{"gene":"CBFA2T2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1998,"finding":"CBFA2T2 (MTGR1) was identified as a novel protein that specifically and strongly interacts with the AML1-MTG8 leukemic fusion protein. The NHR2-containing region (residues 488–538) of AML1-MTG8 is required for stable complex formation with MTGR1, and overexpression of MTGR1 stimulates AML1-MTG8 to induce G-CSF-dependent proliferation of myeloid progenitor cells and to interfere with AML1-dependent transcription.","method":"Molecular cloning, co-immunoprecipitation, C-terminal deletion mutants, ectopic expression in L-G murine myeloid progenitor cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, deletion mapping, and functional cellular assay (G-CSF-dependent proliferation), multiple orthogonal methods in a single rigorous study","pmids":["9447981"],"is_preprint":false},{"year":2005,"finding":"MTGR1 associates with the co-repressor complex components mSin3A, N-CoR, and histone deacetylase 3 (HDAC3), and when tethered to DNA, represses transcription. Loss of Mtgr1 in mice causes a progressive reduction in secretory epithelial cell lineage (goblet, Paneth, enteroendocrine cells) in the small intestine, without loss of progenitor cells expressing Gfi1, indicating MTGR1 acts downstream of progenitor specification to promote secretory cell maturation.","method":"Co-immunoprecipitation (association with mSin3A, N-CoR, HDAC3), DNA-tethered transcription repression assays, Mtgr1-null mouse generation and histological phenotyping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple partners, in vivo KO phenotype with defined cellular readout, multiple orthogonal methods","pmids":["16227606"],"is_preprint":false},{"year":2006,"finding":"MTGR1 is required in the colonic epithelium (not in hematopoietic cells) for survival and regeneration after DSS-induced ulceration. Mtgr1-null mice show increased epithelial apoptosis and failure to regenerate after DSS treatment; bone marrow transplantation experiments confirmed the defect is epithelial-intrinsic.","method":"Mtgr1-null mouse DSS colitis model, bone marrow transplantation (wild-type into Mtgr1-null and reciprocal), apoptosis and proliferation assays","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, epistasis via reciprocal bone marrow transplantation establishing cell-autonomy","pmids":["16890610"],"is_preprint":false},{"year":2009,"finding":"MTGR1 physically interacts with NEUROG2 (a proneural bHLH transcription factor), represses NEUROG2 transcriptional activity, and prevents DNA binding of the NEUROG2/E47 complex. MTGR1 is induced by NEUROG2, constituting a negative feedback loop. Proper termination of NEUROG2 activity by MTGR1 is necessary for normal progression of neurogenesis in the developing spinal cord.","method":"Co-immunoprecipitation (physical interaction), transcriptional reporter assays (repression), DNA-binding assays, in vivo spinal cord neurogenesis analyses","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional transcription assays, single lab with multiple orthogonal methods","pmids":["19646530"],"is_preprint":false},{"year":2009,"finding":"MTGR1 and ETO2/MTG16 are identified as interaction partners of TAL1/SCL in murine erythroid progenitors, forming heteromeric corepressor complexes. The interaction requires the bHLH domain of TAL1 and the TAF110 domain of ETO2. MTGR1 and ETO2 enhance each other's association with TAL1, and co-expression augments TAL1-mediated repression of the Protein 4.2 promoter in MEL cells.","method":"Tandem affinity purification/LC-MS/MS, co-immunoprecipitation in transfected COS-7 and MEL cells, GST pull-down, domain mapping with Gal4 fusions, transient transfection reporter assays, chromatin immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity purification/MS identification confirmed by reciprocal Co-IP, GST pulldown, domain mapping, ChIP, and functional transcription assays, multiple orthogonal methods","pmids":["19799863"],"is_preprint":false},{"year":2011,"finding":"MTGR1 is required in the intestinal epithelium (not in hematopoietic cells) for efficient inflammatory carcinogenesis in the AOM/DSS colitis-associated carcinoma model. Mtgr1-null mice are protected from tumorigenesis with increased apoptosis in tumors and upregulation of inflammatory networks; bone marrow transplantation confirmed the effect is epithelial-intrinsic.","method":"Mtgr1-null mouse AOM/DSS carcinogenesis model, bone marrow transplantation, immunohistochemistry, gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined tumor phenotype, epistasis via reciprocal bone marrow transplantation establishing cell-autonomous epithelial role","pmids":["21303973"],"is_preprint":false},{"year":2014,"finding":"MTGR1 forms a complex with Suppressor of Hairless Homolog (CSL/RBP-Jκ), a key Notch effector, and represses Notch-induced HES1 (Hairy/Enhancer of Split 1) activity. MTGR1 also interacts with GFI1, a corepressor required for Paneth cell differentiation, and represses GFI1 targets. Loss of MTGR1 results in Notch pathway activation in intestinal crypts and loss of secretory cell lineages; pharmacologic Notch inhibition with a γ-secretase inhibitor rescues the hyperproliferative phenotype.","method":"Co-immunoprecipitation (MTGR1–CSL and MTGR1–GFI1 interactions), transcriptional reporter assays (HES1 repression), Mtgr1-null mouse with GSI pharmacologic rescue, transcriptome analysis of laser-capture microdissected crypts, enteroid culture","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with pathway effectors, pharmacologic epistasis rescue, transcriptome and organoid functional readouts in multiple orthogonal experiments","pmids":["25398765"],"is_preprint":false},{"year":2015,"finding":"MTGR1 tightly binds to the pre-SET/SET domains of PRDM14 and co-occupies PRDM14 genomic targets in mouse ESCs. Crystal structure of the PRDM14–MTGR1 complex was determined using monobody-facilitated crystallization. Structure-guided point mutants and a genetically encoded monobody abrogated the PRDM14–MTGR1 interaction, disrupting PRDM14 function in mESC gene expression and PGC formation in vitro.","method":"Crystal structure determination (using monobody-assisted crystallization), co-immunoprecipitation, ChIP-seq (co-occupancy), structure-guided mutagenesis, monobody inhibitor, mESC gene expression and in vitro PGC formation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus ChIP-seq co-occupancy plus functional assays, multiple rigorous orthogonal methods in one study","pmids":["26523391"],"is_preprint":false},{"year":2016,"finding":"CBFA2T2 forms a biochemical complex with PRDM14 and OCT4, oligomerizes to form a scaffold stabilizing these transcription factors on chromatin, and is essential for PGC maturation and epigenetic reprogramming in mice. Cbfa2t2-null mice display severe defects in primordial germ cell maturation.","method":"Co-immunoprecipitation (CBFA2T2–PRDM14 and CBFA2T2–OCT4 complexes), Cbfa2t2-null mouse phenotyping, chromatin assays, biochemical oligomerization assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex identification by Co-IP, in vivo genetic KO with defined PGC phenotype, chromatin stabilization assays, multiple orthogonal methods","pmids":["27281218"],"is_preprint":false},{"year":2018,"finding":"CBFA2T2 is required for BMP-2-induced osteogenic differentiation of mesenchymal stem cells. Knockdown of CBFA2T2 promotes expression of EHMT1 (euchromatic histone methyltransferase 1), leading to increased H3K9me2 at the promoter of RUNX2 (master regulator of osteogenesis), thereby suppressing osteogenic differentiation.","method":"siRNA knockdown, ALP activity assay, Alizarin Red mineralization assay, qRT-PCR/Western blotting for osteogenic markers, chromatin immunoprecipitation (H3K9me2 at Runx2 promoter)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype and ChIP mechanistic readout, single lab with two orthogonal methods","pmids":["29378183"],"is_preprint":false},{"year":2020,"finding":"CBFA2T2 promotes adipogenic differentiation of mesenchymal stem cells. Knockdown of CBFA2T2 increases H3K9me2 and H3K9me3 levels at the promoter of CEBPA (an essential adipogenic transcription factor), inhibiting adipogenic differentiation.","method":"siRNA knockdown, Oil Red O staining, qRT-PCR/Western blotting for adipogenic markers, chromatin immunoprecipitation (H3K9me2/me3 at CEBPA promoter)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype and ChIP mechanistic readout, single lab with two orthogonal methods","pmids":["32703401"],"is_preprint":false},{"year":2024,"finding":"Loss of MTGR1 in mice increases the total number of Lgr5+ intestinal stem cells (ISCs), but these cells have deregulated ISC-associated transcriptional programs. Mtgr1-null intestinal organoids fail to survive and expand ex vivo due to aberrant differentiation and loss of stem/proliferative cells, indicating MTGR1 maintains ISC function in a stem cell-intrinsic manner.","method":"Mtgr1-null mouse intestinal crypt analysis, flow cytometry for Lgr5+ cells, single-cell/bulk transcriptomics, ex vivo intestinal organoid culture","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined ISC phenotype, transcriptomic and organoid functional assays, single lab with multiple orthogonal methods","pmids":["39048708"],"is_preprint":false},{"year":2008,"finding":"Loss-of-function genetic screens identified MTGR1 as an intracellular repressor of β1 integrin-dependent neurite outgrowth in SH-SY5Y neuroblastoma cells. siRNA-mediated knockdown of MTGR1 enhanced neurite outgrowth and increased expression of GAP-43.","method":"Genome-wide retroviral GSE screen, siRNA knockdown, neurite outgrowth assay, GAP-43 expression analysis","journal":"Journal of neuroscience methods","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single genetic screen plus siRNA phenotype, single lab, no direct molecular mechanism established","pmids":["19026687"],"is_preprint":false},{"year":2026,"finding":"CBFA2T2 functions as a histone H3K27 reader: its NHR2 domain recognizes unmodified/non-mutated histone H3K27. CBFA2T2 represses transcription of metabolic genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the TCA cycle through H3K27 binding, altering the α-ketoglutarate/succinate ratio and indirectly reducing H3K27me3 levels by affecting H3K27me3 demethylases.","method":"Biochemical binding assays (histone recognition specificity), domain mapping (NHR2), transcriptome analysis of metabolic gene regulation, metabolite quantification, H3K27me3 level measurements","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical histone-binding assays plus transcriptomic and metabolite functional readouts, single lab with multiple orthogonal methods","pmids":["41703542"],"is_preprint":false}],"current_model":"CBFA2T2 (MTGR1) is a transcriptional co-repressor of the MTG/ETO family that acts through multiple mechanisms: it oligomerizes via its NHR2 domain to scaffold protein complexes (including with PRDM14 and OCT4 in pluripotent/germline cells), recruits classical co-repressor machinery (mSin3A, N-CoR, HDAC3), reads unmodified histone H3K27 through its NHR2 domain to repress metabolic gene transcription, interacts with bHLH transcription factors (TAL1, NEUROG2, AML1-MTG8) to modulate their activity, and represses Notch/CSL and GFI1 signaling in the intestinal epithelium to control secretory lineage allocation, stem cell maintenance, and injury response."},"narrative":{"mechanistic_narrative":"CBFA2T2 (MTGR1) is a transcriptional co-repressor of the MTG/ETO family that scaffolds repressive complexes on chromatin to control lineage allocation, stem cell maintenance, and developmental transcription programs [PMID:16227606, PMID:27281218]. It was first identified through its strong, NHR2-dependent interaction with the AML1-MTG8 leukemic fusion protein, where it potentiates the fusion's interference with AML1-dependent transcription [PMID:9447981]. It assembles classical co-repressor machinery — mSin3A, N-CoR, and HDAC3 — and represses transcription when tethered to DNA [PMID:16227606]. CBFA2T2 modulates the activity of multiple sequence-specific transcription factors by direct physical association: it binds the bHLH factors NEUROG2 and TAL1/SCL to repress their target genes [PMID:19646530, PMID:19799863], and it complexes with the Notch effector CSL/RBP-Jκ and with GFI1 to repress HES1 and GFI1 targets in the intestinal epithelium [PMID:25398765]. In pluripotent and germline cells it binds the pre-SET/SET domains of PRDM14 and oligomerizes with PRDM14 and OCT4 to stabilize these factors on their genomic targets, an activity required for primordial germ cell maturation and epigenetic reprogramming [PMID:26523391, PMID:27281218]. In the intestine MTGR1 acts cell-autonomously to drive secretory lineage maturation, restrain Notch signaling, support epithelial survival and regeneration after injury, and maintain Lgr5+ stem cell function [PMID:16227606, PMID:25398765, PMID:39048708]. Its NHR2 domain reads unmodified histone H3K27 to repress metabolic genes spanning glycolysis/gluconeogenesis and the TCA cycle, thereby influencing the α-ketoglutarate/succinate ratio [PMID:41703542]. Genetically, loss of MTGR1 in mice confers protection from colitis-associated carcinogenesis through an epithelial-intrinsic mechanism [PMID:21303973].","teleology":[{"year":1998,"claim":"Established CBFA2T2's first molecular identity — as a dedicated binding partner of the AML1-MTG8 leukemic fusion that enhances its oncogenic transcriptional interference, framing the protein as a co-regulator co-opted in leukemia.","evidence":"Molecular cloning, reciprocal Co-IP, NHR2-region deletion mapping, and G-CSF-dependent proliferation assay in murine myeloid progenitors","pmids":["9447981"],"confidence":"High","gaps":["Did not define the intrinsic repressive machinery recruited by MTGR1","No physiological (non-leukemic) function established"]},{"year":2005,"claim":"Defined the core repressive mechanism (mSin3A/N-CoR/HDAC3 recruitment) and the first in vivo role, placing MTGR1 downstream of progenitor specification to drive intestinal secretory cell maturation.","evidence":"Co-IP with co-repressor components, DNA-tethered repression assays, and Mtgr1-null mouse histological phenotyping","pmids":["16227606"],"confidence":"High","gaps":["Direct DNA-binding transcription factor partners in the intestine not yet identified","Did not resolve which secretory program targets are directly bound"]},{"year":2006,"claim":"Showed the intestinal requirement is epithelial-intrinsic and extends to survival and regeneration after injury, beyond secretory differentiation.","evidence":"Mtgr1-null DSS colitis model with reciprocal bone marrow transplantation and apoptosis/proliferation assays","pmids":["16890610"],"confidence":"High","gaps":["Molecular targets mediating epithelial survival not defined","Signaling pathway linkage unresolved at this stage"]},{"year":2008,"claim":"Implicated MTGR1 as an intracellular repressor of integrin-dependent neurite outgrowth, hinting at a role in neuronal differentiation control.","evidence":"Genome-wide retroviral GSE screen and siRNA knockdown with neurite outgrowth and GAP-43 readouts in SH-SY5Y cells","pmids":["19026687"],"confidence":"Low","gaps":["Single screen plus siRNA phenotype with no direct molecular mechanism established","No physical partner or target gene identified"]},{"year":2009,"claim":"Identified specific bHLH transcription factor partners (NEUROG2 and TAL1/SCL), establishing MTGR1 as a modulator that represses proneural and erythroid transcriptional programs and blocks bHLH/E-protein DNA binding.","evidence":"Co-IP, GST pull-down, domain mapping, reporter assays, ChIP, and in vivo spinal cord neurogenesis analyses; affinity purification/MS in erythroid progenitors","pmids":["19646530","19799863"],"confidence":"High","gaps":["Whether the same co-repressor machinery is engaged at all bHLH targets not shown","Generality across other bHLH factors untested"]},{"year":2011,"claim":"Demonstrated that MTGR1 is required, cell-autonomously in epithelium, for inflammation-driven colon carcinogenesis, linking its repressive function to tumor promotion.","evidence":"Mtgr1-null AOM/DSS carcinogenesis model with bone marrow transplantation, IHC, and gene expression analysis","pmids":["21303973"],"confidence":"High","gaps":["Direct transcriptional targets driving tumor susceptibility not pinpointed","Mechanistic link between repression and apoptosis/inflammation unresolved"]},{"year":2014,"claim":"Connected MTGR1's intestinal phenotypes to defined signaling effectors, showing it complexes with CSL/RBP-Jκ to repress Notch/HES1 and with GFI1 to control secretory differentiation, with γ-secretase inhibition rescuing the loss phenotype.","evidence":"Co-IP, HES1 reporter assays, Mtgr1-null mouse GSI rescue, laser-capture crypt transcriptomics, and enteroid culture","pmids":["25398765"],"confidence":"High","gaps":["Whether MTGR1 represses CSL directly at chromatin via genome-wide occupancy not mapped","Relative contribution of Notch vs GFI1 arms not dissected"]},{"year":2015,"claim":"Provided structural and genomic resolution of a key partnership, showing CBFA2T2 binds the PRDM14 pre-SET/SET domains and co-occupies its targets to support pluripotency gene expression and PGC formation.","evidence":"Crystal structure of the PRDM14–MTGR1 complex (monobody-assisted), Co-IP, ChIP-seq co-occupancy, structure-guided mutants/monobody, and mESC/PGC assays","pmids":["26523391"],"confidence":"High","gaps":["Did not establish the higher-order scaffold composition beyond the binary interface","In vivo germline requirement addressed in vitro only"]},{"year":2016,"claim":"Established the oligomeric scaffold model in vivo, showing CBFA2T2 self-associates to stabilize PRDM14 and OCT4 on chromatin and is essential for primordial germ cell maturation and epigenetic reprogramming.","evidence":"Co-IP of CBFA2T2–PRDM14 and CBFA2T2–OCT4 complexes, oligomerization assays, chromatin stabilization assays, and Cbfa2t2-null mouse PGC phenotyping","pmids":["27281218"],"confidence":"High","gaps":["Stoichiometry and structural basis of the chromatin-stabilizing oligomer not resolved","How scaffold activity intersects with co-repressor recruitment unclear"]},{"year":2018,"claim":"Extended CBFA2T2 function to mesenchymal lineage commitment, positioning it as a positive regulator of osteogenesis that restrains EHMT1-mediated H3K9me2 deposition at the RUNX2 promoter.","evidence":"siRNA knockdown, ALP/Alizarin Red assays, marker expression, and ChIP for H3K9me2 at the Runx2 promoter","pmids":["29378183"],"confidence":"Medium","gaps":["Direct vs indirect control of EHMT1 not established","Physical interaction with EHMT1 or RUNX2 not demonstrated"]},{"year":2020,"claim":"Showed an analogous, lineage-specific role in adipogenesis, where CBFA2T2 limits repressive H3K9 methylation at the CEBPA promoter to enable adipogenic differentiation.","evidence":"siRNA knockdown, Oil Red O staining, marker analysis, and ChIP for H3K9me2/me3 at the CEBPA promoter","pmids":["32703401"],"confidence":"Medium","gaps":["Mechanism linking CBFA2T2 loss to increased H3K9 methylation not defined","No direct chromatin occupancy data for CBFA2T2 at CEBPA"]},{"year":2024,"claim":"Refined the intestinal role to stem cell biology, showing MTGR1 maintains Lgr5+ ISC function cell-intrinsically — its loss expands but deregulates ISCs and renders organoids unable to survive ex vivo.","evidence":"Mtgr1-null crypt analysis, flow cytometry for Lgr5+ cells, single-cell/bulk transcriptomics, and ex vivo organoid culture","pmids":["39048708"],"confidence":"Medium","gaps":["Direct ISC transcriptional targets not identified","How stem cell maintenance integrates with the Notch/GFI1 axes unresolved"]},{"year":2026,"claim":"Identified a chromatin-reading activity, showing the NHR2 domain recognizes unmodified H3K27 to repress carbon/energy metabolism genes and shape the α-ketoglutarate/succinate ratio and H3K27me3 landscape.","evidence":"Biochemical histone-binding assays, NHR2 domain mapping, metabolic transcriptome analysis, metabolite quantification, and H3K27me3 measurement","pmids":["41703542"],"confidence":"Medium","gaps":["Structural basis of unmodified-H3K27 recognition by NHR2 not solved","Causality between metabolite shifts and H3K27me3 demethylase activity not directly demonstrated"]},{"year":null,"claim":"How CBFA2T2's distinct activities — NHR2-mediated oligomerization, co-repressor recruitment, partner-specific transcription factor binding, and H3K27 reading — are integrated and selected in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how scaffold vs reader vs co-repressor modes are deployed contextually","Genome-wide direct target maps across tissues lacking","Structural basis of NHR2 multifunctionality not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,4,6]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,7,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,13]}],"complexes":["mSin3A/N-CoR/HDAC3 co-repressor complex","PRDM14–OCT4–CBFA2T2 chromatin scaffold","TAL1/SCL–ETO2 corepressor complex"],"partners":["RUNX1T1","PRDM14","POU5F1","TAL1","NEUROG2","RBPJ","GFI1","HDAC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43439","full_name":"Protein CBFA2T2","aliases":["ETO homologous on chromosome 20","MTG8-like protein","MTG8-related protein 1","Myeloid translocation-related protein 1","p85"],"length_aa":604,"mass_kda":67.1,"function":"Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes (PubMed:12559562, PubMed:15203199). Via association with PRDM14 is involved in regulation of embryonic stem cell (ESC) pluripotency (PubMed:27281218). Involved in primordial germ cell (PCG) formation. Stabilizes PRDM14 and OCT4 on chromatin in a homooligomerization-dependent manner (By similarity). Can repress the expression of MMP7 in a ZBTB33-dependent manner (PubMed:23251453). May function as a complex with the chimeric protein RUNX1/AML1-CBFA2T1/MTG8 (AML1-MTG8/ETO fusion protein) which is produced in acute myeloid leukemia with the chromosomal translocation t(8;21). May thus be involved in the repression of AML1-dependent transcription and the induction of G-CSF/CSF3-dependent cell growth. May be a tumor suppressor gene candidate involved in myeloid tumors with the deletion of the 20q11 region. Through heteromerization with CBFA2T3/MTG16 may be involved in regulation of the proliferation and the differentiation of erythroid progenitors by repressing the expression of TAL1 target genes (By similarity). Required for the maintenance of the secretory cell lineage in the small intestine. Can inhibit Notch signaling probably by association with RBPJ and may be involved in GFI1-mediated Paneth cell differentiation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O43439/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBFA2T2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBFA2T2","total_profiled":1310},"omim":[{"mim_id":"603870","title":"CORE-BINDING FACTOR, ALPHA SUBUNIT 2, TRANSLOCATED TO, 3; CBFA2T3","url":"https://www.omim.org/entry/603870"},{"mim_id":"603672","title":"CORE-BINDING FACTOR, RUNT DOMAIN, ALPHA SUBUNIT 2, TRANSLOCATED TO, 2; CBFA2T2","url":"https://www.omim.org/entry/603672"},{"mim_id":"602228","title":"TRANSCRIPTION FACTOR 7-LIKE 2; TCF7L2","url":"https://www.omim.org/entry/602228"},{"mim_id":"133435","title":"RUNT-RELATED TRANSCRIPTION FACTOR 1, TRANSLOCATED TO, 1; RUNX1T1","url":"https://www.omim.org/entry/133435"},{"mim_id":"116806","title":"CATENIN, BETA-1; CTNNB1","url":"https://www.omim.org/entry/116806"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CBFA2T2"},"hgnc":{"alias_symbol":["MTGR1","ZMYND3"],"prev_symbol":[]},"alphafold":{"accession":"O43439","domains":[{"cath_id":"1.20.120.1110","chopping":"111-211","consensus_level":"high","plddt":87.195,"start":111,"end":211},{"cath_id":"-","chopping":"506-543","consensus_level":"medium","plddt":89.1295,"start":506,"end":543}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43439","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43439-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43439-F1-predicted_aligned_error_v6.png","plddt_mean":63.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBFA2T2","jax_strain_url":"https://www.jax.org/strain/search?query=CBFA2T2"},"sequence":{"accession":"O43439","fasta_url":"https://rest.uniprot.org/uniprotkb/O43439.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43439/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43439"}},"corpus_meta":[{"pmid":"9447981","id":"PMC_9447981","title":"The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9447981","citation_count":135,"is_preprint":false},{"pmid":"27281218","id":"PMC_27281218","title":"Co-repressor CBFA2T2 regulates pluripotency and germline development.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27281218","citation_count":54,"is_preprint":false},{"pmid":"16227606","id":"PMC_16227606","title":"Mtgr1 is a transcriptional corepressor that is required for maintenance of the secretory cell lineage in the small intestine.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16227606","citation_count":53,"is_preprint":false},{"pmid":"26523391","id":"PMC_26523391","title":"ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26523391","citation_count":48,"is_preprint":false},{"pmid":"32460831","id":"PMC_32460831","title":"Circ_0008532 promotes bladder cancer progression by regulation of the miR-155-5p/miR-330-5p/MTGR1 axis.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32460831","citation_count":45,"is_preprint":false},{"pmid":"21303973","id":"PMC_21303973","title":"MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21303973","citation_count":35,"is_preprint":false},{"pmid":"32183688","id":"PMC_32183688","title":"Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle.","date":"2020","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/32183688","citation_count":29,"is_preprint":false},{"pmid":"16890610","id":"PMC_16890610","title":"Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16890610","citation_count":25,"is_preprint":false},{"pmid":"19799863","id":"PMC_19799863","title":"Eto2/MTG16 and MTGR1 are heteromeric corepressors of the TAL1/SCL transcription factor in murine erythroid progenitors.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19799863","citation_count":24,"is_preprint":false},{"pmid":"10675041","id":"PMC_10675041","title":"Structure and expression pattern of a human MTG8/ETO family gene, MTGR1.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10675041","citation_count":20,"is_preprint":false},{"pmid":"29378183","id":"PMC_29378183","title":"CBFA2T2 is required for BMP-2-induced osteogenic differentiation of mesenchymal stem cells.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29378183","citation_count":20,"is_preprint":false},{"pmid":"25398765","id":"PMC_25398765","title":"The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25398765","citation_count":15,"is_preprint":false},{"pmid":"19646530","id":"PMC_19646530","title":"Feedback regulation of NEUROG2 activity by MTGR1 is required for progression of neurogenesis.","date":"2009","source":"Molecular and cellular 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methods","url":"https://pubmed.ncbi.nlm.nih.gov/19026687","citation_count":7,"is_preprint":false},{"pmid":"29162985","id":"PMC_29162985","title":"CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.","date":"2017","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/29162985","citation_count":5,"is_preprint":false},{"pmid":"39048708","id":"PMC_39048708","title":"MTGR1 is required to maintain small intestinal stem cell populations.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/39048708","citation_count":4,"is_preprint":false},{"pmid":"37790452","id":"PMC_37790452","title":"MTGR1 is required to maintain small intestinal stem cell populations.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37790452","citation_count":1,"is_preprint":false},{"pmid":"39691258","id":"PMC_39691258","title":"RUNX1::CBFA2T2 rearranged acute myeloid leukemia transformed from JAK2 V617F mutated primary myelofibrosis.","date":"2024","source":"EJHaem","url":"https://pubmed.ncbi.nlm.nih.gov/39691258","citation_count":1,"is_preprint":false},{"pmid":"41703542","id":"PMC_41703542","title":"CBFA2T2: a novel H3K27 reader regulating metabolism and tumor growth.","date":"2026","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41703542","citation_count":0,"is_preprint":false},{"pmid":"29782581","id":"PMC_29782581","title":"Correction to: CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/29782581","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13236,"output_tokens":4084,"usd":0.050484,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11882,"output_tokens":4782,"usd":0.08948,"stage2_stop_reason":"end_turn"},"total_usd":0.139964,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"CBFA2T2 (MTGR1) was identified as a novel protein that specifically and strongly interacts with the AML1-MTG8 leukemic fusion protein. The NHR2-containing region (residues 488–538) of AML1-MTG8 is required for stable complex formation with MTGR1, and overexpression of MTGR1 stimulates AML1-MTG8 to induce G-CSF-dependent proliferation of myeloid progenitor cells and to interfere with AML1-dependent transcription.\",\n      \"method\": \"Molecular cloning, co-immunoprecipitation, C-terminal deletion mutants, ectopic expression in L-G murine myeloid progenitor cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, deletion mapping, and functional cellular assay (G-CSF-dependent proliferation), multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"9447981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MTGR1 associates with the co-repressor complex components mSin3A, N-CoR, and histone deacetylase 3 (HDAC3), and when tethered to DNA, represses transcription. Loss of Mtgr1 in mice causes a progressive reduction in secretory epithelial cell lineage (goblet, Paneth, enteroendocrine cells) in the small intestine, without loss of progenitor cells expressing Gfi1, indicating MTGR1 acts downstream of progenitor specification to promote secretory cell maturation.\",\n      \"method\": \"Co-immunoprecipitation (association with mSin3A, N-CoR, HDAC3), DNA-tethered transcription repression assays, Mtgr1-null mouse generation and histological phenotyping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple partners, in vivo KO phenotype with defined cellular readout, multiple orthogonal methods\",\n      \"pmids\": [\"16227606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MTGR1 is required in the colonic epithelium (not in hematopoietic cells) for survival and regeneration after DSS-induced ulceration. Mtgr1-null mice show increased epithelial apoptosis and failure to regenerate after DSS treatment; bone marrow transplantation experiments confirmed the defect is epithelial-intrinsic.\",\n      \"method\": \"Mtgr1-null mouse DSS colitis model, bone marrow transplantation (wild-type into Mtgr1-null and reciprocal), apoptosis and proliferation assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, epistasis via reciprocal bone marrow transplantation establishing cell-autonomy\",\n      \"pmids\": [\"16890610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MTGR1 physically interacts with NEUROG2 (a proneural bHLH transcription factor), represses NEUROG2 transcriptional activity, and prevents DNA binding of the NEUROG2/E47 complex. MTGR1 is induced by NEUROG2, constituting a negative feedback loop. Proper termination of NEUROG2 activity by MTGR1 is necessary for normal progression of neurogenesis in the developing spinal cord.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction), transcriptional reporter assays (repression), DNA-binding assays, in vivo spinal cord neurogenesis analyses\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional transcription assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19646530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MTGR1 and ETO2/MTG16 are identified as interaction partners of TAL1/SCL in murine erythroid progenitors, forming heteromeric corepressor complexes. The interaction requires the bHLH domain of TAL1 and the TAF110 domain of ETO2. MTGR1 and ETO2 enhance each other's association with TAL1, and co-expression augments TAL1-mediated repression of the Protein 4.2 promoter in MEL cells.\",\n      \"method\": \"Tandem affinity purification/LC-MS/MS, co-immunoprecipitation in transfected COS-7 and MEL cells, GST pull-down, domain mapping with Gal4 fusions, transient transfection reporter assays, chromatin immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity purification/MS identification confirmed by reciprocal Co-IP, GST pulldown, domain mapping, ChIP, and functional transcription assays, multiple orthogonal methods\",\n      \"pmids\": [\"19799863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MTGR1 is required in the intestinal epithelium (not in hematopoietic cells) for efficient inflammatory carcinogenesis in the AOM/DSS colitis-associated carcinoma model. Mtgr1-null mice are protected from tumorigenesis with increased apoptosis in tumors and upregulation of inflammatory networks; bone marrow transplantation confirmed the effect is epithelial-intrinsic.\",\n      \"method\": \"Mtgr1-null mouse AOM/DSS carcinogenesis model, bone marrow transplantation, immunohistochemistry, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined tumor phenotype, epistasis via reciprocal bone marrow transplantation establishing cell-autonomous epithelial role\",\n      \"pmids\": [\"21303973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTGR1 forms a complex with Suppressor of Hairless Homolog (CSL/RBP-Jκ), a key Notch effector, and represses Notch-induced HES1 (Hairy/Enhancer of Split 1) activity. MTGR1 also interacts with GFI1, a corepressor required for Paneth cell differentiation, and represses GFI1 targets. Loss of MTGR1 results in Notch pathway activation in intestinal crypts and loss of secretory cell lineages; pharmacologic Notch inhibition with a γ-secretase inhibitor rescues the hyperproliferative phenotype.\",\n      \"method\": \"Co-immunoprecipitation (MTGR1–CSL and MTGR1–GFI1 interactions), transcriptional reporter assays (HES1 repression), Mtgr1-null mouse with GSI pharmacologic rescue, transcriptome analysis of laser-capture microdissected crypts, enteroid culture\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with pathway effectors, pharmacologic epistasis rescue, transcriptome and organoid functional readouts in multiple orthogonal experiments\",\n      \"pmids\": [\"25398765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTGR1 tightly binds to the pre-SET/SET domains of PRDM14 and co-occupies PRDM14 genomic targets in mouse ESCs. Crystal structure of the PRDM14–MTGR1 complex was determined using monobody-facilitated crystallization. Structure-guided point mutants and a genetically encoded monobody abrogated the PRDM14–MTGR1 interaction, disrupting PRDM14 function in mESC gene expression and PGC formation in vitro.\",\n      \"method\": \"Crystal structure determination (using monobody-assisted crystallization), co-immunoprecipitation, ChIP-seq (co-occupancy), structure-guided mutagenesis, monobody inhibitor, mESC gene expression and in vitro PGC formation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus ChIP-seq co-occupancy plus functional assays, multiple rigorous orthogonal methods in one study\",\n      \"pmids\": [\"26523391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CBFA2T2 forms a biochemical complex with PRDM14 and OCT4, oligomerizes to form a scaffold stabilizing these transcription factors on chromatin, and is essential for PGC maturation and epigenetic reprogramming in mice. Cbfa2t2-null mice display severe defects in primordial germ cell maturation.\",\n      \"method\": \"Co-immunoprecipitation (CBFA2T2–PRDM14 and CBFA2T2–OCT4 complexes), Cbfa2t2-null mouse phenotyping, chromatin assays, biochemical oligomerization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex identification by Co-IP, in vivo genetic KO with defined PGC phenotype, chromatin stabilization assays, multiple orthogonal methods\",\n      \"pmids\": [\"27281218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CBFA2T2 is required for BMP-2-induced osteogenic differentiation of mesenchymal stem cells. Knockdown of CBFA2T2 promotes expression of EHMT1 (euchromatic histone methyltransferase 1), leading to increased H3K9me2 at the promoter of RUNX2 (master regulator of osteogenesis), thereby suppressing osteogenic differentiation.\",\n      \"method\": \"siRNA knockdown, ALP activity assay, Alizarin Red mineralization assay, qRT-PCR/Western blotting for osteogenic markers, chromatin immunoprecipitation (H3K9me2 at Runx2 promoter)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype and ChIP mechanistic readout, single lab with two orthogonal methods\",\n      \"pmids\": [\"29378183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CBFA2T2 promotes adipogenic differentiation of mesenchymal stem cells. Knockdown of CBFA2T2 increases H3K9me2 and H3K9me3 levels at the promoter of CEBPA (an essential adipogenic transcription factor), inhibiting adipogenic differentiation.\",\n      \"method\": \"siRNA knockdown, Oil Red O staining, qRT-PCR/Western blotting for adipogenic markers, chromatin immunoprecipitation (H3K9me2/me3 at CEBPA promoter)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype and ChIP mechanistic readout, single lab with two orthogonal methods\",\n      \"pmids\": [\"32703401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of MTGR1 in mice increases the total number of Lgr5+ intestinal stem cells (ISCs), but these cells have deregulated ISC-associated transcriptional programs. Mtgr1-null intestinal organoids fail to survive and expand ex vivo due to aberrant differentiation and loss of stem/proliferative cells, indicating MTGR1 maintains ISC function in a stem cell-intrinsic manner.\",\n      \"method\": \"Mtgr1-null mouse intestinal crypt analysis, flow cytometry for Lgr5+ cells, single-cell/bulk transcriptomics, ex vivo intestinal organoid culture\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined ISC phenotype, transcriptomic and organoid functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39048708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function genetic screens identified MTGR1 as an intracellular repressor of β1 integrin-dependent neurite outgrowth in SH-SY5Y neuroblastoma cells. siRNA-mediated knockdown of MTGR1 enhanced neurite outgrowth and increased expression of GAP-43.\",\n      \"method\": \"Genome-wide retroviral GSE screen, siRNA knockdown, neurite outgrowth assay, GAP-43 expression analysis\",\n      \"journal\": \"Journal of neuroscience methods\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single genetic screen plus siRNA phenotype, single lab, no direct molecular mechanism established\",\n      \"pmids\": [\"19026687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CBFA2T2 functions as a histone H3K27 reader: its NHR2 domain recognizes unmodified/non-mutated histone H3K27. CBFA2T2 represses transcription of metabolic genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the TCA cycle through H3K27 binding, altering the α-ketoglutarate/succinate ratio and indirectly reducing H3K27me3 levels by affecting H3K27me3 demethylases.\",\n      \"method\": \"Biochemical binding assays (histone recognition specificity), domain mapping (NHR2), transcriptome analysis of metabolic gene regulation, metabolite quantification, H3K27me3 level measurements\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical histone-binding assays plus transcriptomic and metabolite functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41703542\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBFA2T2 (MTGR1) is a transcriptional co-repressor of the MTG/ETO family that acts through multiple mechanisms: it oligomerizes via its NHR2 domain to scaffold protein complexes (including with PRDM14 and OCT4 in pluripotent/germline cells), recruits classical co-repressor machinery (mSin3A, N-CoR, HDAC3), reads unmodified histone H3K27 through its NHR2 domain to repress metabolic gene transcription, interacts with bHLH transcription factors (TAL1, NEUROG2, AML1-MTG8) to modulate their activity, and represses Notch/CSL and GFI1 signaling in the intestinal epithelium to control secretory lineage allocation, stem cell maintenance, and injury response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CBFA2T2 (MTGR1) is a transcriptional co-repressor of the MTG/ETO family that scaffolds repressive complexes on chromatin to control lineage allocation, stem cell maintenance, and developmental transcription programs [#1, #8]. It was first identified through its strong, NHR2-dependent interaction with the AML1-MTG8 leukemic fusion protein, where it potentiates the fusion's interference with AML1-dependent transcription [#0]. It assembles classical co-repressor machinery — mSin3A, N-CoR, and HDAC3 — and represses transcription when tethered to DNA [#1]. CBFA2T2 modulates the activity of multiple sequence-specific transcription factors by direct physical association: it binds the bHLH factors NEUROG2 and TAL1/SCL to repress their target genes [#3, #4], and it complexes with the Notch effector CSL/RBP-Jκ and with GFI1 to repress HES1 and GFI1 targets in the intestinal epithelium [#6]. In pluripotent and germline cells it binds the pre-SET/SET domains of PRDM14 and oligomerizes with PRDM14 and OCT4 to stabilize these factors on their genomic targets, an activity required for primordial germ cell maturation and epigenetic reprogramming [#7, #8]. In the intestine MTGR1 acts cell-autonomously to drive secretory lineage maturation, restrain Notch signaling, support epithelial survival and regeneration after injury, and maintain Lgr5+ stem cell function [#1, #6, #11]. Its NHR2 domain reads unmodified histone H3K27 to repress metabolic genes spanning glycolysis/gluconeogenesis and the TCA cycle, thereby influencing the α-ketoglutarate/succinate ratio [#13]. Genetically, loss of MTGR1 in mice confers protection from colitis-associated carcinogenesis through an epithelial-intrinsic mechanism [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established CBFA2T2's first molecular identity — as a dedicated binding partner of the AML1-MTG8 leukemic fusion that enhances its oncogenic transcriptional interference, framing the protein as a co-regulator co-opted in leukemia.\",\n      \"evidence\": \"Molecular cloning, reciprocal Co-IP, NHR2-region deletion mapping, and G-CSF-dependent proliferation assay in murine myeloid progenitors\",\n      \"pmids\": [\"9447981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the intrinsic repressive machinery recruited by MTGR1\", \"No physiological (non-leukemic) function established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the core repressive mechanism (mSin3A/N-CoR/HDAC3 recruitment) and the first in vivo role, placing MTGR1 downstream of progenitor specification to drive intestinal secretory cell maturation.\",\n      \"evidence\": \"Co-IP with co-repressor components, DNA-tethered repression assays, and Mtgr1-null mouse histological phenotyping\",\n      \"pmids\": [\"16227606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding transcription factor partners in the intestine not yet identified\", \"Did not resolve which secretory program targets are directly bound\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the intestinal requirement is epithelial-intrinsic and extends to survival and regeneration after injury, beyond secretory differentiation.\",\n      \"evidence\": \"Mtgr1-null DSS colitis model with reciprocal bone marrow transplantation and apoptosis/proliferation assays\",\n      \"pmids\": [\"16890610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets mediating epithelial survival not defined\", \"Signaling pathway linkage unresolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Implicated MTGR1 as an intracellular repressor of integrin-dependent neurite outgrowth, hinting at a role in neuronal differentiation control.\",\n      \"evidence\": \"Genome-wide retroviral GSE screen and siRNA knockdown with neurite outgrowth and GAP-43 readouts in SH-SY5Y cells\",\n      \"pmids\": [\"19026687\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single screen plus siRNA phenotype with no direct molecular mechanism established\", \"No physical partner or target gene identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified specific bHLH transcription factor partners (NEUROG2 and TAL1/SCL), establishing MTGR1 as a modulator that represses proneural and erythroid transcriptional programs and blocks bHLH/E-protein DNA binding.\",\n      \"evidence\": \"Co-IP, GST pull-down, domain mapping, reporter assays, ChIP, and in vivo spinal cord neurogenesis analyses; affinity purification/MS in erythroid progenitors\",\n      \"pmids\": [\"19646530\", \"19799863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same co-repressor machinery is engaged at all bHLH targets not shown\", \"Generality across other bHLH factors untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that MTGR1 is required, cell-autonomously in epithelium, for inflammation-driven colon carcinogenesis, linking its repressive function to tumor promotion.\",\n      \"evidence\": \"Mtgr1-null AOM/DSS carcinogenesis model with bone marrow transplantation, IHC, and gene expression analysis\",\n      \"pmids\": [\"21303973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving tumor susceptibility not pinpointed\", \"Mechanistic link between repression and apoptosis/inflammation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected MTGR1's intestinal phenotypes to defined signaling effectors, showing it complexes with CSL/RBP-Jκ to repress Notch/HES1 and with GFI1 to control secretory differentiation, with γ-secretase inhibition rescuing the loss phenotype.\",\n      \"evidence\": \"Co-IP, HES1 reporter assays, Mtgr1-null mouse GSI rescue, laser-capture crypt transcriptomics, and enteroid culture\",\n      \"pmids\": [\"25398765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MTGR1 represses CSL directly at chromatin via genome-wide occupancy not mapped\", \"Relative contribution of Notch vs GFI1 arms not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided structural and genomic resolution of a key partnership, showing CBFA2T2 binds the PRDM14 pre-SET/SET domains and co-occupies its targets to support pluripotency gene expression and PGC formation.\",\n      \"evidence\": \"Crystal structure of the PRDM14–MTGR1 complex (monobody-assisted), Co-IP, ChIP-seq co-occupancy, structure-guided mutants/monobody, and mESC/PGC assays\",\n      \"pmids\": [\"26523391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the higher-order scaffold composition beyond the binary interface\", \"In vivo germline requirement addressed in vitro only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the oligomeric scaffold model in vivo, showing CBFA2T2 self-associates to stabilize PRDM14 and OCT4 on chromatin and is essential for primordial germ cell maturation and epigenetic reprogramming.\",\n      \"evidence\": \"Co-IP of CBFA2T2–PRDM14 and CBFA2T2–OCT4 complexes, oligomerization assays, chromatin stabilization assays, and Cbfa2t2-null mouse PGC phenotyping\",\n      \"pmids\": [\"27281218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the chromatin-stabilizing oligomer not resolved\", \"How scaffold activity intersects with co-repressor recruitment unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended CBFA2T2 function to mesenchymal lineage commitment, positioning it as a positive regulator of osteogenesis that restrains EHMT1-mediated H3K9me2 deposition at the RUNX2 promoter.\",\n      \"evidence\": \"siRNA knockdown, ALP/Alizarin Red assays, marker expression, and ChIP for H3K9me2 at the Runx2 promoter\",\n      \"pmids\": [\"29378183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of EHMT1 not established\", \"Physical interaction with EHMT1 or RUNX2 not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed an analogous, lineage-specific role in adipogenesis, where CBFA2T2 limits repressive H3K9 methylation at the CEBPA promoter to enable adipogenic differentiation.\",\n      \"evidence\": \"siRNA knockdown, Oil Red O staining, marker analysis, and ChIP for H3K9me2/me3 at the CEBPA promoter\",\n      \"pmids\": [\"32703401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CBFA2T2 loss to increased H3K9 methylation not defined\", \"No direct chromatin occupancy data for CBFA2T2 at CEBPA\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the intestinal role to stem cell biology, showing MTGR1 maintains Lgr5+ ISC function cell-intrinsically — its loss expands but deregulates ISCs and renders organoids unable to survive ex vivo.\",\n      \"evidence\": \"Mtgr1-null crypt analysis, flow cytometry for Lgr5+ cells, single-cell/bulk transcriptomics, and ex vivo organoid culture\",\n      \"pmids\": [\"39048708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ISC transcriptional targets not identified\", \"How stem cell maintenance integrates with the Notch/GFI1 axes unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a chromatin-reading activity, showing the NHR2 domain recognizes unmodified H3K27 to repress carbon/energy metabolism genes and shape the α-ketoglutarate/succinate ratio and H3K27me3 landscape.\",\n      \"evidence\": \"Biochemical histone-binding assays, NHR2 domain mapping, metabolic transcriptome analysis, metabolite quantification, and H3K27me3 measurement\",\n      \"pmids\": [\"41703542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of unmodified-H3K27 recognition by NHR2 not solved\", \"Causality between metabolite shifts and H3K27me3 demethylase activity not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CBFA2T2's distinct activities — NHR2-mediated oligomerization, co-repressor recruitment, partner-specific transcription factor binding, and H3K27 reading — are integrated and selected in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how scaffold vs reader vs co-repressor modes are deployed contextually\", \"Genome-wide direct target maps across tissues lacking\", \"Structural basis of NHR2 multifunctionality not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"complexes\": [\n      \"mSin3A/N-CoR/HDAC3 co-repressor complex\",\n      \"PRDM14–OCT4–CBFA2T2 chromatin scaffold\",\n      \"TAL1/SCL–ETO2 corepressor complex\"\n    ],\n    \"partners\": [\n      \"RUNX1T1\",\n      \"PRDM14\",\n      \"POU5F1\",\n      \"TAL1\",\n      \"NEUROG2\",\n      \"RBPJ\",\n      \"GFI1\",\n      \"HDAC3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}