity (negative result), in contrast to what is reported for some other ELM2-SANT associated HDACs.\",\n      \"method\": \"Histone deacetylase activity assay in the presence of IP4\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct enzymatic assay, single lab, single experiment\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MIER2 facilitates P53 deacetylation by binding to HDAC1; deacetylation of P53 reduces its DNA-binding stability and transcriptional activity, thereby suppressing transcription of PGC1A and leading to intracellular lipid accumulation in renal cell carcinoma.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), western blot, co-immunoprecipitation, cell line and animal models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP with functional readouts in cell and animal models, single lab\",\n      \"pmids\": [\"38702028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIER2 is targeted for proteasomal degradation by the Cul3-KBTBD4 E3 ligase complex in the presence of the small molecule UM171; critical recognition elements for this degradation reside within the ELM2 domain of MIER2, and conserved amino acid sites in the N-terminus of the ELM2 domain are essential for UM171-mediated degradation.\",\n      \"method\": \"Global quantitative proteomics, mutational analysis of ELM2 domain residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification followed by mutational validation, single lab\",\n      \"pmids\": [\"36997086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MIER2 forms a stable complex with HDAC1 (referred to as HDAC1:MIER2:MHAP1 complex) along with the novel protein MHAP1 (C16orf87); integrative structural modeling combining crosslinking mass spectrometry data with computational tools revealed IDR-driven assembly involving the ELM2 domain of MIER2.\",\n      \"method\": \"Crosslinking mass spectrometry, integrative structural modeling (I-TASSER, HADDOCK, AlphaFold)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, integrative modeling with experimental crosslinking, single lab, limited direct biochemical validation described in abstract\",\n      \"pmids\": [\"41928988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MIER2 is a predominantly nuclear ELM2-SANT domain-containing transcriptional repressor that recruits HDAC1 (and HDAC2 in some cell lines) through a critical tryptophan residue (W228) in its ELM2 domain to form active deacetylase complexes; it promotes P53 deacetylation via HDAC1, suppressing PGC1A transcription and driving lipid metabolic reprogramming, while its ELM2 domain also serves as a degron recognized by the Cul3-KBTBD4 ubiquitin ligase for UM171-induced proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MIER2 is a predominantly nuclear ELM2-SANT domain transcriptional corepressor that assembles catalytically active histone deacetylase complexes [#0, #2]. It recruits HDAC1, and in a cell-line-dependent manner HDAC2, through its ELM2 domain, with tryptophan 228 (W228) serving as a critical residue for this interaction [#1, #3, #4]; the resulting complexes possess intrinsic deacetylase activity that, unlike some other ELM2-SANT-associated HDACs, is unresponsive to IP4 [#2, #6]. Functionally, MIER2-bound HDAC1 deacetylates P53, reducing its DNA-binding stability and transcriptional activity, thereby suppressing PGC1A transcription and driving intracellular lipid accumulation in renal cell carcinoma [#7]. The ELM2 domain additionally functions as a degron: conserved N-terminal residues within it are recognized by the Cul3-KBTBD4 E3 ubiquitin ligase to mediate UM171-induced proteasomal degradation of MIER2 [#8]. MIER2 does not heterodimerize with its paralogs MIER1 or MIER3 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that MIER2 is a nuclear corepressor that nucleates an enzymatically active HDAC complex and mapped the structural determinant of recruitment, defining its core molecular function.\",\n      \"evidence\": \"Confocal microscopy, reciprocal co-immunoprecipitation across HEK293/MCF7/HeLa, in vitro HDAC activity assay, and deletion plus site-directed mutagenesis of the ELM2 domain\",\n      \"pmids\": [\n        \"28046085\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genomic loci and target genes bound by the MIER2-HDAC complex were not identified\",\n        \"Cell-line dependence of HDAC1 vs HDAC2 recruitment was not mechanistically explained\",\n        \"Structural basis for W228-mediated HDAC contact not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Answered how MIER2 protein levels are controlled, showing the ELM2 domain doubles as a degron for a specific E3 ligase under small-molecule induction.\",\n      \"evidence\": \"Global quantitative proteomics and mutational analysis of ELM2 N-terminal residues identifying Cul3-KBTBD4-mediated, UM171-induced degradation\",\n      \"pmids\": [\n        \"36997086\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous (UM171-independent) regulation of MIER2 stability not addressed\",\n        \"Direct ubiquitination sites on MIER2 not mapped\",\n        \"Functional consequence of MIER2 degradation on its HDAC complexes not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the MIER2-HDAC1 module to a defined downstream pathway, showing it deacetylates P53 to repress PGC1A and reprogram lipid metabolism in cancer.\",\n      \"evidence\": \"ChIP, western blot, co-immunoprecipitation, and cell-line plus animal models in renal cell carcinoma\",\n      \"pmids\": [\n        \"38702028\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MIER2 directly binds chromatin at PGC1A or acts solely through P53 not fully resolved\",\n        \"Generality of the P53/PGC1A axis beyond renal cell carcinoma unknown\",\n        \"Single-lab functional model awaiting independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Began resolving the architecture of the MIER2 corepressor complex, identifying an additional subunit and IDR-driven assembly.\",\n      \"evidence\": \"Crosslinking mass spectrometry with integrative structural modeling (I-TASSER, HADDOCK, AlphaFold) defining an HDAC1:MIER2:MHAP1 (C16orf87) complex (preprint)\",\n      \"pmids\": [\n        \"41928988\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint with limited direct biochemical validation of the modeled complex\",\n        \"Functional role of MHAP1/C16orf87 within the complex not established\",\n        \"Stoichiometry and physiological relevance of the IDR-driven assembly untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide target landscape and the physiological contexts that regulate endogenous MIER2 corepressor activity remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genome-wide chromatin occupancy map for MIER2\",\n        \"No structure of the W228-HDAC interface\",\n        \"Roles outside renal cell carcinoma and beyond the P53/PGC1A axis uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140110\",\n        \"supporting_discovery_ids\": [\n          7\n        ]\n      },\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [\n          2,\n          7\n        ]\n      },\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [\n          1,\n          3,\n          4\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-4839726\",\n        \"supporting_discovery_ids\": [\n          1,\n          2,\n          3\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"HDAC1:MIER2:MHAP1 complex\",\n      \"Cul3-KBTBD4 E3 ligase complex\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"HDAC2\",\n      \"KBTBD4\",\n      \"CUL3\",\n      \"MHAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}