{"gene":"GTF2I","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"TFII-I (GTF2I) was identified as a transcription initiation factor that activates core promoters through an initiator element (Inr), establishing an alternative initiation pathway distinct from TFIIA-dependent initiation. TFII-I and TBP bind cooperatively to Inr-containing TATA-less promoters.","method":"In vitro transcription reconstitution assay; preinitiation complex formation analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro transcription with defined factors, published in two companion papers","pmids":["8377828"],"is_preprint":false},{"year":1993,"finding":"Myc physically interacts with TFII-I and cooperatively binds Inr and E-box elements; however, Myc-TFII-I interaction at the Inr inhibits transcription initiation by preventing complex formation between TBP (TFIID), TFII-I, and the promoter.","method":"In vitro transcription assay; protein-protein interaction; complex formation analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with functional readout and mechanistic dissection","pmids":["8377829"],"is_preprint":false},{"year":1998,"finding":"TFII-I is phosphorylated in vivo at serine/threonine and tyrosine residues; tyrosine phosphorylation is critical for its transcriptional activation activity (via the Vbeta promoter), but not required for specific DNA binding. Mutation of a consensus tyrosine phosphorylation site severely reduces transcriptional activation in vivo.","method":"In vivo phosphorylation assay; site-directed mutagenesis; in vitro transcription; reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with in vitro and in vivo transcription assays","pmids":["9837922"],"is_preprint":false},{"year":2002,"finding":"TFII-I undergoes c-Src-dependent tyrosine phosphorylation at tyrosine residues 248 and 611 and reversibly translocates to the nucleus in response to growth factor signaling; nuclear tyrosine-phosphorylated TFII-I activates the c-fos reporter gene. Phosphorylation-deficient mutants fail to activate c-fos.","method":"Tyrosine phosphorylation assay; subcellular fractionation/nuclear translocation; reporter gene assay; site-directed mutagenesis; antibody microinjection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis, translocation imaging, and functional reporter assay combined","pmids":["11934902"],"is_preprint":false},{"year":2002,"finding":"HDAC3 physically interacts with TFII-I (confirmed by co-immunoprecipitation, GST pull-down, and co-localization). The HDAC3 C-terminus (residues 373-401) and TFII-I residues 363-606 are required for the interaction. An anti-TFII-I immunoprecipitate contains histone deacetylase activity, and HDAC3 overexpression severely reduces TFII-I transcriptional activation.","method":"Co-immunoprecipitation; GST pull-down; immunofluorescence co-localization; HDAC enzyme assay; mutational analysis; transcriptional activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in one study with domain mapping","pmids":["12393887"],"is_preprint":false},{"year":2002,"finding":"Miz1/PIASxbeta/Siz2 (a SUMO E3 ligase) interacts with TFII-I and augments its transcriptional activity; it also interacts with hMusTRD1/BEN. Co-expression of a nuclear-localization-deficient mutant of Miz1 fails to alter TFII-I subcellular localization, and Miz1 relieves repression exerted by nuclear hMusTRD1/BEN on TFII-I.","method":"Yeast two-hybrid; co-immunoprecipitation; transcriptional activity assay; subcellular localization analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and functional reporter assay in single lab, yeast two-hybrid initial identification","pmids":["12193603"],"is_preprint":false},{"year":2005,"finding":"TFII-I is activated by ER stress via c-Src-dependent tyrosine phosphorylation at Tyr248, leading to nuclear translocation and binding to the Grp78/BiP promoter ER stress element. TFII-I is required for optimal ER stress induction of Grp78; c-Src is activated by ER stress (thapsigargin) and stimulates Grp78 promoter activity via TFII-I.","method":"Chromatin immunoprecipitation (ChIP); nuclear translocation (fractionation); stable knockdown cell lines; tyrosine phosphorylation assay; reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP, stable KD with defined phenotype, and phosphorylation mapping in one study","pmids":["15664986"],"is_preprint":false},{"year":2005,"finding":"TFII-I directly activates the cyclin D1 promoter under normal growth conditions and is recruited to it by ChIP. Upon genotoxic stress and p53 activation, TFII-I is ubiquitinated and degraded by the proteasome in a p53- and ATM-dependent manner. Stable expression of TFII-I accelerates S-phase entry and exit, and overcomes p53-mediated cell cycle arrest. Tyrosine phosphorylation at Y248 and Y611 is required for these cell cycle functions.","method":"ChIP; ubiquitination assay; proteasome inhibition; flow cytometry; stable overexpression/knockdown; site-directed mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods; ChIP, mutagenesis, proteasome assay, cell cycle analysis","pmids":["16314517"],"is_preprint":false},{"year":2006,"finding":"TFII-I acts outside the nucleus as a negative regulator of agonist-induced calcium entry (ACE) by suppressing surface accumulation of TRPC3 channels. TFII-I inhibits ACE via phosphotyrosine residues engaging the SH2 domains of PLC-γ and via an interrupted PH-like domain binding the split PH domain of PLC-γ, competing with TRPC3 for PLC-γ binding.","method":"Calcium entry assay; co-immunoprecipitation; domain mapping; cytoplasmic localization experiments; surface TRPC3 accumulation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — domain mapping, co-IP, and functional calcium entry assay with defined mechanism","pmids":["17023658"],"is_preprint":false},{"year":2006,"finding":"TFII-I directly interacts with the ARID-family transcription factor Bright/ARID3a through Bright's protein interaction domain; specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. TFII-I inhibition in B cells decreases heavy-chain transcript levels.","method":"Co-immunoprecipitation; reporter gene assay; siRNA knockdown; domain mapping","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with domain mapping and functional reporter assay in same study","pmids":["16738337"],"is_preprint":false},{"year":2007,"finding":"Loss of TFII-I function in WEHI-231 B cells (stable knockdown) prevents growth arrest upon anti-IgM or TGF-β signaling, associated with upregulation of c-Myc and downregulation of p21/p27. TFII-I controls NF-κB by regulating nuclear translocation of c-rel and DNA-binding activity of p50 homodimer.","method":"Stable siRNA knockdown; flow cytometry; Western blot; EMSA; immunofluorescence","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — stable KD with defined signaling and transcriptional phenotype, multiple readouts","pmids":["17312101"],"is_preprint":false},{"year":2009,"finding":"TFII-I silencing causes significant delay in S-phase entry and progression and G2/M entry, without major mitotic defects. Cyclin D1 and PKC-β are identified as major downstream transcriptional targets. Cdk1 phosphorylates TFII-I at the G2/M boundary, leading to its displacement from condensed chromatin during prophase to pro-metaphase transition.","method":"siRNA knockdown; flow cytometry; microarray; ChIP; Cdk1 kinase assay; functional validation","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with flow cytometry and in vitro kinase assay, microarray plus functional validation","pmids":["19182516"],"is_preprint":false},{"year":2009,"finding":"TFII-I binds the Grp78 promoter and upregulates GRP78 transcription in prostate cancer cells stimulated with α2-macroglobulin (α2M*). α2M* induces tyrosine phosphorylation of c-Src and TFII-I, and TFII-I relocalizes to the nucleus. TFII-I also binds the c-fos promoter in these cells.","method":"ChIP; confocal microscopy (nuclear translocation); radiolabeled amino acid incorporation; siRNA knockdown; tyrosine phosphorylation assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and nuclear translocation with functional readout in same study","pmids":["19097122"],"is_preprint":false},{"year":2005,"finding":"GTF2I-like repeats 4 and 6 of TFII-I exhibit DNA binding properties in vitro, supporting the idea that GTF2I-like (I-repeat) domains serve as a common DNA-binding module.","method":"SELEX; EMSA; domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro SELEX and EMSA with I-repeat domains, single lab","pmids":["15987678"],"is_preprint":false},{"year":2011,"finding":"TFII-I physically interacts with BRCA1 (C-terminus of TFII-I with the BRCT domain of BRCA1) in the nucleus; TFII-I enhances BRCA1-mediated transcriptional activation of the SIRT1 promoter and stimulates BRCA1 transactivation function. Both proteins co-localize in irradiation-induced nuclear foci.","method":"Co-immunoprecipitation; reporter gene assay; immunofluorescence (nuclear foci); domain mapping","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with domain mapping, nuclear foci, and functional reporter assay in same study","pmids":["21407215"],"is_preprint":false},{"year":2015,"finding":"TFII-I is SUMOylated at K221 and K240 by SUMO1; PIAS4 is the E3 ligase responsible for TFII-I SUMOylation, and SENP2 is the SUMO protease (deSUMOylase) for TFII-I. SUMOylation reduces TFII-I binding to its repressor HDAC3, thus promoting TFII-I transcriptional activity and cell proliferation/colony formation.","method":"Large-scale proteomics/mass spectrometry; immunoprecipitation-Western blot; mutagenesis at SUMO sites; functional transcriptional assays; proliferation assays","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific SUMO modification mapped with mutagenesis, writer/eraser identified, functional consequence demonstrated","pmids":["25869096"],"is_preprint":false},{"year":2016,"finding":"Adenovirus E4-ORF3 stimulates SUMOylation and subsequent ubiquitination of TFII-I, leading to its proteasomal degradation. E4-ORF3 is required for ubiquitination of TFII-I and stimulates activity of a TFII-I-repressed viral promoter during infection. This mechanism is specific to Ad species C E4-ORF3.","method":"Infection assay; SUMOylation assay; ubiquitination assay; proteasome inhibition; reporter gene assay; ectopic expression; immunofluorescence","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — multiple PTM assays, proteasome inhibition, functional promoter assay, species specificity control","pmids":["26814176"],"is_preprint":false},{"year":2014,"finding":"17β-estradiol promotes TFII-I phosphorylation via Ras-ERK1/2 signaling, leading to TFII-I nuclear localization and enhanced binding to the Grp78 promoter, resulting in Grp78 induction and protection against ER stress-induced apoptosis in osteoblasts. ERK1/2 inhibition blocks TFII-I phosphorylation.","method":"ChIP; confocal microscopy (nuclear localization); reporter gene assay; ERK1/2 inhibitor; Western blot (phospho-TFII-I)","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and nuclear translocation with kinase-pathway dissection in same study","pmids":["24933421"],"is_preprint":false},{"year":2011,"finding":"Src-induced tyrosine phosphorylation of TFII-I increases its binding to the SSeCKS/AKAP12 proximal promoter, acting as a transcriptional repressor at this locus. siRNA knockdown of TFII-I or expression of TFII-I Y248/249F mutant derepress SSeCKS in Src-transformed cells.","method":"Mass spectrometry (promoter complex identification); ChIP; siRNA knockdown; site-directed mutagenesis; reporter gene assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based identification, ChIP, mutagenesis, and KD with defined phenotype","pmids":["20568114"],"is_preprint":false},{"year":2014,"finding":"TFII-I interacts with MAPK pathway via chromatin: TFII-I binds upstream and downstream of TSS at different classes of genes (active vs. repressed). TFII-I interacts with Elongin A (pull-down assay), implicating TFII-I in transcription elongation; partial depletion of TFII-I reduces Elongin A association with DNMT1 and EFR3A without decreasing Pol II recruitment.","method":"ChIP-seq (biotinylation tagging); pull-down assay; siRNA knockdown; high-throughput sequencing","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq combined with pull-down and functional KD in same study","pmids":["24875474"],"is_preprint":false},{"year":2009,"finding":"TFII-I transcription factors bind to promoters of craniofacial development genes Cfdp1, Sec23a, and Nsd1 in vivo, as demonstrated by ChIP analysis, and siRNA knockdown validates these as direct TFII-I targets.","method":"ChIP; siRNA knockdown; bioinformatics (consensus site identification); microarray","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with siRNA functional validation in same study","pmids":["18579769"],"is_preprint":false},{"year":2017,"finding":"A GTF2I-BRAF fusion gene (GTF2I exons 1-19 fused to BRAF exon 10 onward) was identified in pilocytic astrocytoma. The GTF2I-BRAF fusion retains an intact BRAF kinase domain while losing the inhibitory N-terminal domain, leading to elevated MAPK pathway activation compared to BRAF-WT in functional assays.","method":"RNA sequencing; copy number variation analysis; functional MAPK pathway activation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — fusion identified by RNA-seq, functional MAPK activation validated in same study","pmids":["28448514"],"is_preprint":false},{"year":2020,"finding":"The GTF2I L424H mutant (thymoma-associated) induces cell transformation, aneuploidy, increased survival under metabolic stress, altered glycolytic enzyme expression, and elevated cyclooxygenase-2 expression in thymic epithelial cells. Cyclooxygenase-2 was required for the survival and transformation effects of the mutation.","method":"Gtf2i L424H knockin cell line; cell transformation assay; transcriptome analysis; metabolomics; COX-2 inhibition","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — knockin model with multiple orthogonal mechanistic readouts (transformation, aneuploidy, transcriptome, metabolomics) in one study","pmids":["32034314"],"is_preprint":false},{"year":2019,"finding":"Neuronal deletion of Gtf2i in forebrain excitatory neurons causes decreased mRNA levels of myelination genes, reduced mature oligodendrocyte numbers, reduced myelin thickness, and impaired axonal conductivity. Restoring myelination with clemastine or increasing axonal conductivity rescued behavioral deficits (increased sociability, fine motor deficits, anxiety).","method":"Conditional neuronal Cre-lox knockout; transcriptome analysis; electron microscopy (myelin thickness); electrophysiology (axonal conductivity); drug rescue (clemastine); post-mortem human cortex analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple orthogonal mechanistic readouts, drug rescue, and human tissue validation","pmids":["31011227"],"is_preprint":false},{"year":2021,"finding":"Gtf2i-β/δ isoforms bind the cis-element 5'-ATTAATAACC-3' in the ARMS2 gene locus (identified by EMSA) and their binding enhances transcription of HTRA1 in transfected cells and AMD patient-derived iPSCs.","method":"EMSA; transfection/reporter assay; iPSC-based functional assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct DNA binding demonstrated by EMSA with functional transcriptional readout in iPSCs","pmids":["33636181"],"is_preprint":false},{"year":2023,"finding":"GTF2I dosage controls neural progenitor proliferation and neuronal differentiation in cortical organoids; GTF2I duplication causes precocious excitatory neuron production (rescued by restoring GTF2I levels). GTF2I acts via LSD1 (lysine demethylase 1) as a downstream effector; LSD1 inhibition rescues ASD-like behaviors in Gtf2i-duplication transgenic mice.","method":"Patient-derived cortical organoids; single-cell transcriptomics; proteomics; Gtf2i transgenic mice; LSD1 inhibitor treatment; behavioral assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — human organoids plus transgenic mouse model, rescue with targeted pharmacological intervention defining GTF2I-LSD1 pathway","pmids":["38019906"],"is_preprint":false},{"year":2021,"finding":"GTF2I risk allele SNPs (rs73366469, rs117026326) increase GTF2I expression in salivary gland cells and enhance NF-κB p65-dependent NF-κB activation. GTF2I overexpression enhances NF-κB reporter activity dependent on its N-terminal leucine zipper domain. GTF2I knockdown suppresses inflammatory responses in mouse endothelial cells in vitro and in vivo.","method":"SNP functional analysis; reporter gene assay; siRNA knockdown; domain analysis (leucine zipper); in vivo knockdown model","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional reporter assay and in vivo knockdown","pmids":["34036345"],"is_preprint":false},{"year":2022,"finding":"Conditional knock-in of Gtf2i L424H in Foxn1+ thymic epithelial cells impairs thymic medullary development and maturation of medullary thymic epithelial cells, and causes tumor formation in aged mice. Cell cycle pathways (E2F targets, MYC targets) are enriched in tumor epithelial cells.","method":"Conditional knock-in mouse model; digital spatial profiling (GeoMx); immunohistochemistry; transcriptome analysis","journal":"Journal of thoracic oncology","confidence":"High","confidence_rationale":"Tier 2 — in vivo conditional knock-in with spatial transcriptomics and pathway-level mechanistic readouts","pmids":["36049655"],"is_preprint":false}],"current_model":"TFII-I (GTF2I) is a signal-responsive multifunctional transcription factor that, upon growth factor or stress signaling, undergoes c-Src- or ERK-dependent tyrosine phosphorylation (at Y248/Y611), translocates from cytoplasm to nucleus, and activates target genes (c-fos, cyclin D1, Grp78) via Inr/E-box elements; outside the nucleus it suppresses TRPC3-mediated calcium entry by competing with TRPC3 for PLC-γ binding; its activity is modulated by HDAC3 binding (repression), SUMO1 modification at K221/K240 (activation through reduced HDAC3 interaction, with PIAS4 as writer and SENP2 as eraser), ubiquitin-proteasomal degradation upon genotoxic stress in a p53/ATM-dependent manner, and Cdk1 phosphorylation at G2/M; in neurons, Gtf2i controls myelination gene expression and oligodendrocyte maturation via a GTF2I-LSD1 axis, and the recurrent thymoma-associated L424H mutation drives thymic epithelial cell transformation through altered transcriptome and elevated COX-2/glycolytic gene expression."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of TFII-I as an Inr-binding transcription initiation factor established a TFIIA-independent pathway for activating TATA-less promoters and revealed that Myc can antagonize this function by disrupting TBP–TFII-I–promoter complexes.","evidence":"In vitro transcription reconstitution with defined factors and protein–protein interaction analysis","pmids":["8377828","8377829"],"confidence":"High","gaps":["Crystal structure of TFII-I on Inr DNA not determined","Relative contribution of TFII-I vs. other Inr factors in vivo unknown","Mechanism by which Myc displaces TBP–TFII-I complex not resolved at atomic level"]},{"year":1998,"claim":"Demonstration that tyrosine phosphorylation is required for TFII-I transcriptional activation—but not DNA binding—separated its DNA-recognition and transactivation functions and implicated upstream kinase signaling.","evidence":"In vivo phosphorylation assay with site-directed mutagenesis and reporter gene assays","pmids":["9837922"],"confidence":"High","gaps":["Identity of the responsible kinase not yet established at this stage","Specific phosphorylation sites not mapped"]},{"year":2002,"claim":"Mapping c-Src-dependent phosphorylation to Y248 and Y611 and linking it to reversible nuclear translocation and c-fos activation defined the signal-responsive shuttling mechanism of TFII-I, while simultaneous discovery of HDAC3 as a direct repressive partner explained how TFII-I transcriptional output is restrained.","evidence":"Mutagenesis, subcellular fractionation, reporter assays, co-IP/GST pull-down/co-localization, and HDAC enzymatic assays","pmids":["11934902","12393887"],"confidence":"High","gaps":["How HDAC3 is released upon activation signals not resolved","Whether other HDACs participate is untested","Structural basis of c-Src recognition of Y248/Y611 unknown"]},{"year":2005,"claim":"Extension of TFII-I function to ER stress (Grp78 induction via c-Src/Y248) and cell cycle control (cyclin D1 activation, p53/ATM-dependent proteasomal degradation) broadened the model from a signal-responsive activator to a node linking stress and proliferation.","evidence":"ChIP, stable knockdown, ubiquitination and proteasome inhibition assays, flow cytometry, and SELEX/EMSA for I-repeat domain DNA binding","pmids":["15664986","16314517","15987678"],"confidence":"High","gaps":["E3 ubiquitin ligase mediating p53-dependent TFII-I degradation not identified","Relative importance of individual I-repeat domains for in vivo target selection unclear"]},{"year":2006,"claim":"Discovery that cytoplasmic TFII-I suppresses TRPC3-mediated calcium entry by competing with TRPC3 for PLC-γ binding established a major non-transcriptional function and connected GTF2I haploinsufficiency to the hypersociability phenotype of Williams–Beuren syndrome.","evidence":"Calcium entry assays, co-IP, domain mapping of PH-like and phosphotyrosine interactions with PLC-γ","pmids":["17023658"],"confidence":"High","gaps":["In vivo confirmation of calcium entry dysregulation in GTF2I-haploinsufficient neurons not shown","Whether other TRP channels are similarly regulated is untested"]},{"year":2006,"claim":"Interaction with Bright/ARID3a at immunoglobulin loci and control of B-cell growth arrest via NF-κB (c-rel nuclear translocation, p50 DNA binding) positioned TFII-I as a regulator of B-cell receptor signaling and differentiation.","evidence":"Co-IP with domain mapping, siRNA knockdown, reporter assays, EMSA, flow cytometry in WEHI-231 B cells","pmids":["16738337","17312101"],"confidence":"Medium","gaps":["Genome-wide B-cell targets of TFII-I not mapped","Whether TFII-I directly binds NF-κB subunits or acts indirectly unresolved"]},{"year":2009,"claim":"Identification of Cdk1 as a G2/M-phase kinase for TFII-I, causing chromatin displacement during prophase, and of craniofacial target genes (Cfdp1, Sec23a, Nsd1) expanded the cell cycle and developmental scope of TFII-I function.","evidence":"In vitro kinase assay, flow cytometry, ChIP with siRNA validation, microarray","pmids":["19182516","18579769"],"confidence":"Medium","gaps":["Cdk1 phosphorylation site(s) on TFII-I not mapped","Functional consequences of craniofacial target gene regulation in vivo not tested"]},{"year":2011,"claim":"Physical interaction with BRCA1 at irradiation-induced foci and co-activation of the SIRT1 promoter linked TFII-I to the DNA damage response transcriptional program, while Src-dependent repression of SSeCKS/AKAP12 added a repressive role at specific loci.","evidence":"Co-IP with domain mapping, immunofluorescence of nuclear foci, reporter assays, MS-based promoter complex identification, ChIP","pmids":["21407215","20568114"],"confidence":"Medium","gaps":["Whether TFII-I is required for homologous recombination not tested","Whether SSeCKS repression is relevant to Src-driven transformation in vivo unknown"]},{"year":2014,"claim":"Genome-wide ChIP-seq revealed context-dependent binding of TFII-I upstream and downstream of TSS at active versus repressed genes, and physical interaction with Elongin A implicated TFII-I in transcription elongation control; ERK-dependent phosphorylation was confirmed as another nuclear translocation trigger.","evidence":"ChIP-seq with biotinylation tagging, pull-down with Elongin A, siRNA, ChIP and confocal microscopy with ERK inhibitor","pmids":["24875474","24933421"],"confidence":"Medium","gaps":["Elongin A interaction awaits reciprocal validation and structural characterization","Distinction between Src- and ERK-phosphorylated TFII-I target gene programs not resolved"]},{"year":2015,"claim":"Site-specific mapping of SUMO1 modification at K221/K240, identification of PIAS4 as writer and SENP2 as eraser, and demonstration that SUMOylation reduces HDAC3 binding provided a mechanistic toggle that switches TFII-I between repressed and active states.","evidence":"Mass spectrometry, mutagenesis at SUMO sites, IP-Western, transcriptional and proliferation assays","pmids":["25869096"],"confidence":"High","gaps":["Structural basis of SUMO-mediated HDAC3 displacement unknown","Signal(s) that trigger SUMOylation in physiological contexts not identified"]},{"year":2016,"claim":"Adenovirus E4-ORF3 exploits the SUMO–ubiquitin axis to degrade TFII-I and derepress a viral promoter, establishing TFII-I as a host restriction factor targeted during infection.","evidence":"Infection assay, SUMOylation/ubiquitination assays, proteasome inhibition, reporter assay with species C specificity control","pmids":["26814176"],"confidence":"High","gaps":["Which E3 ubiquitin ligase is recruited by E4-ORF3 for TFII-I degradation not identified","Breadth of TFII-I antiviral restriction beyond Ad species C untested"]},{"year":2019,"claim":"Conditional neuronal knockout of Gtf2i demonstrated that TFII-I in excitatory neurons non-cell-autonomously controls oligodendrocyte maturation and myelination gene expression; drug-induced myelination rescue reversed behavioral deficits, establishing a causal GTF2I–myelination–behavior axis.","evidence":"Cre-lox conditional KO, transcriptome analysis, electron microscopy, electrophysiology, clemastine rescue, human post-mortem cortex validation","pmids":["31011227"],"confidence":"High","gaps":["Neuron-to-oligodendrocyte signaling mediator downstream of TFII-I not identified","Whether myelination defects contribute to Williams–Beuren syndrome cognitive phenotype in humans not directly shown"]},{"year":2020,"claim":"The thymoma-associated GTF2I L424H mutation was shown to be sufficient for thymic epithelial cell transformation, acting through COX-2 upregulation and altered glycolytic gene expression, and conditional knock-in in mice produced thymomas with impaired medullary development.","evidence":"Knockin cell line and conditional knock-in mouse model with transformation assays, transcriptomics, metabolomics, COX-2 inhibition, and spatial profiling","pmids":["32034314","36049655"],"confidence":"High","gaps":["How L424H alters TFII-I DNA binding or protein interactions at the structural level unknown","Whether L424H affects SUMO/ubiquitin modification not tested"]},{"year":2023,"claim":"GTF2I dosage was shown to control cortical progenitor proliferation and excitatory neuron timing through an LSD1-dependent chromatin axis; LSD1 inhibition rescued ASD-like behaviors in Gtf2i-duplication mice, defining a druggable GTF2I–LSD1 pathway.","evidence":"Patient-derived cortical organoids, single-cell transcriptomics, proteomics, transgenic mice, LSD1 inhibitor rescue, behavioral assays","pmids":["38019906"],"confidence":"High","gaps":["Whether TFII-I directly recruits LSD1 or acts indirectly through an intermediate complex unknown","LSD1 genomic targets downstream of GTF2I duplication not comprehensively mapped"]},{"year":null,"claim":"Key unresolved questions include the structural basis of TFII-I multidomain architecture on DNA, the E3 ligase mediating p53-dependent degradation, the neuron-derived signal that controls oligodendrocyte maturation, and whether the calcium entry and transcriptional functions of TFII-I are coordinately regulated in the same cell.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length TFII-I or any I-repeat–DNA complex","Integration of nuclear and cytoplasmic TFII-I functions in single-cell models not demonstrated","Comprehensive phosphoproteomics distinguishing Src- vs. ERK- vs. Cdk1-phosphorylated pools lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,13,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,6,7,15,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,10,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,6,7,14,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3,6,7,15,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,10,17,26]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[20,23,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,27]}],"complexes":[],"partners":["HDAC3","PLCG1","BRCA1","ARID3A","MYC","PIAS4","SENP2","LSD1"],"other_free_text":[]},"mechanistic_narrative":"GTF2I encodes TFII-I, a multifunctional transcription factor that integrates growth factor, stress, and cell cycle signals to regulate gene expression through initiator (Inr) and E-box elements, while also performing a cytoplasmic role in suppressing calcium entry [PMID:8377828, PMID:17023658]. In the nucleus, TFII-I activates target genes including c-fos, cyclin D1, and Grp78 following c-Src- or ERK-dependent tyrosine phosphorylation at Y248/Y611, which drives its nuclear translocation; its transcriptional output is further tuned by SUMO1 modification (written by PIAS4, erased by SENP2) that relieves HDAC3-mediated repression, by Cdk1 phosphorylation at G2/M that displaces it from condensing chromatin, and by p53/ATM-dependent ubiquitin-proteasomal degradation during genotoxic stress [PMID:11934902, PMID:25869096, PMID:19182516, PMID:16314517]. In the cytoplasm, TFII-I competes with TRPC3 channels for PLC-γ binding to suppress agonist-induced calcium entry [PMID:17023658]. In neurons, GTF2I controls myelination gene expression and oligodendrocyte maturation through an LSD1-dependent axis, and the recurrent somatic L424H mutation drives thymic epithelial cell transformation and thymoma formation in vivo [PMID:31011227, PMID:38019906, PMID:32034314, PMID:36049655]."},"prefetch_data":{"uniprot":{"accession":"P78347","full_name":"General transcription factor II-I","aliases":["Bruton tyrosine kinase-associated protein 135","BAP-135","BTK-associated protein 135","SRF-Phox1-interacting protein","SPIN","Williams-Beuren syndrome chromosomal region 6 protein"],"length_aa":998,"mass_kda":112.4,"function":"Interacts with the basal transcription machinery by coordinating the formation of a multiprotein complex at the C-FOS promoter, and linking specific signal responsive activator complexes. Promotes the formation of stable high-order complexes of SRF and PHOX1 and interacts cooperatively with PHOX1 to promote serum-inducible transcription of a reporter gene deriven by the C-FOS serum response element (SRE). Acts as a coregulator for USF1 by binding independently two promoter elements, a pyrimidine-rich initiator (Inr) and an upstream E-box. 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17312101","citation_count":17,"is_preprint":false},{"pmid":"19880526","id":"PMC_19880526","title":"Williams-Beuren syndrome-associated transcription factor TFII-I regulates osteogenic marker genes.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19880526","citation_count":17,"is_preprint":false},{"pmid":"19113768","id":"PMC_19113768","title":"Limits on anomalous spin-spin couplings between neutrons.","date":"2008","source":"Physical review letters","url":"https://pubmed.ncbi.nlm.nih.gov/19113768","citation_count":17,"is_preprint":false},{"pmid":"34036345","id":"PMC_34036345","title":"Sjögren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development.","date":"2021","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34036345","citation_count":16,"is_preprint":false},{"pmid":"36175547","id":"PMC_36175547","title":"Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36175547","citation_count":16,"is_preprint":false},{"pmid":"19111598","id":"PMC_19111598","title":"Alternative splicing and promoter use in TFII-I genes.","date":"2008","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/19111598","citation_count":16,"is_preprint":false},{"pmid":"30803761","id":"PMC_30803761","title":"Spindlin docking protein (SPIN.DOC) interaction with SPIN1 (a histone code reader) regulates Wnt signaling.","date":"2019","source":"Biochemical and biophysical research 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33636181","citation_count":15,"is_preprint":false},{"pmid":"26589175","id":"PMC_26589175","title":"Quantum Mechanical Study of Vicinal J Spin-Spin Coupling Constants for the Protein Backbone.","date":"2013","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/26589175","citation_count":15,"is_preprint":false},{"pmid":"22628223","id":"PMC_22628223","title":"Epigenetic modulation by TFII-I during embryonic stem cell differentiation.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22628223","citation_count":14,"is_preprint":false},{"pmid":"29568691","id":"PMC_29568691","title":"Consistent hypersocial behavior in mice carrying a deletion of Gtf2i but no evidence of hyposocial behavior with Gtf2i duplication: Implications for Williams-Beuren syndrome and autism spectrum disorder.","date":"2017","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/29568691","citation_count":14,"is_preprint":false},{"pmid":"15169256","id":"PMC_15169256","title":"Spin anisotropy and slow dynamics in spin glasses.","date":"2004","source":"Physical review letters","url":"https://pubmed.ncbi.nlm.nih.gov/15169256","citation_count":14,"is_preprint":false},{"pmid":"20568114","id":"PMC_20568114","title":"Role for transcription factor TFII-I in the suppression of SSeCKS/Gravin/Akap12 transcription by Src.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20568114","citation_count":14,"is_preprint":false},{"pmid":"21104762","id":"PMC_21104762","title":"Trivinylphosphine and trivinylphosphine chalcogenides: stereochemical trends of ³¹P-¹H spin-spin coupling constants.","date":"2010","source":"Magnetic resonance in chemistry : MRC","url":"https://pubmed.ncbi.nlm.nih.gov/21104762","citation_count":14,"is_preprint":false},{"pmid":"19527686","id":"PMC_19527686","title":"New TFII-I family target genes involved in embryonic development.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19527686","citation_count":13,"is_preprint":false},{"pmid":"33735563","id":"PMC_33735563","title":"Interaction of Photogenerated Spin Qubit Pairs with a Third Electron Spin in DNA Hairpins.","date":"2021","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/33735563","citation_count":13,"is_preprint":false},{"pmid":"23145914","id":"PMC_23145914","title":"ChIP-Chip Identifies SEC23A, CFDP1, and NSD1 as TFII-I Target Genes in Human Neural Crest Progenitor Cells.","date":"2012","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial 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TFII-I and TBP bind cooperatively to Inr-containing TATA-less promoters.\",\n      \"method\": \"In vitro transcription reconstitution assay; preinitiation complex formation analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro transcription with defined factors, published in two companion papers\",\n      \"pmids\": [\"8377828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Myc physically interacts with TFII-I and cooperatively binds Inr and E-box elements; however, Myc-TFII-I interaction at the Inr inhibits transcription initiation by preventing complex formation between TBP (TFIID), TFII-I, and the promoter.\",\n      \"method\": \"In vitro transcription assay; protein-protein interaction; complex formation analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with functional readout and mechanistic dissection\",\n      \"pmids\": [\"8377829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TFII-I is phosphorylated in vivo at serine/threonine and tyrosine residues; tyrosine phosphorylation is critical for its transcriptional activation activity (via the Vbeta promoter), but not required for specific DNA binding. Mutation of a consensus tyrosine phosphorylation site severely reduces transcriptional activation in vivo.\",\n      \"method\": \"In vivo phosphorylation assay; site-directed mutagenesis; in vitro transcription; reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with in vitro and in vivo transcription assays\",\n      \"pmids\": [\"9837922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TFII-I undergoes c-Src-dependent tyrosine phosphorylation at tyrosine residues 248 and 611 and reversibly translocates to the nucleus in response to growth factor signaling; nuclear tyrosine-phosphorylated TFII-I activates the c-fos reporter gene. Phosphorylation-deficient mutants fail to activate c-fos.\",\n      \"method\": \"Tyrosine phosphorylation assay; subcellular fractionation/nuclear translocation; reporter gene assay; site-directed mutagenesis; antibody microinjection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis, translocation imaging, and functional reporter assay combined\",\n      \"pmids\": [\"11934902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HDAC3 physically interacts with TFII-I (confirmed by co-immunoprecipitation, GST pull-down, and co-localization). The HDAC3 C-terminus (residues 373-401) and TFII-I residues 363-606 are required for the interaction. An anti-TFII-I immunoprecipitate contains histone deacetylase activity, and HDAC3 overexpression severely reduces TFII-I transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation; GST pull-down; immunofluorescence co-localization; HDAC enzyme assay; mutational analysis; transcriptional activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in one study with domain mapping\",\n      \"pmids\": [\"12393887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Miz1/PIASxbeta/Siz2 (a SUMO E3 ligase) interacts with TFII-I and augments its transcriptional activity; it also interacts with hMusTRD1/BEN. Co-expression of a nuclear-localization-deficient mutant of Miz1 fails to alter TFII-I subcellular localization, and Miz1 relieves repression exerted by nuclear hMusTRD1/BEN on TFII-I.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; transcriptional activity assay; subcellular localization analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and functional reporter assay in single lab, yeast two-hybrid initial identification\",\n      \"pmids\": [\"12193603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TFII-I is activated by ER stress via c-Src-dependent tyrosine phosphorylation at Tyr248, leading to nuclear translocation and binding to the Grp78/BiP promoter ER stress element. TFII-I is required for optimal ER stress induction of Grp78; c-Src is activated by ER stress (thapsigargin) and stimulates Grp78 promoter activity via TFII-I.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); nuclear translocation (fractionation); stable knockdown cell lines; tyrosine phosphorylation assay; reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, stable KD with defined phenotype, and phosphorylation mapping in one study\",\n      \"pmids\": [\"15664986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TFII-I directly activates the cyclin D1 promoter under normal growth conditions and is recruited to it by ChIP. Upon genotoxic stress and p53 activation, TFII-I is ubiquitinated and degraded by the proteasome in a p53- and ATM-dependent manner. Stable expression of TFII-I accelerates S-phase entry and exit, and overcomes p53-mediated cell cycle arrest. Tyrosine phosphorylation at Y248 and Y611 is required for these cell cycle functions.\",\n      \"method\": \"ChIP; ubiquitination assay; proteasome inhibition; flow cytometry; stable overexpression/knockdown; site-directed mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods; ChIP, mutagenesis, proteasome assay, cell cycle analysis\",\n      \"pmids\": [\"16314517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TFII-I acts outside the nucleus as a negative regulator of agonist-induced calcium entry (ACE) by suppressing surface accumulation of TRPC3 channels. TFII-I inhibits ACE via phosphotyrosine residues engaging the SH2 domains of PLC-γ and via an interrupted PH-like domain binding the split PH domain of PLC-γ, competing with TRPC3 for PLC-γ binding.\",\n      \"method\": \"Calcium entry assay; co-immunoprecipitation; domain mapping; cytoplasmic localization experiments; surface TRPC3 accumulation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping, co-IP, and functional calcium entry assay with defined mechanism\",\n      \"pmids\": [\"17023658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TFII-I directly interacts with the ARID-family transcription factor Bright/ARID3a through Bright's protein interaction domain; specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. TFII-I inhibition in B cells decreases heavy-chain transcript levels.\",\n      \"method\": \"Co-immunoprecipitation; reporter gene assay; siRNA knockdown; domain mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping and functional reporter assay in same study\",\n      \"pmids\": [\"16738337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of TFII-I function in WEHI-231 B cells (stable knockdown) prevents growth arrest upon anti-IgM or TGF-β signaling, associated with upregulation of c-Myc and downregulation of p21/p27. TFII-I controls NF-κB by regulating nuclear translocation of c-rel and DNA-binding activity of p50 homodimer.\",\n      \"method\": \"Stable siRNA knockdown; flow cytometry; Western blot; EMSA; immunofluorescence\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — stable KD with defined signaling and transcriptional phenotype, multiple readouts\",\n      \"pmids\": [\"17312101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFII-I silencing causes significant delay in S-phase entry and progression and G2/M entry, without major mitotic defects. Cyclin D1 and PKC-β are identified as major downstream transcriptional targets. Cdk1 phosphorylates TFII-I at the G2/M boundary, leading to its displacement from condensed chromatin during prophase to pro-metaphase transition.\",\n      \"method\": \"siRNA knockdown; flow cytometry; microarray; ChIP; Cdk1 kinase assay; functional validation\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with flow cytometry and in vitro kinase assay, microarray plus functional validation\",\n      \"pmids\": [\"19182516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFII-I binds the Grp78 promoter and upregulates GRP78 transcription in prostate cancer cells stimulated with α2-macroglobulin (α2M*). α2M* induces tyrosine phosphorylation of c-Src and TFII-I, and TFII-I relocalizes to the nucleus. TFII-I also binds the c-fos promoter in these cells.\",\n      \"method\": \"ChIP; confocal microscopy (nuclear translocation); radiolabeled amino acid incorporation; siRNA knockdown; tyrosine phosphorylation assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and nuclear translocation with functional readout in same study\",\n      \"pmids\": [\"19097122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GTF2I-like repeats 4 and 6 of TFII-I exhibit DNA binding properties in vitro, supporting the idea that GTF2I-like (I-repeat) domains serve as a common DNA-binding module.\",\n      \"method\": \"SELEX; EMSA; domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro SELEX and EMSA with I-repeat domains, single lab\",\n      \"pmids\": [\"15987678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TFII-I physically interacts with BRCA1 (C-terminus of TFII-I with the BRCT domain of BRCA1) in the nucleus; TFII-I enhances BRCA1-mediated transcriptional activation of the SIRT1 promoter and stimulates BRCA1 transactivation function. Both proteins co-localize in irradiation-induced nuclear foci.\",\n      \"method\": \"Co-immunoprecipitation; reporter gene assay; immunofluorescence (nuclear foci); domain mapping\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with domain mapping, nuclear foci, and functional reporter assay in same study\",\n      \"pmids\": [\"21407215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TFII-I is SUMOylated at K221 and K240 by SUMO1; PIAS4 is the E3 ligase responsible for TFII-I SUMOylation, and SENP2 is the SUMO protease (deSUMOylase) for TFII-I. SUMOylation reduces TFII-I binding to its repressor HDAC3, thus promoting TFII-I transcriptional activity and cell proliferation/colony formation.\",\n      \"method\": \"Large-scale proteomics/mass spectrometry; immunoprecipitation-Western blot; mutagenesis at SUMO sites; functional transcriptional assays; proliferation assays\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific SUMO modification mapped with mutagenesis, writer/eraser identified, functional consequence demonstrated\",\n      \"pmids\": [\"25869096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adenovirus E4-ORF3 stimulates SUMOylation and subsequent ubiquitination of TFII-I, leading to its proteasomal degradation. E4-ORF3 is required for ubiquitination of TFII-I and stimulates activity of a TFII-I-repressed viral promoter during infection. This mechanism is specific to Ad species C E4-ORF3.\",\n      \"method\": \"Infection assay; SUMOylation assay; ubiquitination assay; proteasome inhibition; reporter gene assay; ectopic expression; immunofluorescence\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple PTM assays, proteasome inhibition, functional promoter assay, species specificity control\",\n      \"pmids\": [\"26814176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"17β-estradiol promotes TFII-I phosphorylation via Ras-ERK1/2 signaling, leading to TFII-I nuclear localization and enhanced binding to the Grp78 promoter, resulting in Grp78 induction and protection against ER stress-induced apoptosis in osteoblasts. ERK1/2 inhibition blocks TFII-I phosphorylation.\",\n      \"method\": \"ChIP; confocal microscopy (nuclear localization); reporter gene assay; ERK1/2 inhibitor; Western blot (phospho-TFII-I)\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and nuclear translocation with kinase-pathway dissection in same study\",\n      \"pmids\": [\"24933421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Src-induced tyrosine phosphorylation of TFII-I increases its binding to the SSeCKS/AKAP12 proximal promoter, acting as a transcriptional repressor at this locus. siRNA knockdown of TFII-I or expression of TFII-I Y248/249F mutant derepress SSeCKS in Src-transformed cells.\",\n      \"method\": \"Mass spectrometry (promoter complex identification); ChIP; siRNA knockdown; site-directed mutagenesis; reporter gene assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based identification, ChIP, mutagenesis, and KD with defined phenotype\",\n      \"pmids\": [\"20568114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TFII-I interacts with MAPK pathway via chromatin: TFII-I binds upstream and downstream of TSS at different classes of genes (active vs. repressed). TFII-I interacts with Elongin A (pull-down assay), implicating TFII-I in transcription elongation; partial depletion of TFII-I reduces Elongin A association with DNMT1 and EFR3A without decreasing Pol II recruitment.\",\n      \"method\": \"ChIP-seq (biotinylation tagging); pull-down assay; siRNA knockdown; high-throughput sequencing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq combined with pull-down and functional KD in same study\",\n      \"pmids\": [\"24875474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFII-I transcription factors bind to promoters of craniofacial development genes Cfdp1, Sec23a, and Nsd1 in vivo, as demonstrated by ChIP analysis, and siRNA knockdown validates these as direct TFII-I targets.\",\n      \"method\": \"ChIP; siRNA knockdown; bioinformatics (consensus site identification); microarray\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with siRNA functional validation in same study\",\n      \"pmids\": [\"18579769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A GTF2I-BRAF fusion gene (GTF2I exons 1-19 fused to BRAF exon 10 onward) was identified in pilocytic astrocytoma. The GTF2I-BRAF fusion retains an intact BRAF kinase domain while losing the inhibitory N-terminal domain, leading to elevated MAPK pathway activation compared to BRAF-WT in functional assays.\",\n      \"method\": \"RNA sequencing; copy number variation analysis; functional MAPK pathway activation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fusion identified by RNA-seq, functional MAPK activation validated in same study\",\n      \"pmids\": [\"28448514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GTF2I L424H mutant (thymoma-associated) induces cell transformation, aneuploidy, increased survival under metabolic stress, altered glycolytic enzyme expression, and elevated cyclooxygenase-2 expression in thymic epithelial cells. Cyclooxygenase-2 was required for the survival and transformation effects of the mutation.\",\n      \"method\": \"Gtf2i L424H knockin cell line; cell transformation assay; transcriptome analysis; metabolomics; COX-2 inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockin model with multiple orthogonal mechanistic readouts (transformation, aneuploidy, transcriptome, metabolomics) in one study\",\n      \"pmids\": [\"32034314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neuronal deletion of Gtf2i in forebrain excitatory neurons causes decreased mRNA levels of myelination genes, reduced mature oligodendrocyte numbers, reduced myelin thickness, and impaired axonal conductivity. Restoring myelination with clemastine or increasing axonal conductivity rescued behavioral deficits (increased sociability, fine motor deficits, anxiety).\",\n      \"method\": \"Conditional neuronal Cre-lox knockout; transcriptome analysis; electron microscopy (myelin thickness); electrophysiology (axonal conductivity); drug rescue (clemastine); post-mortem human cortex analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple orthogonal mechanistic readouts, drug rescue, and human tissue validation\",\n      \"pmids\": [\"31011227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gtf2i-β/δ isoforms bind the cis-element 5'-ATTAATAACC-3' in the ARMS2 gene locus (identified by EMSA) and their binding enhances transcription of HTRA1 in transfected cells and AMD patient-derived iPSCs.\",\n      \"method\": \"EMSA; transfection/reporter assay; iPSC-based functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct DNA binding demonstrated by EMSA with functional transcriptional readout in iPSCs\",\n      \"pmids\": [\"33636181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GTF2I dosage controls neural progenitor proliferation and neuronal differentiation in cortical organoids; GTF2I duplication causes precocious excitatory neuron production (rescued by restoring GTF2I levels). GTF2I acts via LSD1 (lysine demethylase 1) as a downstream effector; LSD1 inhibition rescues ASD-like behaviors in Gtf2i-duplication transgenic mice.\",\n      \"method\": \"Patient-derived cortical organoids; single-cell transcriptomics; proteomics; Gtf2i transgenic mice; LSD1 inhibitor treatment; behavioral assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human organoids plus transgenic mouse model, rescue with targeted pharmacological intervention defining GTF2I-LSD1 pathway\",\n      \"pmids\": [\"38019906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GTF2I risk allele SNPs (rs73366469, rs117026326) increase GTF2I expression in salivary gland cells and enhance NF-κB p65-dependent NF-κB activation. GTF2I overexpression enhances NF-κB reporter activity dependent on its N-terminal leucine zipper domain. GTF2I knockdown suppresses inflammatory responses in mouse endothelial cells in vitro and in vivo.\",\n      \"method\": \"SNP functional analysis; reporter gene assay; siRNA knockdown; domain analysis (leucine zipper); in vivo knockdown model\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional reporter assay and in vivo knockdown\",\n      \"pmids\": [\"34036345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knock-in of Gtf2i L424H in Foxn1+ thymic epithelial cells impairs thymic medullary development and maturation of medullary thymic epithelial cells, and causes tumor formation in aged mice. Cell cycle pathways (E2F targets, MYC targets) are enriched in tumor epithelial cells.\",\n      \"method\": \"Conditional knock-in mouse model; digital spatial profiling (GeoMx); immunohistochemistry; transcriptome analysis\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional knock-in with spatial transcriptomics and pathway-level mechanistic readouts\",\n      \"pmids\": [\"36049655\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TFII-I (GTF2I) is a signal-responsive multifunctional transcription factor that, upon growth factor or stress signaling, undergoes c-Src- or ERK-dependent tyrosine phosphorylation (at Y248/Y611), translocates from cytoplasm to nucleus, and activates target genes (c-fos, cyclin D1, Grp78) via Inr/E-box elements; outside the nucleus it suppresses TRPC3-mediated calcium entry by competing with TRPC3 for PLC-γ binding; its activity is modulated by HDAC3 binding (repression), SUMO1 modification at K221/K240 (activation through reduced HDAC3 interaction, with PIAS4 as writer and SENP2 as eraser), ubiquitin-proteasomal degradation upon genotoxic stress in a p53/ATM-dependent manner, and Cdk1 phosphorylation at G2/M; in neurons, Gtf2i controls myelination gene expression and oligodendrocyte maturation via a GTF2I-LSD1 axis, and the recurrent thymoma-associated L424H mutation drives thymic epithelial cell transformation through altered transcriptome and elevated COX-2/glycolytic gene expression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GTF2I encodes TFII-I, a multifunctional transcription factor that integrates growth factor, stress, and cell cycle signals to regulate gene expression through initiator (Inr) and E-box elements, while also performing a cytoplasmic role in suppressing calcium entry [PMID:8377828, PMID:17023658]. In the nucleus, TFII-I activates target genes including c-fos, cyclin D1, and Grp78 following c-Src- or ERK-dependent tyrosine phosphorylation at Y248/Y611, which drives its nuclear translocation; its transcriptional output is further tuned by SUMO1 modification (written by PIAS4, erased by SENP2) that relieves HDAC3-mediated repression, by Cdk1 phosphorylation at G2/M that displaces it from condensing chromatin, and by p53/ATM-dependent ubiquitin-proteasomal degradation during genotoxic stress [PMID:11934902, PMID:25869096, PMID:19182516, PMID:16314517]. In the cytoplasm, TFII-I competes with TRPC3 channels for PLC-γ binding to suppress agonist-induced calcium entry [PMID:17023658]. In neurons, GTF2I controls myelination gene expression and oligodendrocyte maturation through an LSD1-dependent axis, and the recurrent somatic L424H mutation drives thymic epithelial cell transformation and thymoma formation in vivo [PMID:31011227, PMID:38019906, PMID:32034314, PMID:36049655].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of TFII-I as an Inr-binding transcription initiation factor established a TFIIA-independent pathway for activating TATA-less promoters and revealed that Myc can antagonize this function by disrupting TBP–TFII-I–promoter complexes.\",\n      \"evidence\": \"In vitro transcription reconstitution with defined factors and protein–protein interaction analysis\",\n      \"pmids\": [\"8377828\", \"8377829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of TFII-I on Inr DNA not determined\", \"Relative contribution of TFII-I vs. other Inr factors in vivo unknown\", \"Mechanism by which Myc displaces TBP–TFII-I complex not resolved at atomic level\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that tyrosine phosphorylation is required for TFII-I transcriptional activation—but not DNA binding—separated its DNA-recognition and transactivation functions and implicated upstream kinase signaling.\",\n      \"evidence\": \"In vivo phosphorylation assay with site-directed mutagenesis and reporter gene assays\",\n      \"pmids\": [\"9837922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible kinase not yet established at this stage\", \"Specific phosphorylation sites not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping c-Src-dependent phosphorylation to Y248 and Y611 and linking it to reversible nuclear translocation and c-fos activation defined the signal-responsive shuttling mechanism of TFII-I, while simultaneous discovery of HDAC3 as a direct repressive partner explained how TFII-I transcriptional output is restrained.\",\n      \"evidence\": \"Mutagenesis, subcellular fractionation, reporter assays, co-IP/GST pull-down/co-localization, and HDAC enzymatic assays\",\n      \"pmids\": [\"11934902\", \"12393887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HDAC3 is released upon activation signals not resolved\", \"Whether other HDACs participate is untested\", \"Structural basis of c-Src recognition of Y248/Y611 unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extension of TFII-I function to ER stress (Grp78 induction via c-Src/Y248) and cell cycle control (cyclin D1 activation, p53/ATM-dependent proteasomal degradation) broadened the model from a signal-responsive activator to a node linking stress and proliferation.\",\n      \"evidence\": \"ChIP, stable knockdown, ubiquitination and proteasome inhibition assays, flow cytometry, and SELEX/EMSA for I-repeat domain DNA binding\",\n      \"pmids\": [\"15664986\", \"16314517\", \"15987678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase mediating p53-dependent TFII-I degradation not identified\", \"Relative importance of individual I-repeat domains for in vivo target selection unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that cytoplasmic TFII-I suppresses TRPC3-mediated calcium entry by competing with TRPC3 for PLC-γ binding established a major non-transcriptional function and connected GTF2I haploinsufficiency to the hypersociability phenotype of Williams–Beuren syndrome.\",\n      \"evidence\": \"Calcium entry assays, co-IP, domain mapping of PH-like and phosphotyrosine interactions with PLC-γ\",\n      \"pmids\": [\"17023658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of calcium entry dysregulation in GTF2I-haploinsufficient neurons not shown\", \"Whether other TRP channels are similarly regulated is untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Interaction with Bright/ARID3a at immunoglobulin loci and control of B-cell growth arrest via NF-κB (c-rel nuclear translocation, p50 DNA binding) positioned TFII-I as a regulator of B-cell receptor signaling and differentiation.\",\n      \"evidence\": \"Co-IP with domain mapping, siRNA knockdown, reporter assays, EMSA, flow cytometry in WEHI-231 B cells\",\n      \"pmids\": [\"16738337\", \"17312101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide B-cell targets of TFII-I not mapped\", \"Whether TFII-I directly binds NF-κB subunits or acts indirectly unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of Cdk1 as a G2/M-phase kinase for TFII-I, causing chromatin displacement during prophase, and of craniofacial target genes (Cfdp1, Sec23a, Nsd1) expanded the cell cycle and developmental scope of TFII-I function.\",\n      \"evidence\": \"In vitro kinase assay, flow cytometry, ChIP with siRNA validation, microarray\",\n      \"pmids\": [\"19182516\", \"18579769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cdk1 phosphorylation site(s) on TFII-I not mapped\", \"Functional consequences of craniofacial target gene regulation in vivo not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Physical interaction with BRCA1 at irradiation-induced foci and co-activation of the SIRT1 promoter linked TFII-I to the DNA damage response transcriptional program, while Src-dependent repression of SSeCKS/AKAP12 added a repressive role at specific loci.\",\n      \"evidence\": \"Co-IP with domain mapping, immunofluorescence of nuclear foci, reporter assays, MS-based promoter complex identification, ChIP\",\n      \"pmids\": [\"21407215\", \"20568114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TFII-I is required for homologous recombination not tested\", \"Whether SSeCKS repression is relevant to Src-driven transformation in vivo unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide ChIP-seq revealed context-dependent binding of TFII-I upstream and downstream of TSS at active versus repressed genes, and physical interaction with Elongin A implicated TFII-I in transcription elongation control; ERK-dependent phosphorylation was confirmed as another nuclear translocation trigger.\",\n      \"evidence\": \"ChIP-seq with biotinylation tagging, pull-down with Elongin A, siRNA, ChIP and confocal microscopy with ERK inhibitor\",\n      \"pmids\": [\"24875474\", \"24933421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Elongin A interaction awaits reciprocal validation and structural characterization\", \"Distinction between Src- and ERK-phosphorylated TFII-I target gene programs not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Site-specific mapping of SUMO1 modification at K221/K240, identification of PIAS4 as writer and SENP2 as eraser, and demonstration that SUMOylation reduces HDAC3 binding provided a mechanistic toggle that switches TFII-I between repressed and active states.\",\n      \"evidence\": \"Mass spectrometry, mutagenesis at SUMO sites, IP-Western, transcriptional and proliferation assays\",\n      \"pmids\": [\"25869096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SUMO-mediated HDAC3 displacement unknown\", \"Signal(s) that trigger SUMOylation in physiological contexts not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Adenovirus E4-ORF3 exploits the SUMO–ubiquitin axis to degrade TFII-I and derepress a viral promoter, establishing TFII-I as a host restriction factor targeted during infection.\",\n      \"evidence\": \"Infection assay, SUMOylation/ubiquitination assays, proteasome inhibition, reporter assay with species C specificity control\",\n      \"pmids\": [\"26814176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which E3 ubiquitin ligase is recruited by E4-ORF3 for TFII-I degradation not identified\", \"Breadth of TFII-I antiviral restriction beyond Ad species C untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional neuronal knockout of Gtf2i demonstrated that TFII-I in excitatory neurons non-cell-autonomously controls oligodendrocyte maturation and myelination gene expression; drug-induced myelination rescue reversed behavioral deficits, establishing a causal GTF2I–myelination–behavior axis.\",\n      \"evidence\": \"Cre-lox conditional KO, transcriptome analysis, electron microscopy, electrophysiology, clemastine rescue, human post-mortem cortex validation\",\n      \"pmids\": [\"31011227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuron-to-oligodendrocyte signaling mediator downstream of TFII-I not identified\", \"Whether myelination defects contribute to Williams–Beuren syndrome cognitive phenotype in humans not directly shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The thymoma-associated GTF2I L424H mutation was shown to be sufficient for thymic epithelial cell transformation, acting through COX-2 upregulation and altered glycolytic gene expression, and conditional knock-in in mice produced thymomas with impaired medullary development.\",\n      \"evidence\": \"Knockin cell line and conditional knock-in mouse model with transformation assays, transcriptomics, metabolomics, COX-2 inhibition, and spatial profiling\",\n      \"pmids\": [\"32034314\", \"36049655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How L424H alters TFII-I DNA binding or protein interactions at the structural level unknown\", \"Whether L424H affects SUMO/ubiquitin modification not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"GTF2I dosage was shown to control cortical progenitor proliferation and excitatory neuron timing through an LSD1-dependent chromatin axis; LSD1 inhibition rescued ASD-like behaviors in Gtf2i-duplication mice, defining a druggable GTF2I–LSD1 pathway.\",\n      \"evidence\": \"Patient-derived cortical organoids, single-cell transcriptomics, proteomics, transgenic mice, LSD1 inhibitor rescue, behavioral assays\",\n      \"pmids\": [\"38019906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TFII-I directly recruits LSD1 or acts indirectly through an intermediate complex unknown\", \"LSD1 genomic targets downstream of GTF2I duplication not comprehensively mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of TFII-I multidomain architecture on DNA, the E3 ligase mediating p53-dependent degradation, the neuron-derived signal that controls oligodendrocyte maturation, and whether the calcium entry and transcriptional functions of TFII-I are coordinately regulated in the same cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length TFII-I or any I-repeat–DNA complex\", \"Integration of nuclear and cytoplasmic TFII-I functions in single-cell models not demonstrated\", \"Comprehensive phosphoproteomics distinguishing Src- vs. ERK- vs. Cdk1-phosphorylated pools lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 13, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 15, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 10, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6, 7, 14, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 15, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 10, 17, 26]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [20, 23, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HDAC3\", \"PLCG1\", \"BRCA1\", \"ARID3A\", \"MYC\", \"PIAS4\", \"SENP2\", \"LSD1\"],\n    \"other_free_text\": []\n  }\n}\n```"}