{"gene":"HMG20A","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2015,"finding":"HMG20A can replace HMG20B as a mutually exclusive subunit of the LSD1-CoREST histone demethylase complex; both HMG20A and HMG20B interact with BHC80 through a coiled-coil domain. HMG20A is required for SNAI1-dependent repression of epithelial genes and TGF-β-triggered EMT; HMG20A-depleted cells show reduced LSD1 binding to epithelial gene promoters and increased H3K4 methylation. SNAI1 and SMAD4 associate with the LSD1-CoREST complex containing HMG20A.","method":"Co-immunoprecipitation, knockdown (siRNA), ChIP, transcriptomic analysis, cell migration/invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, transcriptomics, and functional assays in a single study with multiple orthogonal methods","pmids":["25639869"],"is_preprint":false},{"year":2000,"finding":"HMG20A contains an HMG box DNA-binding domain most similar to yeast NHP6A (38–42% identity within the HMG domain); outside this domain HMG20A shares no significant homology to other known proteins. HMG20A maps to chromosome 15q24 and has ubiquitous expression with several alternative transcripts.","method":"cDNA sequencing, genomic mapping, expression analysis (Northern/RT-PCR)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and genomic characterization, single lab, foundational structural description","pmids":["10773667"],"is_preprint":false},{"year":2006,"finding":"HMG20A binds to vaccinia virus host range factor CP77 (residues 1–234 of CP77 are sufficient); after viral infection HMG20A translocates from the nucleus to viral factories and binds viral genomic DNA via its HMG box domain. CP77 expression causes dissociation of HMG20A from viral DNA; loss of this dissociation (when CP77 lacks the HMG20A-binding site) blocks vaccinia virus growth in CHO-K1 cells, demonstrating that CP77–HMG20A interaction is essential for viral host range function.","method":"Yeast two-hybrid, GST pulldown, deletion mapping, fluorescence microscopy, chromatin immunoprecipitation (viral genome), vaccinia virus growth assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, pulldown, deletion mapping, imaging, ChIP, functional rescue), single lab but rigorous controls","pmids":["16840350"],"is_preprint":false},{"year":2010,"finding":"HMG20A (iBRAF) directly interacts with beta-dystrobrevin; the interaction was characterized by in vitro and in vivo association assays with high-affinity kinetics. HMG20A activates REST-responsive genes and plays a role in initiating neuronal differentiation; beta-dystrobrevin binding to HMG20A may modulate chromatin dynamics involved in this process.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, in vitro binding assays, reporter (luciferase) assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with kinetic characterization, single lab, multiple orthogonal in vitro/in vivo methods","pmids":["20530487"],"is_preprint":false},{"year":2018,"finding":"HMG20A occupies the Pax4 gene promoter (confirmed by ChIP) and its depletion in beta cells increases Pax4 and REST expression while decreasing NeuroD, MafA, glucokinase, and insulin expression, impairing glucose-stimulated insulin secretion. A T2DM-associated SNP (rs7119) in the 3′ UTR reduces HMG20A expression via luciferase reporter assay in beta cells.","method":"siRNA knockdown, ChIP, qRT-PCR, luciferase reporter assay, glucose-stimulated insulin secretion assay in primary islets and INS-1E cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter occupancy, functional secretion assay, multiple orthogonal methods, single lab","pmids":["29449530"],"is_preprint":false},{"year":2021,"finding":"HMG20A is expressed predominantly in hypothalamic astrocytes; its depletion reduces expression of inflammatory, cholesterol biogenesis, and EMT pathway genes (hallmarks of reactive astrogliosis), impairs mitochondrial bioenergetics, and increases astrocyte apoptosis. Conditioned medium from HMG20A-depleted astrocytes reduces neuron viability. The LSD1-CoREST inhibitor ORY1001 rescues reactive astrogliosis-linked gene expression in HMG20A-ablated astrocytes, placing HMG20A in the LSD1-CoREST axis in this context.","method":"siRNA knockdown, RNA-seq, immunofluorescence, Western blotting, Seahorse metabolic assay, conditioned medium neuronal viability assay, in vivo ORY1001 treatment in mice","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, metabolic assay, in vivo rescue), single lab","pmids":["34093866"],"is_preprint":false},{"year":2022,"finding":"HMG20A forms a stable complex with the histone reader PHF14 via a two-stranded alpha-helical coiled-coil interaction (confirmed by deletion analysis and structural modeling). HMG20A contains: (i) an N-terminal intrinsically disordered domain with transactivation activity; (ii) an HMG box that binds four-way-junction DNA with higher affinity than linear DNA; (iii) a long coiled-coil domain. The PHF14–HMG20A complex interacts directly with TEAD1 transcription factor to modulate the Hippo pathway; loss of either subunit increases epithelial markers (E-cadherin, TP63) and impairs TGF-β-triggered EMT.","method":"Proteomics (mass spectrometry), co-immunoprecipitation, deletion analysis, AlphaFold2 structural modeling, DNA binding assays (four-way junction vs. linear), siRNA knockdown, transcriptomics, cell migration/invasion assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural modeling validated by deletion/Co-IP, DNA binding biochemistry, proteomics, transcriptomics, and functional cell assays in one rigorous study","pmids":["36124662"],"is_preprint":false},{"year":2022,"finding":"HMG20A negatively regulates adipogenesis; gain- and loss-of-function studies show HMG20A inhibits differentiation of SVF and C3H10T1/2 cells into mature adipocytes. HMG20A binds the MEF2C promoter (confirmed by ChIP-PCR) and, together with LSD1, increases H3K4me2 at the MEF2C promoter to upregulate MEF2C expression; LSD1 alleviates the inhibitory effect of HMG20A on adipogenesis.","method":"Gain- and loss-of-function (overexpression/knockdown), RNA-seq, qRT-PCR, ChIP-PCR, adipogenic differentiation assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional differentiation assay, multiple methods, single lab","pmids":["36142473"],"is_preprint":false},{"year":2023,"finding":"HMG20A is part of several chromatin-modifying complexes including NuRD, and associates with the H2A.Z-binding protein PWWP2A. HMG20A localizes to open promoters and enhancers. Depletion of Hmg20a in Xenopus laevis causes severe head and heart defects due to neural crest cell migration and cartilage formation defects; in mESCs, Hmg20a depletion impairs differentiation into neural crest cells and cardiomyocytes, accompanied by chromatin accessibility changes and deregulation of EMT/differentiation transcription programs.","method":"Co-immunoprecipitation/proteomics, ATAC-seq, ChIP-seq, RNA-seq, Xenopus morpholino knockdown (in vivo), mESC differentiation assays, fluorescence microscopy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (proteomics, ATAC-seq, ChIP-seq, RNA-seq, in vivo morpholino, in vitro differentiation), replicated across two model systems","pmids":["36709316"],"is_preprint":false},{"year":2023,"finding":"HMG20A is a physical binding partner of the histone methyltransferase KMT2A within a PHF5A–PHF14–HMG20A–RAI1 RNA polymerase-associated subcomplex in pancreatic cancer stem cells. Targeting this complex with a KMT2A-WDR5 inhibitor attenuates self-renewal capacity, cell viability, and in vivo tumorigenicity of pancreatic cancer stem cells.","method":"Co-immunoprecipitation, proteomics, KMT2A-WDR5 inhibitor treatment, in vivo xenograft","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and proteomics to define complex, functional inhibitor assay in vivo, single lab","pmids":["37709746"],"is_preprint":false},{"year":2022,"finding":"HMG20A physically interacts with SFMBT1 (co-localization by fluorescence and confirmed by co-immunoprecipitation) in colorectal cancer cells; depletion of SFMBT1 downregulates HMG20A downstream, and the SFMBT1/HMG20A axis drives 5-FU resistance and cancer cell migration/invasion.","method":"Immunofluorescence co-localization, co-immunoprecipitation, siRNA knockdown, proliferation/migration/invasion assays, xenograft","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and co-localization, single lab, limited mechanistic depth","pmids":["35577773"],"is_preprint":false},{"year":2022,"finding":"HMG20A binds to metastasis-specific enhancers of ADRM1 and SLC12A7 (confirmed by ChIP-qPCR) in oral squamous cell carcinoma cells, thereby promoting their expression and enabling DNA damage repair; HMG20A knockdown enhances cisplatin sensitivity and inhibits DNA repair.","method":"ChIP-qPCR, siRNA knockdown, CCK-8 cell viability assay, Western blot (DNA repair proteins), Transwell invasion assay","journal":"BMC oral health","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP-qPCR confirms binding but limited mechanistic depth, single lab, single method per claim","pmids":["36335317"],"is_preprint":false},{"year":2023,"finding":"HAX1 promotes HMG20A expression; HMG20A in turn activates TGF-β1/Smads signaling in cardiac fibroblasts. Gen-miR-1 (a plant-derived miRNA) targets the 3′ UTR of HAX1, reducing HAX1 and subsequently HMG20A levels, thereby suppressing TGF-β1/Smads-driven fibrosis and inflammation. The HAX1–HMG20A interaction was confirmed by co-immunoprecipitation.","method":"Co-immunoprecipitation, luciferase reporter assay (HAX1 3′ UTR), Western blot, siRNA knockdown, in vivo myocardial infarction model","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP for HAX1–HMG20A interaction, single lab, limited mechanistic characterization of the direct HMG20A–Smads link","pmids":["37352750"],"is_preprint":false}],"current_model":"HMG20A is a chromatin-regulatory HMG-box protein that functions as a mutually exclusive, context-dependent subunit of the LSD1-CoREST histone demethylase complex (replacing HMG20B via coiled-coil interactions with BHC80), associates with additional complexes including NuRD and a PHF5A–PHF14–RAI1–KMT2A subcomplex, binds four-way-junction DNA through its HMG box, recruits LSD1 to epithelial gene promoters to demethylate H3K4 and repress epithelial genes, cooperates with SNAI1/SMAD4 to drive TGF-β-triggered epithelial-to-mesenchymal transition, regulates neural crest cell and cardiomyocyte differentiation during development, and is required for beta-cell functional maturity and reactive astrogliosis in the adult brain."},"narrative":{"mechanistic_narrative":"HMG20A is a chromatin-regulatory HMG-box protein that operates as a context-dependent subunit of histone-modifying complexes to control epithelial-to-mesenchymal transition (EMT) and lineage differentiation programs [PMID:25639869, PMID:36709316]. It functions as a mutually exclusive subunit of the LSD1-CoREST histone demethylase complex, replacing its paralog HMG20B through a coiled-coil interaction with BHC80, and is recruited with SNAI1 and SMAD4 to epithelial gene promoters where it promotes LSD1-mediated H3K4 demethylation to repress epithelial genes and drive TGF-β-triggered EMT [PMID:25639869]. Structurally, HMG20A combines an N-terminal intrinsically disordered transactivation domain, an HMG box that binds four-way-junction DNA with higher affinity than linear DNA, and a long coiled-coil domain that mediates assembly with the histone reader PHF14; the PHF14–HMG20A complex engages TEAD1 to modulate Hippo signaling and is likewise required for EMT [PMID:36124662]. Beyond LSD1-CoREST, HMG20A associates with NuRD and the H2A.Z-binding protein PWWP2A, localizes to open promoters and enhancers, and is required for neural crest and cardiomyocyte differentiation in Xenopus and mouse ESC models [PMID:36709316]. The same chromatin machinery is deployed in differentiated cells: HMG20A occupies the Pax4 promoter and is required for beta-cell functional maturity and glucose-stimulated insulin secretion [PMID:29449530], and acts through the LSD1-CoREST axis to sustain reactive astrogliosis in hypothalamic astrocytes [PMID:34093866]. HMG20A also participates in a PHF5A–PHF14–HMG20A–RAI1 RNA polymerase-associated subcomplex with KMT2A in pancreatic cancer stem cells [PMID:37709746]. Independently of its host chromatin role, HMG20A is co-opted during vaccinia virus infection, translocating to viral factories and binding viral genomic DNA via its HMG box, an interaction with the host range factor CP77 that is essential for viral replication [PMID:16840350].","teleology":[{"year":2000,"claim":"Establishing HMG20A's basic identity as an HMG-box protein defined it as a sequence-specific/structure-specific DNA-binding factor and bounded its homology to other proteins.","evidence":"cDNA sequencing, genomic mapping, and expression analysis identifying an HMG box most similar to yeast NHP6A","pmids":["10773667"],"confidence":"Medium","gaps":["No complex membership or functional pathway identified","DNA-binding specificity not biochemically characterized at this stage"]},{"year":2006,"claim":"The first direct functional engagement showed HMG20A is a DNA-binding host factor that vaccinia virus must neutralize, demonstrating its HMG box binds genomic DNA in cells.","evidence":"Yeast two-hybrid, GST pulldown, deletion mapping, imaging, viral genome ChIP, and vaccinia growth assay in CHO-K1 cells","pmids":["16840350"],"confidence":"High","gaps":["Endogenous (non-viral) chromatin targets not yet defined","Relationship to host transcriptional complexes unaddressed"]},{"year":2010,"claim":"Linking HMG20A to REST-responsive gene activation and beta-dystrobrevin binding implicated it in neuronal differentiation and chromatin dynamics.","evidence":"Yeast two-hybrid, reciprocal binding assays with kinetics, and luciferase reporter assays","pmids":["20530487"],"confidence":"Medium","gaps":["Mechanism by which beta-dystrobrevin modulates chromatin not resolved","Direct genomic targets in neurons not mapped"]},{"year":2015,"claim":"Defining HMG20A as a mutually exclusive LSD1-CoREST subunit established the central mechanistic model: it recruits LSD1 via BHC80 to demethylate H3K4 and repress epithelial genes, driving SNAI1/SMAD4-dependent EMT.","evidence":"Reciprocal Co-IP, siRNA knockdown, ChIP, transcriptomics, and migration/invasion assays","pmids":["25639869"],"confidence":"High","gaps":["Determinants selecting HMG20A versus HMG20B in a given context unknown","Direct enzymatic role of HMG20A in demethylation versus scaffolding not separated"]},{"year":2018,"claim":"Tissue-specific roles emerged: HMG20A directly occupies the Pax4 promoter and is required for beta-cell maturity and insulin secretion, linking it to T2DM risk via a 3' UTR SNP.","evidence":"siRNA knockdown, ChIP, qRT-PCR, luciferase reporter, and glucose-stimulated insulin secretion in islets and INS-1E cells","pmids":["29449530"],"confidence":"Medium","gaps":["Whether beta-cell function uses the LSD1-CoREST complex not directly tested here","Causal contribution of the rs7119 SNP in vivo not established"]},{"year":2021,"claim":"An adult-brain role was defined showing HMG20A drives reactive astrogliosis gene programs and astrocyte bioenergetics through the LSD1-CoREST axis.","evidence":"siRNA knockdown, RNA-seq, Seahorse metabolic assay, conditioned-medium neuronal viability assay, and in vivo ORY1001 (LSD1 inhibitor) rescue in mice","pmids":["34093866"],"confidence":"Medium","gaps":["Direct chromatin targets in astrocytes not mapped","Mechanism linking gene-expression changes to mitochondrial bioenergetics unresolved"]},{"year":2022,"claim":"Structural and biochemical dissection resolved HMG20A's domain architecture and a new complex: a coiled-coil-mediated PHF14–HMG20A module that binds TEAD1 to modulate Hippo signaling and is required for EMT, with the HMG box preferring four-way-junction DNA.","evidence":"Proteomics, Co-IP, deletion analysis, AlphaFold2 modeling, four-way-junction vs linear DNA binding assays, transcriptomics, and invasion assays","pmids":["36124662"],"confidence":"High","gaps":["How PHF14–HMG20A and LSD1-CoREST associations are coordinated unknown","In vivo significance of four-way-junction DNA preference not established"]},{"year":2022,"claim":"HMG20A was assigned a metabolic differentiation role, acting with LSD1 to deposit H3K4me2 at the MEF2C promoter and restrain adipogenesis.","evidence":"Gain-/loss-of-function, RNA-seq, ChIP-PCR, and adipogenic differentiation assays","pmids":["36142473"],"confidence":"Medium","gaps":["Apparent activating role at MEF2C contrasts with repressive LSD1 demethylase activity and is not mechanistically reconciled","Direct versus indirect H3K4me2 effects not separated"]},{"year":2023,"claim":"Broader complex membership and developmental requirement were established: HMG20A partners with NuRD and PWWP2A, sits at open promoters/enhancers, and is required for neural crest and cardiomyocyte differentiation.","evidence":"Proteomics, ATAC-seq, ChIP-seq, RNA-seq, Xenopus morpholino knockdown, and mESC differentiation assays across two model systems","pmids":["36709316"],"confidence":"High","gaps":["Functional contribution of NuRD versus LSD1-CoREST associations in development not dissected","Direct PWWP2A–HMG20A interaction mode unresolved"]},{"year":2023,"claim":"A KMT2A-containing subcomplex placed HMG20A in pancreatic cancer stem cell maintenance, defining a PHF5A–PHF14–HMG20A–RAI1 RNA polymerase-associated module.","evidence":"Co-IP, proteomics, KMT2A-WDR5 inhibitor treatment, and in vivo xenograft","pmids":["37709746"],"confidence":"Medium","gaps":["Direct role of HMG20A within the inhibitor's mechanism not isolated","Chromatin targets of this subcomplex not mapped"]},{"year":2023,"claim":"HMG20A was linked to cardiac fibrosis as a downstream effector of HAX1 activating TGF-β1/Smads signaling.","evidence":"Co-IP, luciferase reporter (HAX1 3' UTR), Western blot, siRNA knockdown, and in vivo myocardial infarction model","pmids":["37352750"],"confidence":"Low","gaps":["Co-IP for HAX1–HMG20A without reciprocal validation; direct HMG20A–Smads link not characterized","Whether the effect requires HMG20A's chromatin complexes untested"]},{"year":null,"claim":"What governs the choice among HMG20A's multiple complexes (LSD1-CoREST, NuRD, PHF14–TEAD1, PHF5A–PHF14–KMT2A–RAI1) and whether it acts as an activator or repressor in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling repressive (H3K4 demethylation) and activating (H3K4me2 deposition) outcomes","Cell-type-specific determinants of complex assembly unknown","No high-resolution structure of full-length HMG20A within an assembled complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6]}],"complexes":["LSD1-CoREST complex","NuRD","PHF14-HMG20A complex","PHF5A-PHF14-HMG20A-RAI1 subcomplex"],"partners":["HMG20B","BHC80","LSD1","SNAI1","SMAD4","PHF14","TEAD1","KMT2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NP66","full_name":"High mobility group protein 20A","aliases":["HMG box-containing protein 20A","HMG domain-containing protein 1","HMG domain-containing protein HMGX1"],"length_aa":347,"mass_kda":40.1,"function":"Plays a role in neuronal differentiation as chromatin-associated protein. Acts as inhibitor of HMG20B. Overcomes the repressive effects of the neuronal silencer REST and induces the activation of neuronal-specific genes. Involved in the recruitment of the histone methyltransferase KMT2A/MLL1 and consequent increased methylation of histone H3 lysine 4 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NP66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HMG20A","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM3","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HMG20A","total_profiled":1310},"omim":[{"mim_id":"605535","title":"HIGH MOBILITY GROUP PROTEIN 20B; HMG20B","url":"https://www.omim.org/entry/605535"},{"mim_id":"605534","title":"HIGH MOBILITY GROUP PROTEIN 20A; HMG20A","url":"https://www.omim.org/entry/605534"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HMG20A"},"hgnc":{"alias_symbol":["HMGX1","FLJ10739","HMGXB1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NP66","domains":[{"cath_id":"1.10.30.10","chopping":"100-199","consensus_level":"medium","plddt":87.4741,"start":100,"end":199},{"cath_id":"-","chopping":"281-345","consensus_level":"medium","plddt":88.1746,"start":281,"end":345}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP66","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP66-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP66-F1-predicted_aligned_error_v6.png","plddt_mean":74.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HMG20A","jax_strain_url":"https://www.jax.org/strain/search?query=HMG20A"},"sequence":{"accession":"Q9NP66","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NP66.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NP66/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP66"}},"corpus_meta":[{"pmid":"25639869","id":"PMC_25639869","title":"HMG20A is required for SNAI1-mediated epithelial to mesenchymal transition.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25639869","citation_count":41,"is_preprint":false},{"pmid":"29449530","id":"PMC_29449530","title":"The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29449530","citation_count":36,"is_preprint":false},{"pmid":"16840350","id":"PMC_16840350","title":"A poxvirus host range protein, CP77, binds to a cellular protein, HMG20A, and regulates its dissociation from the vaccinia virus genome in CHO-K1 cells.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16840350","citation_count":33,"is_preprint":false},{"pmid":"10773667","id":"PMC_10773667","title":"HMG20A and HMG20B map to human chromosomes 15q24 and 19p13.3 and constitute a distinct class of HMG-box genes with ubiquitous expression.","date":"2000","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10773667","citation_count":32,"is_preprint":false},{"pmid":"20530487","id":"PMC_20530487","title":"The interaction with HMG20a/b proteins suggests a potential role for beta-dystrobrevin in neuronal differentiation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20530487","citation_count":28,"is_preprint":false},{"pmid":"31889891","id":"PMC_31889891","title":"Circular RNA ABCB10 promotes hepatocellular carcinoma progression by increasing HMG20A expression by sponging miR-670-3p.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31889891","citation_count":24,"is_preprint":false},{"pmid":"34093866","id":"PMC_34093866","title":"The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34093866","citation_count":21,"is_preprint":false},{"pmid":"36709316","id":"PMC_36709316","title":"The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36709316","citation_count":16,"is_preprint":false},{"pmid":"32329795","id":"PMC_32329795","title":"Influence of IGF2BP2, HMG20A, and HNF1B genetic polymorphisms on the susceptibility to Type 2 diabetes mellitus in Chinese Han population.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32329795","citation_count":13,"is_preprint":false},{"pmid":"37709746","id":"PMC_37709746","title":"KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics.","date":"2023","source":"Nature 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phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37352750","citation_count":6,"is_preprint":false},{"pmid":"36142473","id":"PMC_36142473","title":"HMG20A Inhibit Adipogenesis by Transcriptional and Epigenetic Regulation of MEF2C Expression.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36142473","citation_count":5,"is_preprint":false},{"pmid":"35577773","id":"PMC_35577773","title":"SFMBT1 facilitates colon cancer cell metastasis and drug resistance combined with HMG20A.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35577773","citation_count":4,"is_preprint":false},{"pmid":"36335317","id":"PMC_36335317","title":"HMG20A was identified as a key enhancer driver associated with DNA damage repair in oral squamous cell carcinomas.","date":"2022","source":"BMC oral health","url":"https://pubmed.ncbi.nlm.nih.gov/36335317","citation_count":2,"is_preprint":false},{"pmid":"33041666","id":"PMC_33041666","title":"Retraction Note to: Circular RNA ABCB10 promotes hepatocellular carcinoma progression by increasing HMG20A expression by sponging miR-670-3p.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33041666","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11560,"output_tokens":3818,"usd":0.045975,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11529,"output_tokens":4280,"usd":0.082323,"stage2_stop_reason":"end_turn"},"total_usd":0.128298,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"HMG20A can replace HMG20B as a mutually exclusive subunit of the LSD1-CoREST histone demethylase complex; both HMG20A and HMG20B interact with BHC80 through a coiled-coil domain. HMG20A is required for SNAI1-dependent repression of epithelial genes and TGF-β-triggered EMT; HMG20A-depleted cells show reduced LSD1 binding to epithelial gene promoters and increased H3K4 methylation. SNAI1 and SMAD4 associate with the LSD1-CoREST complex containing HMG20A.\",\n      \"method\": \"Co-immunoprecipitation, knockdown (siRNA), ChIP, transcriptomic analysis, cell migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, transcriptomics, and functional assays in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"25639869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HMG20A contains an HMG box DNA-binding domain most similar to yeast NHP6A (38–42% identity within the HMG domain); outside this domain HMG20A shares no significant homology to other known proteins. HMG20A maps to chromosome 15q24 and has ubiquitous expression with several alternative transcripts.\",\n      \"method\": \"cDNA sequencing, genomic mapping, expression analysis (Northern/RT-PCR)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and genomic characterization, single lab, foundational structural description\",\n      \"pmids\": [\"10773667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HMG20A binds to vaccinia virus host range factor CP77 (residues 1–234 of CP77 are sufficient); after viral infection HMG20A translocates from the nucleus to viral factories and binds viral genomic DNA via its HMG box domain. CP77 expression causes dissociation of HMG20A from viral DNA; loss of this dissociation (when CP77 lacks the HMG20A-binding site) blocks vaccinia virus growth in CHO-K1 cells, demonstrating that CP77–HMG20A interaction is essential for viral host range function.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, deletion mapping, fluorescence microscopy, chromatin immunoprecipitation (viral genome), vaccinia virus growth assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, pulldown, deletion mapping, imaging, ChIP, functional rescue), single lab but rigorous controls\",\n      \"pmids\": [\"16840350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HMG20A (iBRAF) directly interacts with beta-dystrobrevin; the interaction was characterized by in vitro and in vivo association assays with high-affinity kinetics. HMG20A activates REST-responsive genes and plays a role in initiating neuronal differentiation; beta-dystrobrevin binding to HMG20A may modulate chromatin dynamics involved in this process.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, in vitro binding assays, reporter (luciferase) assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with kinetic characterization, single lab, multiple orthogonal in vitro/in vivo methods\",\n      \"pmids\": [\"20530487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HMG20A occupies the Pax4 gene promoter (confirmed by ChIP) and its depletion in beta cells increases Pax4 and REST expression while decreasing NeuroD, MafA, glucokinase, and insulin expression, impairing glucose-stimulated insulin secretion. A T2DM-associated SNP (rs7119) in the 3′ UTR reduces HMG20A expression via luciferase reporter assay in beta cells.\",\n      \"method\": \"siRNA knockdown, ChIP, qRT-PCR, luciferase reporter assay, glucose-stimulated insulin secretion assay in primary islets and INS-1E cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter occupancy, functional secretion assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29449530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMG20A is expressed predominantly in hypothalamic astrocytes; its depletion reduces expression of inflammatory, cholesterol biogenesis, and EMT pathway genes (hallmarks of reactive astrogliosis), impairs mitochondrial bioenergetics, and increases astrocyte apoptosis. Conditioned medium from HMG20A-depleted astrocytes reduces neuron viability. The LSD1-CoREST inhibitor ORY1001 rescues reactive astrogliosis-linked gene expression in HMG20A-ablated astrocytes, placing HMG20A in the LSD1-CoREST axis in this context.\",\n      \"method\": \"siRNA knockdown, RNA-seq, immunofluorescence, Western blotting, Seahorse metabolic assay, conditioned medium neuronal viability assay, in vivo ORY1001 treatment in mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, metabolic assay, in vivo rescue), single lab\",\n      \"pmids\": [\"34093866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMG20A forms a stable complex with the histone reader PHF14 via a two-stranded alpha-helical coiled-coil interaction (confirmed by deletion analysis and structural modeling). HMG20A contains: (i) an N-terminal intrinsically disordered domain with transactivation activity; (ii) an HMG box that binds four-way-junction DNA with higher affinity than linear DNA; (iii) a long coiled-coil domain. The PHF14–HMG20A complex interacts directly with TEAD1 transcription factor to modulate the Hippo pathway; loss of either subunit increases epithelial markers (E-cadherin, TP63) and impairs TGF-β-triggered EMT.\",\n      \"method\": \"Proteomics (mass spectrometry), co-immunoprecipitation, deletion analysis, AlphaFold2 structural modeling, DNA binding assays (four-way junction vs. linear), siRNA knockdown, transcriptomics, cell migration/invasion assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural modeling validated by deletion/Co-IP, DNA binding biochemistry, proteomics, transcriptomics, and functional cell assays in one rigorous study\",\n      \"pmids\": [\"36124662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMG20A negatively regulates adipogenesis; gain- and loss-of-function studies show HMG20A inhibits differentiation of SVF and C3H10T1/2 cells into mature adipocytes. HMG20A binds the MEF2C promoter (confirmed by ChIP-PCR) and, together with LSD1, increases H3K4me2 at the MEF2C promoter to upregulate MEF2C expression; LSD1 alleviates the inhibitory effect of HMG20A on adipogenesis.\",\n      \"method\": \"Gain- and loss-of-function (overexpression/knockdown), RNA-seq, qRT-PCR, ChIP-PCR, adipogenic differentiation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional differentiation assay, multiple methods, single lab\",\n      \"pmids\": [\"36142473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMG20A is part of several chromatin-modifying complexes including NuRD, and associates with the H2A.Z-binding protein PWWP2A. HMG20A localizes to open promoters and enhancers. Depletion of Hmg20a in Xenopus laevis causes severe head and heart defects due to neural crest cell migration and cartilage formation defects; in mESCs, Hmg20a depletion impairs differentiation into neural crest cells and cardiomyocytes, accompanied by chromatin accessibility changes and deregulation of EMT/differentiation transcription programs.\",\n      \"method\": \"Co-immunoprecipitation/proteomics, ATAC-seq, ChIP-seq, RNA-seq, Xenopus morpholino knockdown (in vivo), mESC differentiation assays, fluorescence microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (proteomics, ATAC-seq, ChIP-seq, RNA-seq, in vivo morpholino, in vitro differentiation), replicated across two model systems\",\n      \"pmids\": [\"36709316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMG20A is a physical binding partner of the histone methyltransferase KMT2A within a PHF5A–PHF14–HMG20A–RAI1 RNA polymerase-associated subcomplex in pancreatic cancer stem cells. Targeting this complex with a KMT2A-WDR5 inhibitor attenuates self-renewal capacity, cell viability, and in vivo tumorigenicity of pancreatic cancer stem cells.\",\n      \"method\": \"Co-immunoprecipitation, proteomics, KMT2A-WDR5 inhibitor treatment, in vivo xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and proteomics to define complex, functional inhibitor assay in vivo, single lab\",\n      \"pmids\": [\"37709746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMG20A physically interacts with SFMBT1 (co-localization by fluorescence and confirmed by co-immunoprecipitation) in colorectal cancer cells; depletion of SFMBT1 downregulates HMG20A downstream, and the SFMBT1/HMG20A axis drives 5-FU resistance and cancer cell migration/invasion.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, siRNA knockdown, proliferation/migration/invasion assays, xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and co-localization, single lab, limited mechanistic depth\",\n      \"pmids\": [\"35577773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMG20A binds to metastasis-specific enhancers of ADRM1 and SLC12A7 (confirmed by ChIP-qPCR) in oral squamous cell carcinoma cells, thereby promoting their expression and enabling DNA damage repair; HMG20A knockdown enhances cisplatin sensitivity and inhibits DNA repair.\",\n      \"method\": \"ChIP-qPCR, siRNA knockdown, CCK-8 cell viability assay, Western blot (DNA repair proteins), Transwell invasion assay\",\n      \"journal\": \"BMC oral health\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP-qPCR confirms binding but limited mechanistic depth, single lab, single method per claim\",\n      \"pmids\": [\"36335317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HAX1 promotes HMG20A expression; HMG20A in turn activates TGF-β1/Smads signaling in cardiac fibroblasts. Gen-miR-1 (a plant-derived miRNA) targets the 3′ UTR of HAX1, reducing HAX1 and subsequently HMG20A levels, thereby suppressing TGF-β1/Smads-driven fibrosis and inflammation. The HAX1–HMG20A interaction was confirmed by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay (HAX1 3′ UTR), Western blot, siRNA knockdown, in vivo myocardial infarction model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP for HAX1–HMG20A interaction, single lab, limited mechanistic characterization of the direct HMG20A–Smads link\",\n      \"pmids\": [\"37352750\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMG20A is a chromatin-regulatory HMG-box protein that functions as a mutually exclusive, context-dependent subunit of the LSD1-CoREST histone demethylase complex (replacing HMG20B via coiled-coil interactions with BHC80), associates with additional complexes including NuRD and a PHF5A–PHF14–RAI1–KMT2A subcomplex, binds four-way-junction DNA through its HMG box, recruits LSD1 to epithelial gene promoters to demethylate H3K4 and repress epithelial genes, cooperates with SNAI1/SMAD4 to drive TGF-β-triggered epithelial-to-mesenchymal transition, regulates neural crest cell and cardiomyocyte differentiation during development, and is required for beta-cell functional maturity and reactive astrogliosis in the adult brain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMG20A is a chromatin-regulatory HMG-box protein that operates as a context-dependent subunit of histone-modifying complexes to control epithelial-to-mesenchymal transition (EMT) and lineage differentiation programs [#0, #8]. It functions as a mutually exclusive subunit of the LSD1-CoREST histone demethylase complex, replacing its paralog HMG20B through a coiled-coil interaction with BHC80, and is recruited with SNAI1 and SMAD4 to epithelial gene promoters where it promotes LSD1-mediated H3K4 demethylation to repress epithelial genes and drive TGF-\\u03b2-triggered EMT [#0]. Structurally, HMG20A combines an N-terminal intrinsically disordered transactivation domain, an HMG box that binds four-way-junction DNA with higher affinity than linear DNA, and a long coiled-coil domain that mediates assembly with the histone reader PHF14; the PHF14\\u2013HMG20A complex engages TEAD1 to modulate Hippo signaling and is likewise required for EMT [#6]. Beyond LSD1-CoREST, HMG20A associates with NuRD and the H2A.Z-binding protein PWWP2A, localizes to open promoters and enhancers, and is required for neural crest and cardiomyocyte differentiation in Xenopus and mouse ESC models [#8]. The same chromatin machinery is deployed in differentiated cells: HMG20A occupies the Pax4 promoter and is required for beta-cell functional maturity and glucose-stimulated insulin secretion [#4], and acts through the LSD1-CoREST axis to sustain reactive astrogliosis in hypothalamic astrocytes [#5]. HMG20A also participates in a PHF5A\\u2013PHF14\\u2013HMG20A\\u2013RAI1 RNA polymerase-associated subcomplex with KMT2A in pancreatic cancer stem cells [#9]. Independently of its host chromatin role, HMG20A is co-opted during vaccinia virus infection, translocating to viral factories and binding viral genomic DNA via its HMG box, an interaction with the host range factor CP77 that is essential for viral replication [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing HMG20A's basic identity as an HMG-box protein defined it as a sequence-specific/structure-specific DNA-binding factor and bounded its homology to other proteins.\",\n      \"evidence\": \"cDNA sequencing, genomic mapping, and expression analysis identifying an HMG box most similar to yeast NHP6A\",\n      \"pmids\": [\"10773667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No complex membership or functional pathway identified\", \"DNA-binding specificity not biochemically characterized at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The first direct functional engagement showed HMG20A is a DNA-binding host factor that vaccinia virus must neutralize, demonstrating its HMG box binds genomic DNA in cells.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, deletion mapping, imaging, viral genome ChIP, and vaccinia growth assay in CHO-K1 cells\",\n      \"pmids\": [\"16840350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous (non-viral) chromatin targets not yet defined\", \"Relationship to host transcriptional complexes unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking HMG20A to REST-responsive gene activation and beta-dystrobrevin binding implicated it in neuronal differentiation and chromatin dynamics.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal binding assays with kinetics, and luciferase reporter assays\",\n      \"pmids\": [\"20530487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which beta-dystrobrevin modulates chromatin not resolved\", \"Direct genomic targets in neurons not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining HMG20A as a mutually exclusive LSD1-CoREST subunit established the central mechanistic model: it recruits LSD1 via BHC80 to demethylate H3K4 and repress epithelial genes, driving SNAI1/SMAD4-dependent EMT.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, ChIP, transcriptomics, and migration/invasion assays\",\n      \"pmids\": [\"25639869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting HMG20A versus HMG20B in a given context unknown\", \"Direct enzymatic role of HMG20A in demethylation versus scaffolding not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific roles emerged: HMG20A directly occupies the Pax4 promoter and is required for beta-cell maturity and insulin secretion, linking it to T2DM risk via a 3' UTR SNP.\",\n      \"evidence\": \"siRNA knockdown, ChIP, qRT-PCR, luciferase reporter, and glucose-stimulated insulin secretion in islets and INS-1E cells\",\n      \"pmids\": [\"29449530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether beta-cell function uses the LSD1-CoREST complex not directly tested here\", \"Causal contribution of the rs7119 SNP in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An adult-brain role was defined showing HMG20A drives reactive astrogliosis gene programs and astrocyte bioenergetics through the LSD1-CoREST axis.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, Seahorse metabolic assay, conditioned-medium neuronal viability assay, and in vivo ORY1001 (LSD1 inhibitor) rescue in mice\",\n      \"pmids\": [\"34093866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets in astrocytes not mapped\", \"Mechanism linking gene-expression changes to mitochondrial bioenergetics unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and biochemical dissection resolved HMG20A's domain architecture and a new complex: a coiled-coil-mediated PHF14\\u2013HMG20A module that binds TEAD1 to modulate Hippo signaling and is required for EMT, with the HMG box preferring four-way-junction DNA.\",\n      \"evidence\": \"Proteomics, Co-IP, deletion analysis, AlphaFold2 modeling, four-way-junction vs linear DNA binding assays, transcriptomics, and invasion assays\",\n      \"pmids\": [\"36124662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PHF14\\u2013HMG20A and LSD1-CoREST associations are coordinated unknown\", \"In vivo significance of four-way-junction DNA preference not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"HMG20A was assigned a metabolic differentiation role, acting with LSD1 to deposit H3K4me2 at the MEF2C promoter and restrain adipogenesis.\",\n      \"evidence\": \"Gain-/loss-of-function, RNA-seq, ChIP-PCR, and adipogenic differentiation assays\",\n      \"pmids\": [\"36142473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent activating role at MEF2C contrasts with repressive LSD1 demethylase activity and is not mechanistically reconciled\", \"Direct versus indirect H3K4me2 effects not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broader complex membership and developmental requirement were established: HMG20A partners with NuRD and PWWP2A, sits at open promoters/enhancers, and is required for neural crest and cardiomyocyte differentiation.\",\n      \"evidence\": \"Proteomics, ATAC-seq, ChIP-seq, RNA-seq, Xenopus morpholino knockdown, and mESC differentiation assays across two model systems\",\n      \"pmids\": [\"36709316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of NuRD versus LSD1-CoREST associations in development not dissected\", \"Direct PWWP2A\\u2013HMG20A interaction mode unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A KMT2A-containing subcomplex placed HMG20A in pancreatic cancer stem cell maintenance, defining a PHF5A\\u2013PHF14\\u2013HMG20A\\u2013RAI1 RNA polymerase-associated module.\",\n      \"evidence\": \"Co-IP, proteomics, KMT2A-WDR5 inhibitor treatment, and in vivo xenograft\",\n      \"pmids\": [\"37709746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of HMG20A within the inhibitor's mechanism not isolated\", \"Chromatin targets of this subcomplex not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"HMG20A was linked to cardiac fibrosis as a downstream effector of HAX1 activating TGF-\\u03b21/Smads signaling.\",\n      \"evidence\": \"Co-IP, luciferase reporter (HAX1 3' UTR), Western blot, siRNA knockdown, and in vivo myocardial infarction model\",\n      \"pmids\": [\"37352750\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-IP for HAX1\\u2013HMG20A without reciprocal validation; direct HMG20A\\u2013Smads link not characterized\", \"Whether the effect requires HMG20A's chromatin complexes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What governs the choice among HMG20A's multiple complexes (LSD1-CoREST, NuRD, PHF14\\u2013TEAD1, PHF5A\\u2013PHF14\\u2013KMT2A\\u2013RAI1) and whether it acts as an activator or repressor in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling repressive (H3K4 demethylation) and activating (H3K4me2 deposition) outcomes\", \"Cell-type-specific determinants of complex assembly unknown\", \"No high-resolution structure of full-length HMG20A within an assembled complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\n      \"LSD1-CoREST complex\",\n      \"NuRD\",\n      \"PHF14-HMG20A complex\",\n      \"PHF5A-PHF14-HMG20A-RAI1 subcomplex\"\n    ],\n    \"partners\": [\n      \"HMG20B\",\n      \"BHC80\",\n      \"LSD1\",\n      \"SNAI1\",\n      \"SMAD4\",\n      \"PHF14\",\n      \"TEAD1\",\n      \"KMT2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}