{"gene":"MGA","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"MGA (Max gene associated) contains a Myc-like bHLHZip motif and requires heterodimerization with MAX for binding to the CACGTG E-box sequence (preferred Myc-Max binding site). MGA also contains a T-box/T-domain that binds the preferred Brachyury-binding sequence. As a transcription factor, MGA represses reporter genes containing Brachyury-binding sites but is converted to a transcription activator of both Myc-Max and Brachyury site-containing reporters in a MAX-dependent manner.","method":"Heterodimerization and DNA-binding assays; transcriptional reporter assays; protein domain analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA-binding assays with functional reporter validation, foundational characterization paper establishing dual-specificity mechanism","pmids":["10601024"],"is_preprint":false},{"year":2018,"finding":"MGA is required for genomic targeting of the non-canonical Polycomb repressive complex PRC1.6. CRISPR/Cas-mediated ablation of MGA in human cells causes complete loss of PRC1.6 binding genome-wide. Rescue experiments show MGA recruits PRC1.6 both through DNA binding-dependent and DNA binding-independent mechanisms. L3MBTL2 and E2F6 (but not PCGF6) mediate locus-specific PRC1.6 loading at distinct promoter sets.","method":"ChIP-seq; CRISPR/Cas9 ablation; rescue experiments; genome-wide colocalization analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with CRISPR knockout and rescue experiments using multiple orthogonal approaches across human and mouse cell lines","pmids":["29381691"],"is_preprint":false},{"year":2021,"finding":"MGA loss in mouse lung cancer models de-represses non-canonical PRC1.6 (ncPRC1.6) target genes including those involved in metastasis and meiosis. MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and MGA stabilizes ncPRC1.6 subunits. MGA loss in human lung adenocarcinoma lines augments invasive capabilities, establishing MGA as a bona fide tumor suppressor acting through widespread transcriptional attenuation of MYC and E2F target genes via the MGA-MAX/ncPRC1.6 complex.","method":"CRISPR-based Mga inactivation in mouse lung cancer models; ChIP-seq; RNA-seq; Co-IP for complex stabilization; invasion assays; human colon organoids","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR KO in vivo, ChIP-seq, Co-IP, functional assays) across two mouse models and human cell lines","pmids":["34236315"],"is_preprint":false},{"year":2019,"finding":"MGA interacts with a non-canonical PCGF6-PRC1 complex containing MAX and E2F6 (but not MYC) as determined by mass spectrometry-based affinity proteomics. MGA binds to and represses genes that are bound and activated by MYC, acting antagonistically to MYC in transcriptional regulation and cellular proliferation.","method":"Mass spectrometry-based affinity proteomics; ChIP-seq; RNA-seq; proliferation assays","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based affinity proteomics plus ChIP-seq and functional assays providing multiple orthogonal lines of evidence","pmids":["31862696"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, MGA coimmunoprecipitates with both MAX and SMAD4 in embryo extracts, and the three proteins form a complex in vitro. All three proteins bind to a DNA fragment upstream of the bmp2b transcription start site. Targeted depletion of MGA, MAX, or SMAD4 from the yolk syncytial layer (YSL) reduces BMP signaling and causes a dorsalized phenotype, demonstrating MGA-MAX-SMAD4 act together in the YSL to initiate a positive feedback loop of Bmp2b/Swirl signaling.","method":"Co-immunoprecipitation from embryo extracts; in vitro complex reconstitution; DNA binding assay; targeted depletion by morpholino injection; BMP signaling readouts","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP from embryo extracts, in vitro complex formation, DNA binding, and functional rescue in a vertebrate developmental model","pmids":["24525188"],"is_preprint":false},{"year":2015,"finding":"Mga is essential for survival of pluripotent inner cell mass (ICM) and epiblast cells in peri-implantation mouse embryos. Loss of Mga causes death of proliferating pluripotent ICM cells in vivo and of embryonic stem cells (ESCs) in vitro. Odc1 (rate-limiting enzyme in polyamine synthesis) expression is reduced in Mga mutant cells, and survival of mutant ICM cells and ESCs is rescued by addition of exogenous putrescine, indicating MGA regulates pluripotent cell survival through the polyamine biosynthesis pathway.","method":"Loss-of-function allele and RNA knockdown; in vivo embryo analysis; ESC culture; gene expression analysis; putrescine rescue experiment","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function allele combined with RNA knockdown, in vivo and in vitro phenotypic readouts, and molecular rescue by putrescine providing mechanistic pathway placement","pmids":["25516968"],"is_preprint":false},{"year":2021,"finding":"MGA deletion in mouse ESCs leads to spontaneous differentiation to primitive endoderm (PE). MGA serves as a scaffold for PRC1.6 assembly and guides this complex to specific genomic targets including genes encoding endodermal factors GATA4, GATA6, and SOX17, acting as a gatekeeper to prevent ESCs from entering the PE lineage.","method":"CRISPR-based loss-of-function screen in ESCs; ChIP-seq; RNA-seq; genetic complementation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus ChIP-seq and functional differentiation assays with multiple orthogonal methods in a single study","pmids":["33523934"],"is_preprint":false},{"year":2021,"finding":"MGA's bHLHZ and T-box DNA-binding domains each repress distinct sets of genes in mouse ESCs, with substantial overlap at meiosis-related genes. The bHLHZ domain is specifically required for repressing Meiosin, a gene essential for meiotic entry with STRA8, revealing the molecular mechanism by which MGA links PRC1.6 to negative regulation of meiotic onset.","method":"Domain-specific mutation analysis; ChIP-seq; RNA-seq in murine ESCs; gene expression analysis","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis combined with genome-wide ChIP-seq and RNA-seq in ESCs","pmids":["34224650"],"is_preprint":false},{"year":2021,"finding":"Germ cells produce a variant MGA mRNA bearing a premature termination codon (PTC) during meiosis via alternative splicing. This variant encodes an anomalous MGA protein lacking the bHLHZ domain that functions as a dominant negative regulator of PRC1.6, helping to impede PRC1.6 function as a prerequisite for meiotic progression. The variant mRNA is stably maintained in spermatocytes and spermatids due to inefficient nonsense-mediated mRNA decay.","method":"Identification of variant mRNA by sequencing; functional characterization of truncated protein as dominant negative; NMD analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — variant mRNA identification and dominant-negative characterization, but PRC1.6 disruption mechanism inferred rather than directly reconstituted","pmids":["33958653"],"is_preprint":false},{"year":2025,"finding":"MGA directly recruits the SETDB1/ATF7IP complex to meiosis-related gene loci in mouse ESCs through physical interaction with ATF7IP. This results in H3K9me3 deposition at these loci, establishing a more robustly repressed state beyond PRC1/PRC2-dependent modifications (H2AK119ub1 and H3K27me3). MGA thus plays a dual scaffolding role in PRC1.6 assembly and in recruiting SETDB1-mediated H3K9me3.","method":"Co-immunoprecipitation; ChIP-seq for H3K9me3; functional knockdown of SETDB1 and ATF7IP; analysis in Mga-null ESCs","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP combined with ChIP-seq and functional knockout experiments demonstrating mechanistic recruitment pathway","pmids":["40727931"],"is_preprint":false},{"year":2024,"finding":"MGA deletion drives Richter's transformation (CLL to aggressive lymphoma) via elevation of oxidative phosphorylation (OXPHOS). MGA directly regulates NME1 (nucleoside diphosphate kinase), and loss of MGA upregulates NME1 to drive OXPHOS. Concurrent inhibition of MYC and ETC complex II substantially prolongs survival in an RT mouse model.","method":"CRISPR-Cas9 Mga knockout in Sf3b1/Mdr CLL mouse model; RNA-seq; functional OXPHOS characterization; pharmacological inhibition experiments in vivo","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO mouse model combined with RNA-seq, functional OXPHOS assays, and in vivo pharmacological rescue","pmids":["39083585"],"is_preprint":false},{"year":2024,"finding":"Representative patient-derived MGA mutations (in RUNX1::RUNX1T1 AML) abolish protein-protein interactions and transcriptional activity. Loss of MGA upregulates MYC and E2F targets, cell cycle genes, mTOR signaling, and OXPHOS in hematopoietic cells. MGA loss induces open chromatin at promoters of proliferation genes. RUNX1::RUNX1T1 in Mga-deficient murine hematopoietic cells leads to more aggressive AML with shortened latency.","method":"Protein-protein interaction assays; transcriptional reporter assays; conditional knockout mouse; RNA-seq; ATAC-seq; mouse AML model","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (interaction assays, reporter assays, conditional KO mouse, genome-wide chromatin and expression profiling, in vivo leukemia model)","pmids":["38454121"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2 Nsp6 physically interacts with host proteins of the MGA/MAX complex (MGA, PCGF6, and TFDP1) in the Drosophila heart. This interaction blocks the antagonistic MGA/MAX complex, shifting the balance toward MYC/MAX and activating glycolysis, leading to mitochondrial dysfunction and cardiac pathology. Inhibiting glycolysis with 2-deoxy-D-glucose attenuates the Nsp6-induced cardiac phenotype.","method":"Expression of individual SARS-CoV-2 proteins in Drosophila heart; protein interaction assays; transcriptomic analysis; mouse cardiomyocyte experiments; 2-DG pharmacological intervention","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction plus functional transcriptomic analysis and pharmacological rescue in fly and mouse models, but mechanism partially inferred","pmids":["36180527"],"is_preprint":false},{"year":2010,"finding":"In zebrafish, mga depletion causes morphogenetic defects in brain, heart, and gut. The heart and gut phenotypes resemble loss-of-function of gata4. Mga loss increases gata4 transcripts in lateral mesoderm, and knockdown of gata4 rescues the early heart-looping defect (but not gut defect), placing mga upstream of gata4 in heart development. Transcript profiling shows mga influences key regulators of mesendoderm including tbx6, cas, and sox17.","method":"Morpholino knockdown; transcript profiling; genetic epistasis (double-knockdown rescue); in situ hybridization","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"High","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown combined with genetic epistasis rescue experiments and transcript profiling in zebrafish","pmids":["20044811"],"is_preprint":false},{"year":2012,"finding":"In Xenopus, maternal MGA is required for dorsal axis formation and organizer gene expression. MGA potentiates β-catenin activity in the induction of organizer-specific genes. Depletion of XTcf3 does not rescue organizer gene expression in Xmga-depleted embryos, placing Xmga downstream of XTcf3 during organizer induction. MGA is thus required for β-catenin function in the Wnt signaling pathway.","method":"Morpholino knockdown; overexpression experiments; genetic epistasis analysis","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino depletion with epistasis experiments in Xenopus, single lab","pmids":["23070227"],"is_preprint":false},{"year":2018,"finding":"In zebrafish, MGA protein localized in the cytoplasm modulates BMPR1A activity by physical association with ZMYND11/BS69. The MYND domain of BS69 binds the kinase domain of BMPR1A, interfering with its phosphorylation and activation of SMAD1/5/8. MGA antagonizes BS69 to facilitate the BMP signaling pathway by disrupting the BS69-BMPR1A association. This was established using TALEN and CRISPR/Cas9-mediated loss-of-function assays.","method":"TALEN and CRISPR/Cas9 loss-of-function; co-immunoprecipitation; protein interaction mapping; BMP signaling readouts (pSMAD1/5/8)","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP combined with CRISPR/TALEN loss-of-function in zebrafish, single lab","pmids":["30324105"],"is_preprint":false},{"year":2021,"finding":"MAX restitution in MAX-deficient small-cell lung cancer (SCLC) cells restricts global MGA occupancy when MAX is absent, selectively driving MGA recruitment toward E2F6-binding motifs. MAX restitution enhances MGA occupancy genome-wide to repress genes involved in stem cell and DNA repair/replication functions. Thus, MAX is required for full MGA genomic occupancy and ncPRC1.6-mediated gene repression.","method":"Genetically modified MAX-deficient SCLC cells; ChIP-seq; proteomics; transcriptomics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq combined with proteomics and transcriptomics in genetically defined cell lines with MAX restitution","pmids":["34493659"],"is_preprint":false},{"year":2024,"finding":"In a cardiac ischemia-reperfusion model, LTβR activation by TNFSF14 induces competitive binding of MAX to MGA rather than to c-Myc, suppressing c-Myc-mediated transcription of Cx43 (connexin 43). This mechanism underlies post-MIR reduction of Cx43 and arrhythmia. Valtrate promotes N-linked glycosylation of LTβR, reversing TNFSF14-induced MGA-MAX competitive displacement and restoring Cx43.","method":"In vitro cardiomyocyte experiments; protein interaction/competition assays; animal model with MIR; pharmacological intervention with valtrate","journal":"Journal of cardiovascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction competition assays in cardiomyocytes supported by animal model data, but mechanistic details of MGA-MAX-cMyc competition not fully reconstituted in vitro","pmids":["39028940"],"is_preprint":false},{"year":2024,"finding":"In vivo CRISPR screens identified MGA as an immune evasion gene in triple-negative breast cancer (TNBC). MGA knockout significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA-seq show MGA influences multiple immune-related pathways in the tumor microenvironment.","method":"In vivo CRISPR screens across seven syngeneic tumor models; RNA-seq; single-cell RNA-seq","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR screens with transcriptomic follow-up, but specific molecular mechanism in immune regulation not resolved","pmids":["39298484"],"is_preprint":false},{"year":2024,"finding":"Heterozygous loss-of-function variants of MGA cause premature ovarian insufficiency (POI) in humans. Mga+/- female mice are subfertile, with shorter reproductive lifespan and decreased follicle number compared to wild type, demonstrating MGA haploinsufficiency is sufficient to impair female reproductive function.","method":"Exome-wide gene-based case-control analysis; Mga+/- mouse model; follicle counting; reproductive lifespan analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic analysis replicated in multiple cohorts plus mouse haploinsufficiency model, but molecular mechanism downstream of MGA loss not resolved","pmids":["39545409"],"is_preprint":false}],"current_model":"MGA (MAX gene associated / MAD5 / MXD5) is a dual-specificity transcription factor that heterodimerizes with MAX through its bHLHZip domain to bind E-box (CACGTG) sequences and independently binds T-box sequences; it functions primarily as a transcriptional repressor by serving as a scaffolding component of the non-canonical Polycomb repressive complex PRC1.6 (containing PCGF6, L3MBTL2, E2F6, and MAX), recruits SETDB1/ATF7IP for H3K9me3 deposition at meiosis-related and MYC/E2F target genes, and antagonizes MYC-driven transcription—with MGA loss de-repressing these targets to promote cell proliferation, tumor progression, impaired female fertility, and lymphoma transformation via upregulation of the MGA-NME1-OXPHOS axis."},"narrative":{"mechanistic_narrative":"MGA is a dual-specificity transcription factor that, through a Myc-like bHLHZip motif and a separate T-box domain, binds E-box (CACGTG) sequences in a MAX-dependent manner and Brachyury T-box sites, acting predominantly as a transcriptional repressor antagonistic to MYC [PMID:10601024, PMID:31862696]. Its central role is as the obligate scaffolding subunit of the non-canonical Polycomb repressive complex PRC1.6 (with MAX, E2F6, L3MBTL2, and PCGF6): MGA ablation abolishes genome-wide PRC1.6 chromatin binding, and MGA stabilizes the complex's subunits while recruiting it via both DNA-binding-dependent and -independent mechanisms [PMID:29381691, PMID:34236315, PMID:31862696]. MGA layers an additional repressive mark onto its targets by physically recruiting the SETDB1/ATF7IP complex through ATF7IP to deposit H3K9me3 at meiosis-related loci, reinforcing PRC1/PRC2-dependent repression [PMID:40727931], and its bHLHZ and T-box domains repress distinct yet overlapping gene sets, with the bHLHZ domain specifically silencing the meiotic-entry gene Meiosin [PMID:34224650]. Through these activities MGA functions as a tumor suppressor, attenuating MYC and E2F target genes; its loss de-represses proliferation, metastasis, and OXPHOS programs—driving lung cancer invasion [PMID:34236315], Richter's transformation via the NME1-OXPHOS axis [PMID:39083585], and aggressive RUNX1::RUNX1T1 AML [PMID:38454121]. MGA also gatekeeps cell-fate decisions, sustaining pluripotent ICM/ESC survival through the polyamine pathway [PMID:25516968] and preventing primitive-endoderm differentiation by repressing GATA4/GATA6/SOX17 [PMID:33523934]. Heterozygous loss-of-function MGA variants cause premature ovarian insufficiency in humans, recapitulated by subfertility in Mga+/- mice [PMID:39545409]. Beyond its repressor role, MGA participates in vertebrate developmental signaling, cooperating with MAX-SMAD4 and modulating BMP and Wnt/β-catenin pathways in zebrafish and Xenopus embryos [PMID:24525188, PMID:20044811, PMID:23070227, PMID:30324105].","teleology":[{"year":1999,"claim":"Established MGA as a dual-specificity transcription factor, defining how a single protein engages two distinct DNA recognition systems and depends on MAX for E-box binding.","evidence":"In vitro heterodimerization and DNA-binding assays with transcriptional reporters and domain analysis","pmids":["10601024"],"confidence":"High","gaps":["Did not place MGA in a specific repressive complex","In vivo target genes not identified"]},{"year":2010,"claim":"Showed MGA acts upstream of gata4 and mesendoderm regulators in vertebrate development, positioning it within early embryonic patterning beyond transcriptional repression in cell lines.","evidence":"Morpholino knockdown, transcript profiling, and genetic epistasis rescue in zebrafish","pmids":["20044811"],"confidence":"High","gaps":["Direct vs. indirect regulation of gata4 not distinguished","Molecular complex mediating repression not defined"]},{"year":2012,"claim":"Linked MGA to Wnt/β-catenin signaling by showing it potentiates β-catenin in organizer induction downstream of XTcf3.","evidence":"Morpholino knockdown, overexpression, and epistasis in Xenopus","pmids":["23070227"],"confidence":"Medium","gaps":["Single lab, single model organism","Mechanism of β-catenin potentiation not resolved"]},{"year":2014,"claim":"Demonstrated a non-PRC1.6 developmental role: MGA forms a complex with MAX and SMAD4 to drive a BMP signaling feedback loop in zebrafish.","evidence":"Co-IP from embryo extracts, in vitro complex reconstitution, DNA binding, and morpholino depletion","pmids":["24525188"],"confidence":"High","gaps":["Relationship between this activating complex and the repressive PRC1.6 role unclear","Mammalian relevance not established"]},{"year":2015,"claim":"Identified MGA as essential for pluripotent cell survival, acting through the polyamine biosynthesis pathway via Odc1 regulation.","evidence":"Loss-of-function allele and RNAi with in vivo embryo and ESC phenotypes rescued by exogenous putrescine","pmids":["25516968"],"confidence":"High","gaps":["Whether Odc1 is a direct MGA target not shown","Connection to PRC1.6 repression not made at this stage"]},{"year":2018,"claim":"Established MGA as the essential targeting subunit of PRC1.6, answering how the non-canonical complex finds its genomic loci.","evidence":"ChIP-seq with CRISPR ablation and rescue across human and mouse cells","pmids":["29381691"],"confidence":"High","gaps":["DNA-binding-independent recruitment mechanism not molecularly defined","Repressive chromatin output downstream of binding not characterized"]},{"year":2019,"claim":"Defined the PRC1.6 composition (MAX, E2F6, PCGF6, no MYC) by affinity proteomics and showed MGA represses MYC-activated genes, formalizing MGA-MYC antagonism.","evidence":"Mass spectrometry affinity proteomics, ChIP-seq, RNA-seq, and proliferation assays","pmids":["31862696"],"confidence":"High","gaps":["Stoichiometry and structural arrangement of complex unresolved"]},{"year":2021,"claim":"Consolidated MGA's tumor-suppressor identity and dissected its targeting determinants: it stabilizes ncPRC1.6 to attenuate MYC/E2F targets, with MAX required for full genomic occupancy and the bHLHZ/T-box domains repressing distinct gene sets including meiotic genes and endoderm factors.","evidence":"CRISPR inactivation in mouse lung cancer models, ESC differentiation and screen, domain mutagenesis, MAX-restitution SCLC lines, ChIP-seq/RNA-seq and invasion assays","pmids":["34236315","31862696","33523934","34224650","34493659"],"confidence":"High","gaps":["How DNA-binding-independent recruitment is achieved still open","Precise determinants of domain-specific target selection incomplete"]},{"year":2021,"claim":"Revealed a meiosis-specific antagonistic mechanism in which germ cells produce a PTC-bearing MGA splice variant acting as a dominant-negative against PRC1.6 to permit meiotic progression.","evidence":"Variant mRNA sequencing, dominant-negative functional characterization, and NMD analysis","pmids":["33958653"],"confidence":"Medium","gaps":["PRC1.6 disruption by the variant inferred rather than reconstituted","In vivo requirement of the variant not demonstrated"]},{"year":2022,"claim":"Showed that pathogen interference with the MGA/MAX complex (by SARS-CoV-2 Nsp6) shifts balance toward MYC/MAX to drive glycolysis and cardiac dysfunction, linking MGA function to metabolic reprogramming.","evidence":"SARS-CoV-2 protein expression and interaction assays in Drosophila heart, transcriptomics, mouse cardiomyocytes, and 2-DG rescue","pmids":["36180527"],"confidence":"Medium","gaps":["Mechanism partially inferred","Direct interaction of Nsp6 with each subunit not fully mapped"]},{"year":2024,"claim":"Demonstrated MGA loss drives metabolic reprogramming toward OXPHOS in malignant transformation, identifying NME1 as a direct MGA target and an actionable MYC/ETC vulnerability.","evidence":"CRISPR Mga knockout in CLL mouse model, RNA-seq, OXPHOS assays, and in vivo pharmacological inhibition","pmids":["39083585"],"confidence":"High","gaps":["Whether NME1 regulation requires PRC1.6 not shown","Generality of OXPHOS axis beyond Richter's transformation untested"]},{"year":2024,"claim":"Validated patient-derived MGA mutations as loss-of-function in leukemia and showed MGA loss opens proliferation-gene chromatin and accelerates AML, plus a tumor-immune evasion role in TNBC.","evidence":"Interaction and reporter assays, conditional KO mouse, RNA-seq/ATAC-seq, AML model, and in vivo CRISPR immune screens","pmids":["38454121","39298484"],"confidence":"Medium","gaps":["Molecular basis of immune-evasion phenotype not resolved","Direct chromatin targets driving accessibility changes not fully enumerated"]},{"year":2024,"claim":"Established a human Mendelian phenotype: MGA haploinsufficiency causes premature ovarian insufficiency, demonstrating dosage sensitivity of MGA in reproduction.","evidence":"Exome-wide case-control analysis and Mga+/- mouse fertility and follicle phenotyping","pmids":["39545409"],"confidence":"Medium","gaps":["Downstream molecular mechanism in the ovary not resolved","Whether PRC1.6/meiotic targets mediate the phenotype not shown"]},{"year":2024,"claim":"Showed MAX-MGA competition is dynamically regulated by extracellular signaling, with LTβR activation diverting MAX from c-Myc to MGA to suppress Cx43 and promote arrhythmia.","evidence":"Cardiomyocyte interaction/competition assays, ischemia-reperfusion animal model, and valtrate pharmacological intervention","pmids":["39028940"],"confidence":"Medium","gaps":["MGA-MAX-cMyc competition not fully reconstituted in vitro","Direct vs. indirect Cx43 regulation unresolved"]},{"year":2025,"claim":"Identified a second chromatin-modifying axis: MGA directly recruits SETDB1/ATF7IP via ATF7IP to deposit H3K9me3, layering an additional repressive mark beyond PRC1/PRC2 modifications.","evidence":"Reciprocal Co-IP, H3K9me3 ChIP-seq, and SETDB1/ATF7IP knockdown in Mga-null ESCs","pmids":["40727931"],"confidence":"High","gaps":["Whether SETDB1 recruitment is coupled to or independent of PRC1.6 assembly unclear","Structural basis of MGA-ATF7IP interaction not defined"]},{"year":null,"claim":"How MGA's DNA-binding-independent recruitment of PRC1.6, its dual chromatin-modifying outputs, and its context-specific signaling roles are integrated into a unified mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of MGA within PRC1.6 or with ATF7IP","Determinants selecting between repressive and developmental-signaling roles unknown","Molecular mechanism of POI and immune-evasion phenotypes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,10,11,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,14,15]}],"complexes":["PRC1.6 (non-canonical PCGF6-PRC1)","MGA-MAX heterodimer","SETDB1/ATF7IP complex","MGA-MAX-SMAD4 complex"],"partners":["MAX","E2F6","L3MBTL2","PCGF6","ATF7IP","SETDB1","SMAD4","TFDP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWI9","full_name":"MAX gene-associated protein","aliases":["MAX dimerization protein 5"],"length_aa":3065,"mass_kda":336.2,"function":"Functions as a dual-specificity transcription factor, regulating the expression of both MAX-network and T-box family target genes. Functions as a repressor or an activator. Binds to 5'-AATTTCACACCTAGGTGTGAAATT-3' core sequence and seems to regulate MYC-MAX target genes. Suppresses transcriptional activation by MYC and inhibits MYC-dependent cell transformation. Function activated by heterodimerization with MAX. This heterodimerization serves the dual function of both generating an E-box-binding heterodimer and simultaneously blocking interaction of a corepressor (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IWI9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MGA","classification":"Not Classified","n_dependent_lines":58,"n_total_lines":1208,"dependency_fraction":0.048013245033112585},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MGA","total_profiled":1310},"omim":[{"mim_id":"621065","title":"PREMATURE OVARIAN FAILURE 26; POF26","url":"https://www.omim.org/entry/621065"},{"mim_id":"620359","title":"MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 7; MC5DN7","url":"https://www.omim.org/entry/620359"},{"mim_id":"619835","title":"3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA; 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\"mrp\" and \"emm\" genes in the mga regulon of the Streptococcus pyogenes strain ST4547.","date":"2002","source":"Journal of biochemistry, molecular biology, and biophysics : JBMBB : the official journal of the Federation of Asian and Oceanian Biochemists and Molecular Biologists (FAOBMB)","url":"https://pubmed.ncbi.nlm.nih.gov/12186779","citation_count":1,"is_preprint":false},{"pmid":"36053973","id":"PMC_36053973","title":"Alternative splicing for germ cell-specific Mga transcript can be eliminated without compromising mouse viability or fertility.","date":"2022","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36053973","citation_count":0,"is_preprint":false},{"pmid":"38750516","id":"PMC_38750516","title":"Genetic organization of an M protein trans-acting positive regulator (Mga) orthologue and its adjacent M-like protein (SCM) alleles in Streptococcus canis.","date":"2024","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/38750516","citation_count":0,"is_preprint":false},{"pmid":"39028940","id":"PMC_39028940","title":"Valtrate Suppresses TNFSF14-Mediated Arrhythmia After Myocardial Ischemia-Reperfusion by Inducing N-linked Glycosylation of LTβR to Regulate MGA/MAX/c-Myc/Cx43.","date":"2024","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39028940","citation_count":0,"is_preprint":false},{"pmid":"40547665","id":"PMC_40547665","title":"Investigation on the Substrate Specificity of Serine Protease Neuropsin by Molecular Dynamics Simulation and Marmoset Gene Atlas (MGA).","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/40547665","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.24.690200","title":"Glycerol suppresses lactose-dependent growth of  <i>Streptococcus pyogenes</i>  through a transcription-independent mechanism","date":"2025-11-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.24.690200","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39756,"output_tokens":5504,"usd":0.100914,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14100,"output_tokens":4930,"usd":0.096875,"stage2_stop_reason":"end_turn"},"total_usd":0.197789,"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\": 1999,\n      \"finding\": \"MGA (Max gene associated) contains a Myc-like bHLHZip motif and requires heterodimerization with MAX for binding to the CACGTG E-box sequence (preferred Myc-Max binding site). MGA also contains a T-box/T-domain that binds the preferred Brachyury-binding sequence. As a transcription factor, MGA represses reporter genes containing Brachyury-binding sites but is converted to a transcription activator of both Myc-Max and Brachyury site-containing reporters in a MAX-dependent manner.\",\n      \"method\": \"Heterodimerization and DNA-binding assays; transcriptional reporter assays; protein domain analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA-binding assays with functional reporter validation, foundational characterization paper establishing dual-specificity mechanism\",\n      \"pmids\": [\"10601024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MGA is required for genomic targeting of the non-canonical Polycomb repressive complex PRC1.6. CRISPR/Cas-mediated ablation of MGA in human cells causes complete loss of PRC1.6 binding genome-wide. Rescue experiments show MGA recruits PRC1.6 both through DNA binding-dependent and DNA binding-independent mechanisms. L3MBTL2 and E2F6 (but not PCGF6) mediate locus-specific PRC1.6 loading at distinct promoter sets.\",\n      \"method\": \"ChIP-seq; CRISPR/Cas9 ablation; rescue experiments; genome-wide colocalization analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with CRISPR knockout and rescue experiments using multiple orthogonal approaches across human and mouse cell lines\",\n      \"pmids\": [\"29381691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MGA loss in mouse lung cancer models de-represses non-canonical PRC1.6 (ncPRC1.6) target genes including those involved in metastasis and meiosis. MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and MGA stabilizes ncPRC1.6 subunits. MGA loss in human lung adenocarcinoma lines augments invasive capabilities, establishing MGA as a bona fide tumor suppressor acting through widespread transcriptional attenuation of MYC and E2F target genes via the MGA-MAX/ncPRC1.6 complex.\",\n      \"method\": \"CRISPR-based Mga inactivation in mouse lung cancer models; ChIP-seq; RNA-seq; Co-IP for complex stabilization; invasion assays; human colon organoids\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR KO in vivo, ChIP-seq, Co-IP, functional assays) across two mouse models and human cell lines\",\n      \"pmids\": [\"34236315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MGA interacts with a non-canonical PCGF6-PRC1 complex containing MAX and E2F6 (but not MYC) as determined by mass spectrometry-based affinity proteomics. MGA binds to and represses genes that are bound and activated by MYC, acting antagonistically to MYC in transcriptional regulation and cellular proliferation.\",\n      \"method\": \"Mass spectrometry-based affinity proteomics; ChIP-seq; RNA-seq; proliferation assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based affinity proteomics plus ChIP-seq and functional assays providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"31862696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, MGA coimmunoprecipitates with both MAX and SMAD4 in embryo extracts, and the three proteins form a complex in vitro. All three proteins bind to a DNA fragment upstream of the bmp2b transcription start site. Targeted depletion of MGA, MAX, or SMAD4 from the yolk syncytial layer (YSL) reduces BMP signaling and causes a dorsalized phenotype, demonstrating MGA-MAX-SMAD4 act together in the YSL to initiate a positive feedback loop of Bmp2b/Swirl signaling.\",\n      \"method\": \"Co-immunoprecipitation from embryo extracts; in vitro complex reconstitution; DNA binding assay; targeted depletion by morpholino injection; BMP signaling readouts\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP from embryo extracts, in vitro complex formation, DNA binding, and functional rescue in a vertebrate developmental model\",\n      \"pmids\": [\"24525188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mga is essential for survival of pluripotent inner cell mass (ICM) and epiblast cells in peri-implantation mouse embryos. Loss of Mga causes death of proliferating pluripotent ICM cells in vivo and of embryonic stem cells (ESCs) in vitro. Odc1 (rate-limiting enzyme in polyamine synthesis) expression is reduced in Mga mutant cells, and survival of mutant ICM cells and ESCs is rescued by addition of exogenous putrescine, indicating MGA regulates pluripotent cell survival through the polyamine biosynthesis pathway.\",\n      \"method\": \"Loss-of-function allele and RNA knockdown; in vivo embryo analysis; ESC culture; gene expression analysis; putrescine rescue experiment\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function allele combined with RNA knockdown, in vivo and in vitro phenotypic readouts, and molecular rescue by putrescine providing mechanistic pathway placement\",\n      \"pmids\": [\"25516968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MGA deletion in mouse ESCs leads to spontaneous differentiation to primitive endoderm (PE). MGA serves as a scaffold for PRC1.6 assembly and guides this complex to specific genomic targets including genes encoding endodermal factors GATA4, GATA6, and SOX17, acting as a gatekeeper to prevent ESCs from entering the PE lineage.\",\n      \"method\": \"CRISPR-based loss-of-function screen in ESCs; ChIP-seq; RNA-seq; genetic complementation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus ChIP-seq and functional differentiation assays with multiple orthogonal methods in a single study\",\n      \"pmids\": [\"33523934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MGA's bHLHZ and T-box DNA-binding domains each repress distinct sets of genes in mouse ESCs, with substantial overlap at meiosis-related genes. The bHLHZ domain is specifically required for repressing Meiosin, a gene essential for meiotic entry with STRA8, revealing the molecular mechanism by which MGA links PRC1.6 to negative regulation of meiotic onset.\",\n      \"method\": \"Domain-specific mutation analysis; ChIP-seq; RNA-seq in murine ESCs; gene expression analysis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis combined with genome-wide ChIP-seq and RNA-seq in ESCs\",\n      \"pmids\": [\"34224650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Germ cells produce a variant MGA mRNA bearing a premature termination codon (PTC) during meiosis via alternative splicing. This variant encodes an anomalous MGA protein lacking the bHLHZ domain that functions as a dominant negative regulator of PRC1.6, helping to impede PRC1.6 function as a prerequisite for meiotic progression. The variant mRNA is stably maintained in spermatocytes and spermatids due to inefficient nonsense-mediated mRNA decay.\",\n      \"method\": \"Identification of variant mRNA by sequencing; functional characterization of truncated protein as dominant negative; NMD analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — variant mRNA identification and dominant-negative characterization, but PRC1.6 disruption mechanism inferred rather than directly reconstituted\",\n      \"pmids\": [\"33958653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MGA directly recruits the SETDB1/ATF7IP complex to meiosis-related gene loci in mouse ESCs through physical interaction with ATF7IP. This results in H3K9me3 deposition at these loci, establishing a more robustly repressed state beyond PRC1/PRC2-dependent modifications (H2AK119ub1 and H3K27me3). MGA thus plays a dual scaffolding role in PRC1.6 assembly and in recruiting SETDB1-mediated H3K9me3.\",\n      \"method\": \"Co-immunoprecipitation; ChIP-seq for H3K9me3; functional knockdown of SETDB1 and ATF7IP; analysis in Mga-null ESCs\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP combined with ChIP-seq and functional knockout experiments demonstrating mechanistic recruitment pathway\",\n      \"pmids\": [\"40727931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MGA deletion drives Richter's transformation (CLL to aggressive lymphoma) via elevation of oxidative phosphorylation (OXPHOS). MGA directly regulates NME1 (nucleoside diphosphate kinase), and loss of MGA upregulates NME1 to drive OXPHOS. Concurrent inhibition of MYC and ETC complex II substantially prolongs survival in an RT mouse model.\",\n      \"method\": \"CRISPR-Cas9 Mga knockout in Sf3b1/Mdr CLL mouse model; RNA-seq; functional OXPHOS characterization; pharmacological inhibition experiments in vivo\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO mouse model combined with RNA-seq, functional OXPHOS assays, and in vivo pharmacological rescue\",\n      \"pmids\": [\"39083585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Representative patient-derived MGA mutations (in RUNX1::RUNX1T1 AML) abolish protein-protein interactions and transcriptional activity. Loss of MGA upregulates MYC and E2F targets, cell cycle genes, mTOR signaling, and OXPHOS in hematopoietic cells. MGA loss induces open chromatin at promoters of proliferation genes. RUNX1::RUNX1T1 in Mga-deficient murine hematopoietic cells leads to more aggressive AML with shortened latency.\",\n      \"method\": \"Protein-protein interaction assays; transcriptional reporter assays; conditional knockout mouse; RNA-seq; ATAC-seq; mouse AML model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (interaction assays, reporter assays, conditional KO mouse, genome-wide chromatin and expression profiling, in vivo leukemia model)\",\n      \"pmids\": [\"38454121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2 Nsp6 physically interacts with host proteins of the MGA/MAX complex (MGA, PCGF6, and TFDP1) in the Drosophila heart. This interaction blocks the antagonistic MGA/MAX complex, shifting the balance toward MYC/MAX and activating glycolysis, leading to mitochondrial dysfunction and cardiac pathology. Inhibiting glycolysis with 2-deoxy-D-glucose attenuates the Nsp6-induced cardiac phenotype.\",\n      \"method\": \"Expression of individual SARS-CoV-2 proteins in Drosophila heart; protein interaction assays; transcriptomic analysis; mouse cardiomyocyte experiments; 2-DG pharmacological intervention\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction plus functional transcriptomic analysis and pharmacological rescue in fly and mouse models, but mechanism partially inferred\",\n      \"pmids\": [\"36180527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In zebrafish, mga depletion causes morphogenetic defects in brain, heart, and gut. The heart and gut phenotypes resemble loss-of-function of gata4. Mga loss increases gata4 transcripts in lateral mesoderm, and knockdown of gata4 rescues the early heart-looping defect (but not gut defect), placing mga upstream of gata4 in heart development. Transcript profiling shows mga influences key regulators of mesendoderm including tbx6, cas, and sox17.\",\n      \"method\": \"Morpholino knockdown; transcript profiling; genetic epistasis (double-knockdown rescue); in situ hybridization\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown combined with genetic epistasis rescue experiments and transcript profiling in zebrafish\",\n      \"pmids\": [\"20044811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Xenopus, maternal MGA is required for dorsal axis formation and organizer gene expression. MGA potentiates β-catenin activity in the induction of organizer-specific genes. Depletion of XTcf3 does not rescue organizer gene expression in Xmga-depleted embryos, placing Xmga downstream of XTcf3 during organizer induction. MGA is thus required for β-catenin function in the Wnt signaling pathway.\",\n      \"method\": \"Morpholino knockdown; overexpression experiments; genetic epistasis analysis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino depletion with epistasis experiments in Xenopus, single lab\",\n      \"pmids\": [\"23070227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish, MGA protein localized in the cytoplasm modulates BMPR1A activity by physical association with ZMYND11/BS69. The MYND domain of BS69 binds the kinase domain of BMPR1A, interfering with its phosphorylation and activation of SMAD1/5/8. MGA antagonizes BS69 to facilitate the BMP signaling pathway by disrupting the BS69-BMPR1A association. This was established using TALEN and CRISPR/Cas9-mediated loss-of-function assays.\",\n      \"method\": \"TALEN and CRISPR/Cas9 loss-of-function; co-immunoprecipitation; protein interaction mapping; BMP signaling readouts (pSMAD1/5/8)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP combined with CRISPR/TALEN loss-of-function in zebrafish, single lab\",\n      \"pmids\": [\"30324105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAX restitution in MAX-deficient small-cell lung cancer (SCLC) cells restricts global MGA occupancy when MAX is absent, selectively driving MGA recruitment toward E2F6-binding motifs. MAX restitution enhances MGA occupancy genome-wide to repress genes involved in stem cell and DNA repair/replication functions. Thus, MAX is required for full MGA genomic occupancy and ncPRC1.6-mediated gene repression.\",\n      \"method\": \"Genetically modified MAX-deficient SCLC cells; ChIP-seq; proteomics; transcriptomics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq combined with proteomics and transcriptomics in genetically defined cell lines with MAX restitution\",\n      \"pmids\": [\"34493659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a cardiac ischemia-reperfusion model, LTβR activation by TNFSF14 induces competitive binding of MAX to MGA rather than to c-Myc, suppressing c-Myc-mediated transcription of Cx43 (connexin 43). This mechanism underlies post-MIR reduction of Cx43 and arrhythmia. Valtrate promotes N-linked glycosylation of LTβR, reversing TNFSF14-induced MGA-MAX competitive displacement and restoring Cx43.\",\n      \"method\": \"In vitro cardiomyocyte experiments; protein interaction/competition assays; animal model with MIR; pharmacological intervention with valtrate\",\n      \"journal\": \"Journal of cardiovascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction competition assays in cardiomyocytes supported by animal model data, but mechanistic details of MGA-MAX-cMyc competition not fully reconstituted in vitro\",\n      \"pmids\": [\"39028940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vivo CRISPR screens identified MGA as an immune evasion gene in triple-negative breast cancer (TNBC). MGA knockout significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA-seq show MGA influences multiple immune-related pathways in the tumor microenvironment.\",\n      \"method\": \"In vivo CRISPR screens across seven syngeneic tumor models; RNA-seq; single-cell RNA-seq\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR screens with transcriptomic follow-up, but specific molecular mechanism in immune regulation not resolved\",\n      \"pmids\": [\"39298484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Heterozygous loss-of-function variants of MGA cause premature ovarian insufficiency (POI) in humans. Mga+/- female mice are subfertile, with shorter reproductive lifespan and decreased follicle number compared to wild type, demonstrating MGA haploinsufficiency is sufficient to impair female reproductive function.\",\n      \"method\": \"Exome-wide gene-based case-control analysis; Mga+/- mouse model; follicle counting; reproductive lifespan analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic analysis replicated in multiple cohorts plus mouse haploinsufficiency model, but molecular mechanism downstream of MGA loss not resolved\",\n      \"pmids\": [\"39545409\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MGA (MAX gene associated / MAD5 / MXD5) is a dual-specificity transcription factor that heterodimerizes with MAX through its bHLHZip domain to bind E-box (CACGTG) sequences and independently binds T-box sequences; it functions primarily as a transcriptional repressor by serving as a scaffolding component of the non-canonical Polycomb repressive complex PRC1.6 (containing PCGF6, L3MBTL2, E2F6, and MAX), recruits SETDB1/ATF7IP for H3K9me3 deposition at meiosis-related and MYC/E2F target genes, and antagonizes MYC-driven transcription—with MGA loss de-repressing these targets to promote cell proliferation, tumor progression, impaired female fertility, and lymphoma transformation via upregulation of the MGA-NME1-OXPHOS axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MGA is a dual-specificity transcription factor that, through a Myc-like bHLHZip motif and a separate T-box domain, binds E-box (CACGTG) sequences in a MAX-dependent manner and Brachyury T-box sites, acting predominantly as a transcriptional repressor antagonistic to MYC [#0, #3]. Its central role is as the obligate scaffolding subunit of the non-canonical Polycomb repressive complex PRC1.6 (with MAX, E2F6, L3MBTL2, and PCGF6): MGA ablation abolishes genome-wide PRC1.6 chromatin binding, and MGA stabilizes the complex's subunits while recruiting it via both DNA-binding-dependent and -independent mechanisms [#1, #2, #3]. MGA layers an additional repressive mark onto its targets by physically recruiting the SETDB1/ATF7IP complex through ATF7IP to deposit H3K9me3 at meiosis-related loci, reinforcing PRC1/PRC2-dependent repression [#9], and its bHLHZ and T-box domains repress distinct yet overlapping gene sets, with the bHLHZ domain specifically silencing the meiotic-entry gene Meiosin [#7]. Through these activities MGA functions as a tumor suppressor, attenuating MYC and E2F target genes; its loss de-represses proliferation, metastasis, and OXPHOS programs—driving lung cancer invasion [#2], Richter's transformation via the NME1-OXPHOS axis [#10], and aggressive RUNX1::RUNX1T1 AML [#11]. MGA also gatekeeps cell-fate decisions, sustaining pluripotent ICM/ESC survival through the polyamine pathway [#5] and preventing primitive-endoderm differentiation by repressing GATA4/GATA6/SOX17 [#6]. Heterozygous loss-of-function MGA variants cause premature ovarian insufficiency in humans, recapitulated by subfertility in Mga+/- mice [#19]. Beyond its repressor role, MGA participates in vertebrate developmental signaling, cooperating with MAX-SMAD4 and modulating BMP and Wnt/\\u03b2-catenin pathways in zebrafish and Xenopus embryos [#4, #13, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established MGA as a dual-specificity transcription factor, defining how a single protein engages two distinct DNA recognition systems and depends on MAX for E-box binding.\",\n      \"evidence\": \"In vitro heterodimerization and DNA-binding assays with transcriptional reporters and domain analysis\",\n      \"pmids\": [\"10601024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place MGA in a specific repressive complex\", \"In vivo target genes not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed MGA acts upstream of gata4 and mesendoderm regulators in vertebrate development, positioning it within early embryonic patterning beyond transcriptional repression in cell lines.\",\n      \"evidence\": \"Morpholino knockdown, transcript profiling, and genetic epistasis rescue in zebrafish\",\n      \"pmids\": [\"20044811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect regulation of gata4 not distinguished\", \"Molecular complex mediating repression not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked MGA to Wnt/\\u03b2-catenin signaling by showing it potentiates \\u03b2-catenin in organizer induction downstream of XTcf3.\",\n      \"evidence\": \"Morpholino knockdown, overexpression, and epistasis in Xenopus\",\n      \"pmids\": [\"23070227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single model organism\", \"Mechanism of \\u03b2-catenin potentiation not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a non-PRC1.6 developmental role: MGA forms a complex with MAX and SMAD4 to drive a BMP signaling feedback loop in zebrafish.\",\n      \"evidence\": \"Co-IP from embryo extracts, in vitro complex reconstitution, DNA binding, and morpholino depletion\",\n      \"pmids\": [\"24525188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between this activating complex and the repressive PRC1.6 role unclear\", \"Mammalian relevance not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified MGA as essential for pluripotent cell survival, acting through the polyamine biosynthesis pathway via Odc1 regulation.\",\n      \"evidence\": \"Loss-of-function allele and RNAi with in vivo embryo and ESC phenotypes rescued by exogenous putrescine\",\n      \"pmids\": [\"25516968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Odc1 is a direct MGA target not shown\", \"Connection to PRC1.6 repression not made at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established MGA as the essential targeting subunit of PRC1.6, answering how the non-canonical complex finds its genomic loci.\",\n      \"evidence\": \"ChIP-seq with CRISPR ablation and rescue across human and mouse cells\",\n      \"pmids\": [\"29381691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding-independent recruitment mechanism not molecularly defined\", \"Repressive chromatin output downstream of binding not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the PRC1.6 composition (MAX, E2F6, PCGF6, no MYC) by affinity proteomics and showed MGA represses MYC-activated genes, formalizing MGA-MYC antagonism.\",\n      \"evidence\": \"Mass spectrometry affinity proteomics, ChIP-seq, RNA-seq, and proliferation assays\",\n      \"pmids\": [\"31862696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural arrangement of complex unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated MGA's tumor-suppressor identity and dissected its targeting determinants: it stabilizes ncPRC1.6 to attenuate MYC/E2F targets, with MAX required for full genomic occupancy and the bHLHZ/T-box domains repressing distinct gene sets including meiotic genes and endoderm factors.\",\n      \"evidence\": \"CRISPR inactivation in mouse lung cancer models, ESC differentiation and screen, domain mutagenesis, MAX-restitution SCLC lines, ChIP-seq/RNA-seq and invasion assays\",\n      \"pmids\": [\"34236315\", \"31862696\", \"33523934\", \"34224650\", \"34493659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNA-binding-independent recruitment is achieved still open\", \"Precise determinants of domain-specific target selection incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a meiosis-specific antagonistic mechanism in which germ cells produce a PTC-bearing MGA splice variant acting as a dominant-negative against PRC1.6 to permit meiotic progression.\",\n      \"evidence\": \"Variant mRNA sequencing, dominant-negative functional characterization, and NMD analysis\",\n      \"pmids\": [\"33958653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PRC1.6 disruption by the variant inferred rather than reconstituted\", \"In vivo requirement of the variant not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that pathogen interference with the MGA/MAX complex (by SARS-CoV-2 Nsp6) shifts balance toward MYC/MAX to drive glycolysis and cardiac dysfunction, linking MGA function to metabolic reprogramming.\",\n      \"evidence\": \"SARS-CoV-2 protein expression and interaction assays in Drosophila heart, transcriptomics, mouse cardiomyocytes, and 2-DG rescue\",\n      \"pmids\": [\"36180527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism partially inferred\", \"Direct interaction of Nsp6 with each subunit not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated MGA loss drives metabolic reprogramming toward OXPHOS in malignant transformation, identifying NME1 as a direct MGA target and an actionable MYC/ETC vulnerability.\",\n      \"evidence\": \"CRISPR Mga knockout in CLL mouse model, RNA-seq, OXPHOS assays, and in vivo pharmacological inhibition\",\n      \"pmids\": [\"39083585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NME1 regulation requires PRC1.6 not shown\", \"Generality of OXPHOS axis beyond Richter's transformation untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Validated patient-derived MGA mutations as loss-of-function in leukemia and showed MGA loss opens proliferation-gene chromatin and accelerates AML, plus a tumor-immune evasion role in TNBC.\",\n      \"evidence\": \"Interaction and reporter assays, conditional KO mouse, RNA-seq/ATAC-seq, AML model, and in vivo CRISPR immune screens\",\n      \"pmids\": [\"38454121\", \"39298484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of immune-evasion phenotype not resolved\", \"Direct chromatin targets driving accessibility changes not fully enumerated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a human Mendelian phenotype: MGA haploinsufficiency causes premature ovarian insufficiency, demonstrating dosage sensitivity of MGA in reproduction.\",\n      \"evidence\": \"Exome-wide case-control analysis and Mga+/- mouse fertility and follicle phenotyping\",\n      \"pmids\": [\"39545409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream molecular mechanism in the ovary not resolved\", \"Whether PRC1.6/meiotic targets mediate the phenotype not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MAX-MGA competition is dynamically regulated by extracellular signaling, with LT\\u03b2R activation diverting MAX from c-Myc to MGA to suppress Cx43 and promote arrhythmia.\",\n      \"evidence\": \"Cardiomyocyte interaction/competition assays, ischemia-reperfusion animal model, and valtrate pharmacological intervention\",\n      \"pmids\": [\"39028940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MGA-MAX-cMyc competition not fully reconstituted in vitro\", \"Direct vs. indirect Cx43 regulation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a second chromatin-modifying axis: MGA directly recruits SETDB1/ATF7IP via ATF7IP to deposit H3K9me3, layering an additional repressive mark beyond PRC1/PRC2 modifications.\",\n      \"evidence\": \"Reciprocal Co-IP, H3K9me3 ChIP-seq, and SETDB1/ATF7IP knockdown in Mga-null ESCs\",\n      \"pmids\": [\"40727931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SETDB1 recruitment is coupled to or independent of PRC1.6 assembly unclear\", \"Structural basis of MGA-ATF7IP interaction not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MGA's DNA-binding-independent recruitment of PRC1.6, its dual chromatin-modifying outputs, and its context-specific signaling roles are integrated into a unified mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of MGA within PRC1.6 or with ATF7IP\", \"Determinants selecting between repressive and developmental-signaling roles unknown\", \"Molecular mechanism of POI and immune-evasion phenotypes unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 10, 11, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 14, 15]}\n    ],\n    \"complexes\": [\"PRC1.6 (non-canonical PCGF6-PRC1)\", \"MGA-MAX heterodimer\", \"SETDB1/ATF7IP complex\", \"MGA-MAX-SMAD4 complex\"],\n    \"partners\": [\"MAX\", \"E2F6\", \"L3MBTL2\", \"PCGF6\", \"ATF7IP\", \"SETDB1\", \"SMAD4\", \"TFDP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}