{"gene":"FLI1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"Human FLI1 encodes a 452-residue protein with two ETS homology domains: a 3'-ETS domain responsible for sequence-specific DNA binding (shared by all ETS family members) and a 5'-ETS homology region conserved only in FLI1, c-ets-1, ets-2, GABP-alpha, and ERG, suggesting a shared biological function among this subset.","method":"cDNA cloning, nucleotide sequence analysis, structural domain mapping","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural characterization from primary cloning paper, single lab, sequence analysis only","pmids":["1394211"],"is_preprint":false},{"year":1993,"finding":"FLI-1 functions as a sequence-specific transcriptional activator with two autonomous transcriptional activation domains (one N-terminal, one C-terminal). In the EWS-FLI1 fusion, the EWS domain acts as a modulatory/regulatory domain that activates the C-terminal transcriptional activation domain of FLI1, making EWS-FLI1 a transcriptional activator stronger than wild-type FLI1.","method":"Deletion analysis, transcriptional activation assays in cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional deletion mapping with transcriptional assays, single lab but multiple constructs tested","pmids":["7503813"],"is_preprint":false},{"year":1994,"finding":"The ETS domain of FLI1 is necessary and sufficient for sequence-specific DNA binding, with a consensus binding sequence of ACCGGAAG/aT/c, showing greater specificity 5' of the GGAA core than other ETS proteins. EWS-FLI1 displays the same DNA binding specificity and affinity as wild-type FLI1.","method":"Epitope-tagging and SELEX-like binding site selection, truncation analysis, in vitro DNA binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA binding with systematic truncation mutagenesis, replicated across constructs in single study","pmids":["7517940"],"is_preprint":false},{"year":1996,"finding":"Unlike wild-type FLI1, EWS-FLI1 can form a ternary complex on the c-fos serum response element (SRE) and binds DNA at this site without requiring SRF. Both FLI1 and EWS-FLI1 interact directly with SRF in vitro in the absence of DNA. Deletion of the N-terminal region of FLI1 (normally an inhibitory domain) converts it to behave like EWS-FLI1 with respect to SRE binding.","method":"EMSA, GST pull-down assay, deletion analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding and pull-down with mutagenesis, single lab","pmids":["8604338"],"is_preprint":false},{"year":1999,"finding":"FLI-1 overexpression in primary erythroblasts inhibits Epo-induced terminal differentiation, inhibits apoptosis following Epo withdrawal, and induces proliferation. Enhanced survival correlates with FLI-1-driven upregulation of BCL-2 and prevention of cyclin D2/D3 downregulation during differentiation.","method":"Retroviral transduction of primary avian erythroblasts, differentiation/proliferation assays, gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary cell system with multiple phenotypic readouts, single lab","pmids":["10102630"],"is_preprint":false},{"year":2000,"finding":"Fli-1 null mice die at embryonic day 11.5 with loss of vascular integrity causing cerebral meningeal bleeding and specific downregulation of Tek/Tie-2 (angiopoietin-1 receptor), demonstrating a required role for Fli-1 in vascular development. Fli-1 null embryos also exhibit dysmegakaryopoiesis resembling Jacobsen/Paris-Trousseau syndrome.","method":"Targeted null mutation (knockout mouse), histology, gene expression analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with specific molecular and cellular phenotypes, published in high-impact journal","pmids":["10981960"],"is_preprint":false},{"year":2001,"finding":"FLI-1 inhibits COL1A2 (collagen alpha2(I)) promoter activity and collagen production in dermal fibroblasts through both direct DNA binding at a critical ETS site and indirect mechanisms via protein-protein interaction with Sp1. Fli-1 and Ets-1 compete for the same COL1A2 promoter site with opposing effects (Fli-1 inhibits; Ets-1 stimulates).","method":"Stable transfection, in vitro DNA binding (EMSA), promoter deletion/mutation analysis, Gal4 reporter assays, dominant-negative and DNA-binding mutant constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including EMSA, mutagenesis, and reporter assays in multiple cell types","pmids":["11278621"],"is_preprint":false},{"year":2002,"finding":"FLI-1 directly binds to specific ETS binding sites in the BCL-2 promoter in transformed erythroblasts and transactivates BCL-2 expression. The ability of FLI-1 mutants to transactivate BCL-2 correlates with their ability to inhibit apoptosis. BCL-2 is an in vivo target gene of FLI-1 required for survival of FLI-1-transformed erythroblasts.","method":"ChIP, in vitro binding assays, FLI-1 deletion/point mutants, promoter reporter assays, BCL-2 inhibitor studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP confirming in vivo binding, corroborated by mutagenesis and functional rescue experiments","pmids":["11847117"],"is_preprint":false},{"year":2002,"finding":"Ets-1 directly activates transcription from the fli-1 gene promoter by binding to ETS binding sites including a third site unique to Ets-1 (not used by Spi-1). Endogenous Fli-1 also binds its own promoter and promotes auto-regulatory transcription, establishing a positive feedback loop of Fli-1 expression in endothelial cells.","method":"Promoter deletion/mutation analysis, transient transfection reporter assays, ChIP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays in endothelial cells, single lab, two orthogonal methods","pmids":["11991951"],"is_preprint":false},{"year":2003,"finding":"FLI-1 represses EKLF-dependent transcription (including the beta-globin promoter) by two mechanisms: (1) direct repression activity of the ETS DNA-binding domain (which behaves as an autonomous repression domain when fused to Gal4-DBD), and (2) indirect recruitment to erythroid promoters via protein-protein interaction with EKLF. FLI-1 also interacts with GATA-1, enhancing GATA-1 activity rather than repressing it. Reciprocally, EKLF represses FLI-1-dependent megakaryocytic GPIX promoter activity, suggesting cross-antagonism controls erythroid vs. megakaryocytic fate.","method":"Co-immunoprecipitation, Gal4 fusion reporter assays, promoter reporter assays, domain mapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, Gal4 domain analysis, multiple promoter assays across cell types, single lab with multiple orthogonal methods","pmids":["12556498"],"is_preprint":false},{"year":2003,"finding":"EWS-FLI1 self-associates and can interact with both germline EWS and wild-type FLI1. Self-association of EWS-FLI1 is mediated by its C-terminal FLI1 DNA-binding motif and is RNA-independent. The EWS N-terminal domain mediates homotypic and heterotypic interactions of EWS and EWS-FLI1. Despite oligomerization capacity, EWS-FLI1 binds a tandem ETS-binding site as a monomer.","method":"FRET, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, RNase A treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — four orthogonal methods (FRET, M2H, GST pull-down, co-IP) in single study","pmids":["14534527"],"is_preprint":false},{"year":2004,"finding":"EWS-FLI1 and FLI-1 interact with CBP (CREB-binding protein) through their amino-terminal region and inhibit CBP-dependent transcriptional activity of RXR. This antiapoptotic activity is independent of the DNA-binding activity of EWS-FLI1/FLI-1. Dominant-negative CBP sensitizes Ewing sarcoma cells to apoptosis.","method":"Co-immunoprecipitation, transcriptional reporter assays, dominant-negative CBP expression, apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional assays, single lab, two orthogonal methods","pmids":["15273724"],"is_preprint":false},{"year":2005,"finding":"Fli1, Elf1, and Ets1 directly bind to three conserved ETS sites in the LMO2 proximal promoter and activate its transcription in hematopoietic progenitor and endothelial cells. In vivo, the LMO2 proximal promoter is sufficient for endothelial but not hematopoietic expression in transgenic mice.","method":"ChIP, transient/stable transfection reporter assays, transgenic mouse analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with in vivo transgenic validation, single lab","pmids":["15994290"],"is_preprint":false},{"year":2006,"finding":"RNA helicase A (RHA) binds directly to EWS-FLI1 (specifically to RHA amino acids 630-1020 containing the region identified by phage display). Endogenous RHA forms a protein complex with EWS-FLI1 in ESFT cells; both co-occupy EWS-FLI1 target gene promoters by ChIP. RHA stimulates transcriptional activity of EWS-FLI1 regulated promoters including Id2 and enhances anchorage-independent growth of EWS-FLI1-expressing cells.","method":"Phage display, GST pull-down, ELISA, co-immunoprecipitation, ChIP, transcriptional reporter assays, anchorage-independent growth assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (phage display, GST pull-down, co-IP, ChIP, functional assays) in single study","pmids":["16740692"],"is_preprint":false},{"year":2007,"finding":"Gata2, Fli1, and Scl/Tal1 form a recursively wired gene-regulatory circuit during hematopoiesis. All three transcription factors bind to each other's enhancers (Gata2-3, Fli1+12, Scl+19) in embryonic hematopoietic tissues, forming a fully connected triad. The Fli1+12 enhancer relies on a combination of Ets, Gata, and E-Box motifs and targets hematopoietic stem cells.","method":"ChIP, enhancer reporter assays, transgenic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirmed binding at all three enhancers in multiple tissue types plus transgenic validation, single lab with multiple orthogonal methods","pmids":["17962413"],"is_preprint":false},{"year":2009,"finding":"FLI-1 interacts directly with RUNX-1 in a differentiation-dependent manner during megakaryocyte development, synergistically activating the c-mpl promoter. This interaction is absent in uninduced megakaryoblastic cells and correlates with dephosphorylation of FLI-1 at serine 10. Substitution of Ser10 with phosphomimetic aspartate impairs RUNX-1 binding and abrogates synergy; alanine substitution (blocking phosphorylation) augments primary megakaryocyte differentiation.","method":"Protein complex purification, co-immunoprecipitation, gel filtration chromatography, reporter assays, phosphorylation analysis, point mutation studies, primary fetal liver megakaryocyte differentiation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical purification plus reciprocal co-IP, gel filtration, phosphomimetic mutagenesis, and primary cell functional assays in single study","pmids":["19470763"],"is_preprint":false},{"year":2009,"finding":"Fli-1 directly binds to promoters of ribosome biogenesis genes (containing conserved ETS binding sites) in Friend erythroleukemic cells and contributes to their transcriptional activation. Fli-1 and Spi-1 additively regulate this common set of targets. Fli-1 knockdown contributes to proliferation arrest, apoptosis induction, and differentiation of erythroleukemic cells.","method":"Inducible shRNA knockdown, ChIP, transcriptome profiling, clonal analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming promoter binding plus functional knockdown, single lab","pmids":["19289502"],"is_preprint":false},{"year":2012,"finding":"FLI-1 inhibitors decrease Fli-1 DNA binding to target genes (SHIP-1, GATA-1) and reveal a positive relationship between loss of Fli-1 DNA binding activity and increased Fli-1 phosphorylation. Fli-1 represses its own expression via a Fli-1-miR-145 autoregulatory loop (Fli-1 normally represses the miR-145 promoter; loss of Fli-1 allows miR-145 upregulation which further suppresses Fli-1).","method":"Drug screening, DNA binding assays, ChIP, miRNA expression analysis, promoter reporter assays","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and DNA binding assays with functional correlation, single lab","pmids":["22829238"],"is_preprint":false},{"year":2013,"finding":"The C-terminal transcriptional activation domain (CTA) of Fli-1 negatively regulates mononuclear phagocyte (monocyte, macrophage, dendritic cell) development. Fli-1 protein directly binds the Flt3L gene promoter, suppressing Flt3L expression in multipotent progenitors.","method":"Truncated Fli-1 CTA-deletion knock-in mice, bone marrow reconstitution, flow cytometry, ChIP","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus in vivo genetic model, single lab, two orthogonal methods","pmids":["23320737"],"is_preprint":false},{"year":2014,"finding":"Fli-1 directly binds ETS binding sites in the distal region of the CCL5/RANTES promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain significantly reduces this activation. Ets1 competes with Fli-1 for binding, acting as a dominant-negative for Fli-1-driven CCL5 transcription.","method":"ChIP, transient transfection reporter assays, promoter deletion/mutation analysis, siRNA knockdown","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays with domain mutation, single lab","pmids":["25098295"],"is_preprint":false},{"year":2014,"finding":"EWS-FLI1 reprograms gene regulatory circuits by two mechanisms: (1) at GGAA repeat elements lacking evolutionary conservation, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters; (2) at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors to inactivate enhancers.","method":"ChIP-seq, ATAC-seq, 3C/chromatin interaction assays, gene expression analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, chromatin accessibility, and 3D chromatin interaction data with mechanistic model validated across multiple approaches","pmids":["25453903"],"is_preprint":false},{"year":2015,"finding":"EWS-FLI1 regulates alternative splicing by interacting with spliceosomal complex partners including DDX5, hnRNP K, and PRPF6. In CLIP-seq, EWS-FLI1 RNA-binding motifs occur most frequently adjacent to intron-exon boundaries. EWS-FLI1 alters splicing of oncogenesis-related genes including CLK1, CASP3, PPFIBP1, and TERT.","method":"CLIP-seq, exon array, RNA-seq, co-immunoprecipitation, small molecule inhibitor (YK-4-279) validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CLIP-seq, co-IP for direct binding partners, exon array and RNA-seq, validated by small-molecule disruption","pmids":["25737553"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of the FLI1 DNA-binding domain (ETS/DBD) alone and in complex with cognate GGAA-containing DNA reveal a previously unrecognized homodimer, with a helix-swapped dimerization interface dominated by hydrophobic interactions including Phe362. Mutation of Phe362 to alanine disrupts dimerization without perturbing structure or DNA binding function, supporting a role for DBD dimerization in transcriptional regulation at promoters with multiple FLI1 binding sites.","method":"X-ray crystallography, solution dimerization assays, site-directed mutagenesis (F362A)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of apo and DNA-bound forms plus mutagenesis validation, rigorous structural study","pmids":["26618620"],"is_preprint":false},{"year":2016,"finding":"Fli-1 directly binds the G-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in 94% loss of transcriptional activation. Mutation of a known acetylation site within Fli-1 leads to increased G-CSF promoter activation; p300/CBP and PCAF acetyltransferases decrease Fli-1-specific activation of the G-CSF promoter, indicating acetylation negatively regulates Fli-1 activity at this promoter.","method":"ChIP, transient transfection reporter assays, site-directed mutagenesis, siRNA knockdown","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter assays with mutagenesis, single lab","pmids":["27431361"],"is_preprint":false},{"year":2017,"finding":"Fli1 directly regulates AIRE expression in thymic epithelial cells; keratinocyte/epithelial-specific Fli1 knockout mice develop thymic defects with AIRE downregulation, systemic autoimmunity, and organ fibrosis. Fli1 occupancy of the AIRE promoter was demonstrated by ChIP.","method":"Conditional Keratin14-Cre Fli1 knockout mice, ChIP, gene expression analysis, histology","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with ChIP validation, single lab","pmids":["28232470"],"is_preprint":false},{"year":2017,"finding":"FLI-1 deficiency in human dermal microvascular endothelial cells promotes migration, proliferation, and cell survival while impairing tube formation on Matrigel, demonstrating that FLI-1 normally limits angiogenic sprouting behavior.","method":"siRNA knockdown, scratch assay, transwell migration, BrdU proliferation assay, flow cytometry apoptosis assay, Matrigel tube formation assay","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cellular assays, single lab, clean siRNA knockdown","pmids":["28370536"],"is_preprint":false},{"year":2017,"finding":"FLI1 haploinsufficiency impairs megakaryocyte yield, proplatelet formation, and platelet half-life/function. FLI1 overexpression in iPSC-derived megakaryocytes increases iMeg yield and improves in vivo platelet yield, half-life, and functionality. FLI1 appears to negatively regulate ETS1 expression during megakaryopoiesis.","method":"iPSC-derived megakaryocytes (Paris-Trousseau patient and FLI1+/- targeted iPSCs), in vivo platelet infusion and survival studies","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic iPSC system with in vivo platelet function validation, single lab","pmids":["28432223"],"is_preprint":false},{"year":2017,"finding":"Combined knockdown of ERG and FLI1 in endothelial cells induces endothelial-to-mesenchymal transition (EndMT) accompanied by dynamic epigenomic changes. ERG and FLI1 act as critical transcriptional activators for EC-specific genes; their loss reduces microRNA-126 expression, which partially contributes to EndMT induction.","method":"siRNA double knockdown, RNA-seq, ChIP-seq, genome-wide chromatin analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq and RNA-seq with functional knockdown, single lab","pmids":["30500808"],"is_preprint":false},{"year":2017,"finding":"FLI1 deficiency in Foxd1-derived pericytes prevents CLP-induced pericyte loss, vascular leak, and improves survival in sepsis. FLI-1 transcriptionally regulates inflammatory cytokines and chemokines in pericytes, and CLP-induced pericyte pyroptosis is mitigated by pericyte-specific Fli-1 knockout.","method":"Foxd1-Cre conditional Fli-1 knockout mice, CLP sepsis model, siRNA knockdown in cultured pericytes, gene expression analysis","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo plus siRNA in vitro, single lab","pmids":["30053030"],"is_preprint":false},{"year":2018,"finding":"Fli-1 directly occupies the IL33 and IL6 promoters in dermal fibroblasts (demonstrated by ChIP). Fli-1 haploinsufficiency leads to overproduction of IL-33 and IL-6 in fibroblasts, and IL-33 from Fli-1-deficient fibroblasts drives Th2-like Treg transdifferentiation in skin.","method":"ChIP, co-culture experiments with neutralizing antibodies, flow cytometry, qRT-PCR in Fli-1+/- mice","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter occupancy plus functional co-culture validation, single lab","pmids":["29415756"],"is_preprint":false},{"year":2018,"finding":"EWS-FLI1 increases transcription at target loci, causing accumulation of R-loops that block BRCA1 repair. BRCA1 is enriched in interaction with the elongating transcription machinery in Ewing sarcoma cells, impairing homologous recombination. Wild-type EWSR1 normally suppresses R-loops and promotes homologous recombination.","method":"R-loop detection, co-immunoprecipitation, DNA damage response assays, replication stress markers, PARP inhibitor sensitivity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods in high-impact study; mechanistic model validated by multiple assays including co-IP, R-loop mapping, and PARP inhibitor sensitivity","pmids":["29513652"],"is_preprint":false},{"year":2019,"finding":"USP19 deubiquitinase stabilizes EWS-FLI1 by binding to the N-terminal EWS region and deubiquitinating it. Depletion of USP19 reduces EWS-FLI1 protein levels and Ewing sarcoma cell growth in vitro and in vivo. Notably, USP19 does not stabilize wild-type FLI1 protein, despite binding to the EWS domain present in both EWS-FLI1 and EWSR1.","method":"siRNA screen, co-immunoprecipitation, Western blot of protein levels after modulation, shRNA stable depletion, xenograft mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional in vitro and in vivo validation, single lab","pmids":["30700749"],"is_preprint":false},{"year":2019,"finding":"Diterpenoid compounds inhibit Fli-1 transcriptional activity by binding to nucleotide residues in a pocket near the major groove of the Fli-1 DNA-binding domain (computational docking). Functional inhibition of Fli-1 triggers a Fli-1-miR145 autoregulatory loop: loss of Fli-1 activity upregulates miR-145 (whose promoter is normally repressed by Fli-1), which further suppresses Fli-1 translation.","method":"High-content transcriptional reporter screen, apoptosis/differentiation assays, computational docking, miR-145 expression analysis, leukemia mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — computational docking (Tier 4) supported by functional assays and in vivo model, autoregulatory loop demonstrated by expression data","pmids":["30741932"],"is_preprint":false},{"year":2019,"finding":"Fli-1 directly binds caspase-1 promoter regions (demonstrated by ChIP and luciferase reporter assay) and drives caspase-1 and IL-18 expression in lung pericytes. Overexpressed Fli-1 increases caspase-1 and IL-18; Fli-1 siRNA blocks outer membrane vesicle-induced caspase-1, caspase-11, and IL-18 expression.","method":"ChIP, luciferase reporter assay, siRNA knockdown, bacterial OMV model of pyroptosis","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay confirming direct promoter binding, single lab","pmids":["30739075"],"is_preprint":false},{"year":2020,"finding":"Fli-1 in CD8+ T cells binds to cis-regulatory elements of effector-associated genes to restrain effector T cell (TEFF) lineage differentiation. Loss of Fli-1 increases chromatin accessibility at ETS:RUNX motifs, enabling more efficient Runx3-driven TEFF biology. Genetic deletion of Fli-1 enhances TEFF responses without compromising memory or exhaustion precursor populations.","method":"In vivo CRISPR screen, conditional genetic deletion, ATAC-seq, ChIP-seq, viral infection and tumor protection models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin and binding studies with in vivo CRISPR genetic validation across multiple infection and tumor models","pmids":["33636129"],"is_preprint":false},{"year":2020,"finding":"FLI1 controls expression of CCND1 (cyclin D1) and E2F2, regulating G1/S cell cycle progression. FLI1 depletion causes G1/S arrest and reduced cell proliferation in pancreatic cancer cells. FLI1 preferentially binds the mutant hTERT core promoter and regulates hTERT expression.","method":"siRNA knockdown, cell cycle analysis, protein microarray of transcription factor DNA-binding domains, gene expression analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockdown with cell cycle analysis, single lab, mechanistic connection to CCND1/E2F2 established by expression but limited direct promoter data","pmids":["31846072"],"is_preprint":false},{"year":2020,"finding":"Fli-1 directly binds the GM-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in significant loss of activation. Mutation of a phosphorylation site within Fli-1 leads to increased GM-CSF promoter activation, indicating that phosphorylation negatively regulates Fli-1 activity at this promoter. Fli-1 acts additively with Sp1 in regulating GM-CSF expression.","method":"ChIP, transient transfection reporter assays, site-directed mutagenesis (DNA-binding domain and phosphorylation site), siRNA knockdown","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays with mutagenesis, single lab","pmids":["33268481"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of ERG/FLI1 DNA-binding domain in complex with Runx2, core-binding factor beta (Cbfβ), and mithramycin (MTM) on a DNA enhancer site reveal that MTM allosterically inhibits ERG and FLI1 transactions by disrupting the FLI1-DBD/Runx2/DNA complex rather than directly blocking DNA binding.","method":"X-ray crystallography (series of crystal structures), DNA binding assays with MTM and analogues","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional DNA binding validation across multiple drug analogues in single study","pmids":["33275876"],"is_preprint":false},{"year":2021,"finding":"SPOP (E3 ubiquitin ligase) and OTUD7A (deubiquitinase) are the bona fide regulators of EWS-FLI1 protein stability. Casein kinase 1-mediated phosphorylation of the VTSSS degron in the FLI1 domain of EWS-FLI1 enhances SPOP-mediated degradation. OTUD7A counteracts SPOP by deubiquitinating and stabilizing EWS-FLI1.","method":"Co-immunoprecipitation, ubiquitination assays, phosphorylation mapping, siRNA/shRNA depletion, xenograft mouse model, AI-based virtual drug screen","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of ubiquitination, phosphodegron identification, reciprocal co-IP, functional in vivo validation","pmids":["34060252"],"is_preprint":false},{"year":2021,"finding":"EWS-FLI1 incorporates into a protein granule/assembly in cells through its low-complexity (LC) domain. Cross-linking studies show the LC domain is required for the observed protein assemblies. EWS-FLI1 can bind RNA polymerase II and self-assemble through its LC domain, potentially enabling interaction with its wide network of protein partners.","method":"siRNA knockdown, RNA-seq, cross-linking-based protein assembly detection, co-immunoprecipitation","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-linking assembly assays plus functional RNA-seq, single lab, mechanistic insights from LC domain studies","pmids":["34035145"],"is_preprint":false},{"year":2021,"finding":"YAP interacts with TEAD1, and this complex inhibits FLI1 expression during endothelial differentiation from pluripotent stem cells. Luciferase assay confirms TEAD1-mediated inhibition of the FLI1 promoter. FLI1 overexpression rescues the inhibition of endothelial differentiation caused by YAP overexpression.","method":"Luciferase reporter assay, siRNA/overexpression, microarray analysis, rescue experiments","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay plus functional rescue experiments, single lab","pmids":["34666000"],"is_preprint":false},{"year":2022,"finding":"Fli-1 promotes the transcription of Th1/Th17 pathways and TCR-inducible transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells, as revealed by single-cell RNA-seq analysis of heterozygous and homozygous Fli1-deficient T cells.","method":"Genetic Fli-1 deletion (hetero- and homozygous), single-cell RNA-seq, GVHD allogeneic models, xenograft model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq in genetic model with in vivo disease validation, single lab","pmids":["36074578"],"is_preprint":false},{"year":2023,"finding":"ETV6 competes with EWS-FLI1 for binding to DNA elements enriched for short GGAA repeat sequences. Inactivation of ETV6 allows EWS-FLI1 to overtake and hyper-activate these cis-elements, promoting mesenchymal differentiation with SOX11 as a key downstream target. A dominant-interfering peptide that squelches ETV6 phenocopies these effects and suppresses Ewing sarcoma growth in vivo.","method":"Domain-focused CRISPR screen, biochemical DNA binding assays, ChIP-seq/epigenomics, dominant-interfering peptide, in vivo xenograft","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide epigenomic studies, biochemical competition assays, and in vivo functional validation with mechanistic peptide approach","pmids":["36658219"],"is_preprint":false},{"year":2023,"finding":"FLI1 orchestrates IDO1 transcriptional activation in response to IFN-γ by regulating expression of CBP and STAT1, facilitating chromatin accessibility at the IDO1 locus. This leads to kynurenine production, CD8+ T cell exhaustion, and Treg differentiation, enabling immune evasion in nasopharyngeal carcinoma.","method":"siRNA knockdown, ChIP assays, chromatin accessibility assays, gene expression analysis, T cell co-culture functional assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and chromatin accessibility assays plus functional immune assays, single lab","pmids":["38816360"],"is_preprint":false},{"year":2023,"finding":"FLI1 directly upregulates TIE1 transcription by binding to the TIE1 promoter (demonstrated by ChIP and dual luciferase reporter assay), thereby activating the PI3K/AKT signaling pathway to promote radiotherapy resistance in nasopharyngeal carcinoma.","method":"ChIP, dual luciferase reporter assay, RNA-seq, loss/gain-of-function in vitro and in vivo","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay confirming direct promoter binding, single lab","pmids":["36814284"],"is_preprint":false},{"year":2017,"finding":"FLI1 variants (c.1010G>A and c.1033A>G) cause macrothrombocytopenia with dense granule deficiency. Carrier platelets show defects in aggregation, ATP secretion, and mepacrine uptake/release. In vitro megakaryocyte studies reveal maturation defect and reduced proplatelet formation. The FLI1 variants show significantly reduced nuclear accumulation and transcriptional activity.","method":"High-throughput gene sequencing, electron microscopy, flow cytometry, megakaryocyte differentiation from CD34+ cells, transcriptional activity assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional variant characterization in patient cells with in vitro megakaryocyte modeling, single lab","pmids":["28255014"],"is_preprint":false}],"current_model":"FLI1 is an ETS family transcription factor that binds GGAA-containing DNA sequences through its C-terminal ETS domain (which can homodimerize), activates or represses target gene transcription through context-dependent interactions with co-factors including RUNX1, GATA-1, EKLF, CBP, Sp1, and RHA, directly regulates genes controlling hematopoiesis (BCL-2, c-mpl, GATA-1, SHIP-1), vascular homeostasis (Tek/Tie-2, TIE1), immunity (CCL5, G-CSF, GM-CSF, caspase-1, IDO1), and collagen production (COL1A2); its protein stability is controlled by SPOP-mediated ubiquitination (enhanced by CK1 phosphorylation of a VTSSS degron) opposed by the deubiquitinase OTUD7A; and it participates in a recursive gene-regulatory network with GATA2 and SCL during hematopoietic stem cell specification, while in CD8+ T cells it restrains effector differentiation by occupying cis-regulatory elements that otherwise allow Runx3-driven effector programs."},"narrative":{"mechanistic_narrative":"FLI1 is an ETS-family sequence-specific transcription factor that orchestrates hematopoietic, megakaryocytic, vascular, and immune gene-regulatory programs through a C-terminal ETS DNA-binding domain that recognizes GGAA-core elements [PMID:7517940, PMID:10981960, PMID:17962413]. Its DNA-binding domain can form a helix-swapped homodimer (disrupted by the F362A mutation), enabling regulation at promoters bearing multiple FLI1 sites [PMID:26618620]. FLI1 acts in a context-dependent manner—as an activator or repressor—through both autonomous activation domains and combinatorial protein partnerships: it interacts with RUNX1 in a phosphorylation-controlled (Ser10) switch to synergistically drive megakaryocytic genes such as c-mpl [PMID:19470763], with EKLF and GATA-1 to balance erythroid versus megakaryocytic fate [PMID:12556498], and with Sp1 to repress collagen COL1A2 production in fibroblasts [PMID:11278621]. It participates in a recursively wired triad with GATA2 and SCL/TAL1 during hematopoietic stem cell specification and autoregulates its own locus, including through a Fli-1–miR-145 repressive loop [PMID:17962413, PMID:11991951, PMID:22829238]. FLI1 directly binds and transactivates survival and lineage genes including BCL-2 [PMID:11847117], and is required in vivo for vascular integrity via Tek/Tie-2, with its loss causing embryonic vascular failure and dysmegakaryopoiesis [PMID:10981960]. It broadly governs inflammatory and immune gene expression—directly occupying CCL5, G-CSF, GM-CSF, caspase-1, IL33/IL6, and IDO1 regulatory regions—where its output is tuned by phosphorylation and acetylation [PMID:25098295, PMID:27431361, PMID:33268481, PMID:30739075, PMID:29415756, PMID:38816360]. In CD8+ T cells FLI1 restrains effector differentiation by occupying ETS:RUNX cis-elements that otherwise license Runx3-driven effector programs [PMID:33636129]. FLI1 protein stability is set by SPOP-mediated ubiquitination, enhanced by CK1 phosphorylation of a VTSSS degron and opposed by the deubiquitinase OTUD7A [PMID:34060252]. The oncogenic EWS-FLI1 fusion repurposes these activities, creating de novo enhancers at non-conserved GGAA microsatellites while displacing wild-type ETS factors at conserved enhancers [PMID:25453903], with competition from ETV6 and ETS1 shaping its genomic occupancy [PMID:36658219]. FLI1 missense variants cause autosomal macrothrombocytopenia with platelet granule and secretion defects [PMID:28255014].","teleology":[{"year":1992,"claim":"Establishing that FLI1 encodes an ETS-family protein with a conserved DNA-binding domain framed it as a candidate sequence-specific transcription factor and placed it within a defined ETS subset.","evidence":"cDNA cloning and structural domain mapping of the 452-residue human protein","pmids":["1394211"],"confidence":"Medium","gaps":["No direct demonstration of DNA-binding specificity or target genes at this stage","Functional role of the 5'-ETS homology region undefined"]},{"year":1994,"claim":"Defining the ETS domain as necessary and sufficient for binding a specific GGAA-core consensus established the molecular grammar of FLI1 target-site recognition.","evidence":"Binding-site selection and truncation analysis with in vitro DNA binding assays","pmids":["7517940"],"confidence":"High","gaps":["In vitro consensus does not establish in vivo occupancy","Does not address cofactor-dependent target selection"]},{"year":1995,"claim":"Mapping two autonomous activation domains and showing the EWS fusion potentiates the C-terminal domain distinguished wild-type transcriptional output from the stronger oncogenic fusion.","evidence":"Deletion analysis and transcriptional activation assays in cell lines","pmids":["7503813"],"confidence":"Medium","gaps":["Cofactors mediating activation not identified","Native target genes not yet defined"]},{"year":2000,"claim":"The Fli-1 knockout showed FLI1 is required in vivo for vascular integrity (via Tek/Tie-2) and normal megakaryopoiesis, anchoring its physiological role beyond in vitro transcription.","evidence":"Targeted null mouse with histology and gene expression analysis","pmids":["10981960"],"confidence":"High","gaps":["Embryonic lethality limits analysis of later/tissue-specific roles","Direct versus indirect regulation of Tek not resolved at the chromatin level"]},{"year":2003,"claim":"Reciprocal interactions with EKLF and GATA-1 revealed FLI1 as a bifunctional regulator that balances erythroid versus megakaryocytic fate through both intrinsic repression and partner recruitment.","evidence":"Co-IP, Gal4 domain mapping, and promoter reporter assays across cell types","pmids":["12556498"],"confidence":"High","gaps":["Quantitative contribution of direct repression versus tethering not separated in vivo","Switch controlling activator versus repressor mode not defined"]},{"year":2002,"claim":"Identifying BCL-2 as a directly bound, functionally required FLI1 target linked FLI1 transcriptional activity to survival of transformed erythroblasts.","evidence":"ChIP, in vitro binding, mutant rescue, and BCL-2 inhibitor studies","pmids":["11847117"],"confidence":"High","gaps":["Generalizability of the survival program to normal cells unclear","Cofactors at the BCL-2 promoter not defined"]},{"year":2007,"claim":"Demonstrating a fully connected GATA2–FLI1–SCL enhancer triad established FLI1 as a node in a recursive regulatory network specifying hematopoietic stem cells.","evidence":"ChIP, enhancer reporter assays, and transgenic analysis","pmids":["17962413"],"confidence":"High","gaps":["Dynamics of triad assembly over differentiation not resolved","Quantitative weight of each input on Fli1+12 enhancer undefined"]},{"year":2009,"claim":"Showing that Ser10 dephosphorylation gates FLI1–RUNX1 interaction during megakaryocyte differentiation revealed a phospho-switch coupling signaling to combinatorial transcription.","evidence":"Complex purification, reciprocal co-IP, gel filtration, and phosphomimetic mutagenesis in primary megakaryocytes","pmids":["19470763"],"confidence":"High","gaps":["Kinase/phosphatase acting on Ser10 not identified","Whether the switch operates at other FLI1 targets unknown"]},{"year":2015,"claim":"Crystal structures of the apo and DNA-bound FLI1 DBD revealed a helix-swapped homodimer, providing a structural basis for cooperative regulation at multi-site promoters.","evidence":"X-ray crystallography with F362A dimer-disrupting mutagenesis","pmids":["26618620"],"confidence":"High","gaps":["In vivo significance of DBD dimerization not directly tested at native loci","Which target promoters require dimerization unresolved"]},{"year":2016,"claim":"Mapping direct FLI1 occupancy of inflammatory cytokine/chemokine promoters (CCL5, G-CSF, GM-CSF) showed FLI1 is a dose-dependent transcriptional driver whose output is tuned by acetylation and phosphorylation.","evidence":"ChIP, reporter assays, and site-directed mutagenesis of DNA-binding and modification sites","pmids":["25098295","27431361","33268481"],"confidence":"Medium","gaps":["Enzymes responsible for the modifications not all identified","Cell-type specificity of these promoter programs not fully mapped"]},{"year":2017,"claim":"Conditional knockouts and human variant/iPSC studies extended FLI1 function to thymic AIRE control, fibroblast cytokine restraint, megakaryocyte maturation, and human macrothrombocytopenia.","evidence":"Tissue-specific Cre knockouts, ChIP, patient/isogenic iPSC megakaryocytes, and variant transcriptional assays","pmids":["28232470","29415756","28432223","28255014"],"confidence":"Medium","gaps":["Mechanistic link between haploinsufficiency dosage and distinct phenotypes incompletely resolved","Direct targets driving autoimmunity/fibrosis not fully enumerated"]},{"year":2020,"claim":"Genome-wide chromatin and in vivo CRISPR studies in CD8+ T cells defined FLI1 as a brake on effector differentiation by occupying ETS:RUNX cis-elements competing with Runx3.","evidence":"In vivo CRISPR screen, conditional deletion, ATAC-seq/ChIP-seq, and infection/tumor models","pmids":["33636129","36074578"],"confidence":"High","gaps":["Mechanism by which FLI1 occupancy reduces accessibility not fully resolved","Lineage-specific cofactors distinguishing CD4 versus CD8 effects undefined"]},{"year":2021,"claim":"Identifying SPOP/CK1/OTUD7A control of the VTSSS degron established the post-translational machinery setting FLI1 (and EWS-FLI1) protein abundance.","evidence":"Ubiquitination assays, phospho-degron mapping, reciprocal co-IP, and xenograft validation","pmids":["34060252"],"confidence":"High","gaps":["Signals controlling CK1 activity on the degron not defined","Whether degron control is differentiation-stage-regulated unknown"]},{"year":2023,"claim":"Linking FLI1 to IDO1/TIE1 transcriptional programs connected FLI1 to immune evasion and therapy resistance in carcinoma, broadening its role into the tumor immune microenvironment.","evidence":"ChIP, chromatin accessibility, RNA-seq, and T-cell co-culture functional assays","pmids":["38816360","36814284"],"confidence":"Medium","gaps":["Causal hierarchy between FLI1, CBP/STAT1, and IDO1 not fully dissected","Generalizability beyond nasopharyngeal carcinoma untested"]},{"year":null,"claim":"How FLI1's mode-switching between activation and repression is selected at individual loci—integrating partner identity, post-translational modification, DBD dimerization, and chromatin state—remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phospho/acetyl state to activator-versus-repressor output genome-wide","Stoichiometry of cofactor competition (ETS1, ETV6, EKLF) at native loci unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,6,7,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,9,6,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[45]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,6,9,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,14,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[34,41,43]}],"complexes":[],"partners":["RUNX1","GATA1","EKLF","SP1","CBP","ERG","GATA2","SCL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01543","full_name":"Friend leukemia integration 1 transcription factor","aliases":["Proto-oncogene Fli-1","Transcription factor ERGB"],"length_aa":452,"mass_kda":51.0,"function":"Sequence-specific transcriptional activator (PubMed:24100448, PubMed:26316623, PubMed:28255014). Recognizes the DNA sequence 5'-C[CA]GGAAGT-3'","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q01543/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FLI1","classification":"Not Classified","n_dependent_lines":68,"n_total_lines":1208,"dependency_fraction":0.056291390728476824},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FLI1","total_profiled":1310},"omim":[{"mim_id":"620491","title":"MATURIN, NEURAL PROGENITOR DIFFERENTIATION REGULATOR HOMOLOG; MTURN","url":"https://www.omim.org/entry/620491"},{"mim_id":"617443","title":"BLEEDING DISORDER, PLATELET-TYPE, 21; BDPLT21","url":"https://www.omim.org/entry/617443"},{"mim_id":"616492","title":"EWING SARCOMA-ASSOCIATED TRANSCRIPT 1, NONCODING; EWSAT1","url":"https://www.omim.org/entry/616492"},{"mim_id":"615815","title":"SMOOTH MUSCLE- AND ENDOTHELIAL CELL-ENRICHED MIGRATION/DIFFERENTIATION-ASSOCIATED LONG NONCODING RNA; SENCR","url":"https://www.omim.org/entry/615815"},{"mim_id":"612219","title":"EWING SARCOMA; ES","url":"https://www.omim.org/entry/612219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":65.9}],"url":"https://www.proteinatlas.org/search/FLI1"},"hgnc":{"alias_symbol":["SIC-1","EWSR2","FLI-1"],"prev_symbol":[]},"alphafold":{"accession":"Q01543","domains":[{"cath_id":"1.10.150.50","chopping":"125-200","consensus_level":"high","plddt":88.0053,"start":125,"end":200},{"cath_id":"1.10.10.10","chopping":"274-368","consensus_level":"high","plddt":92.0366,"start":274,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01543","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01543-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01543-F1-predicted_aligned_error_v6.png","plddt_mean":63.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FLI1","jax_strain_url":"https://www.jax.org/strain/search?query=FLI1"},"sequence":{"accession":"Q01543","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01543.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01543/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01543"}},"corpus_meta":[{"pmid":"16234507","id":"PMC_16234507","title":"Immunohistochemical 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sequence analysis, structural domain mapping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural characterization from primary cloning paper, single lab, sequence analysis only\",\n      \"pmids\": [\"1394211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"FLI-1 functions as a sequence-specific transcriptional activator with two autonomous transcriptional activation domains (one N-terminal, one C-terminal). In the EWS-FLI1 fusion, the EWS domain acts as a modulatory/regulatory domain that activates the C-terminal transcriptional activation domain of FLI1, making EWS-FLI1 a transcriptional activator stronger than wild-type FLI1.\",\n      \"method\": \"Deletion analysis, transcriptional activation assays in cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional deletion mapping with transcriptional assays, single lab but multiple constructs tested\",\n      \"pmids\": [\"7503813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The ETS domain of FLI1 is necessary and sufficient for sequence-specific DNA binding, with a consensus binding sequence of ACCGGAAG/aT/c, showing greater specificity 5' of the GGAA core than other ETS proteins. EWS-FLI1 displays the same DNA binding specificity and affinity as wild-type FLI1.\",\n      \"method\": \"Epitope-tagging and SELEX-like binding site selection, truncation analysis, in vitro DNA binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA binding with systematic truncation mutagenesis, replicated across constructs in single study\",\n      \"pmids\": [\"7517940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Unlike wild-type FLI1, EWS-FLI1 can form a ternary complex on the c-fos serum response element (SRE) and binds DNA at this site without requiring SRF. Both FLI1 and EWS-FLI1 interact directly with SRF in vitro in the absence of DNA. Deletion of the N-terminal region of FLI1 (normally an inhibitory domain) converts it to behave like EWS-FLI1 with respect to SRE binding.\",\n      \"method\": \"EMSA, GST pull-down assay, deletion analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding and pull-down with mutagenesis, single lab\",\n      \"pmids\": [\"8604338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FLI-1 overexpression in primary erythroblasts inhibits Epo-induced terminal differentiation, inhibits apoptosis following Epo withdrawal, and induces proliferation. Enhanced survival correlates with FLI-1-driven upregulation of BCL-2 and prevention of cyclin D2/D3 downregulation during differentiation.\",\n      \"method\": \"Retroviral transduction of primary avian erythroblasts, differentiation/proliferation assays, gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary cell system with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"10102630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Fli-1 null mice die at embryonic day 11.5 with loss of vascular integrity causing cerebral meningeal bleeding and specific downregulation of Tek/Tie-2 (angiopoietin-1 receptor), demonstrating a required role for Fli-1 in vascular development. Fli-1 null embryos also exhibit dysmegakaryopoiesis resembling Jacobsen/Paris-Trousseau syndrome.\",\n      \"method\": \"Targeted null mutation (knockout mouse), histology, gene expression analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with specific molecular and cellular phenotypes, published in high-impact journal\",\n      \"pmids\": [\"10981960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FLI-1 inhibits COL1A2 (collagen alpha2(I)) promoter activity and collagen production in dermal fibroblasts through both direct DNA binding at a critical ETS site and indirect mechanisms via protein-protein interaction with Sp1. Fli-1 and Ets-1 compete for the same COL1A2 promoter site with opposing effects (Fli-1 inhibits; Ets-1 stimulates).\",\n      \"method\": \"Stable transfection, in vitro DNA binding (EMSA), promoter deletion/mutation analysis, Gal4 reporter assays, dominant-negative and DNA-binding mutant constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including EMSA, mutagenesis, and reporter assays in multiple cell types\",\n      \"pmids\": [\"11278621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FLI-1 directly binds to specific ETS binding sites in the BCL-2 promoter in transformed erythroblasts and transactivates BCL-2 expression. The ability of FLI-1 mutants to transactivate BCL-2 correlates with their ability to inhibit apoptosis. BCL-2 is an in vivo target gene of FLI-1 required for survival of FLI-1-transformed erythroblasts.\",\n      \"method\": \"ChIP, in vitro binding assays, FLI-1 deletion/point mutants, promoter reporter assays, BCL-2 inhibitor studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP confirming in vivo binding, corroborated by mutagenesis and functional rescue experiments\",\n      \"pmids\": [\"11847117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ets-1 directly activates transcription from the fli-1 gene promoter by binding to ETS binding sites including a third site unique to Ets-1 (not used by Spi-1). Endogenous Fli-1 also binds its own promoter and promotes auto-regulatory transcription, establishing a positive feedback loop of Fli-1 expression in endothelial cells.\",\n      \"method\": \"Promoter deletion/mutation analysis, transient transfection reporter assays, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays in endothelial cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"11991951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FLI-1 represses EKLF-dependent transcription (including the beta-globin promoter) by two mechanisms: (1) direct repression activity of the ETS DNA-binding domain (which behaves as an autonomous repression domain when fused to Gal4-DBD), and (2) indirect recruitment to erythroid promoters via protein-protein interaction with EKLF. FLI-1 also interacts with GATA-1, enhancing GATA-1 activity rather than repressing it. Reciprocally, EKLF represses FLI-1-dependent megakaryocytic GPIX promoter activity, suggesting cross-antagonism controls erythroid vs. megakaryocytic fate.\",\n      \"method\": \"Co-immunoprecipitation, Gal4 fusion reporter assays, promoter reporter assays, domain mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, Gal4 domain analysis, multiple promoter assays across cell types, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12556498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EWS-FLI1 self-associates and can interact with both germline EWS and wild-type FLI1. Self-association of EWS-FLI1 is mediated by its C-terminal FLI1 DNA-binding motif and is RNA-independent. The EWS N-terminal domain mediates homotypic and heterotypic interactions of EWS and EWS-FLI1. Despite oligomerization capacity, EWS-FLI1 binds a tandem ETS-binding site as a monomer.\",\n      \"method\": \"FRET, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, RNase A treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — four orthogonal methods (FRET, M2H, GST pull-down, co-IP) in single study\",\n      \"pmids\": [\"14534527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EWS-FLI1 and FLI-1 interact with CBP (CREB-binding protein) through their amino-terminal region and inhibit CBP-dependent transcriptional activity of RXR. This antiapoptotic activity is independent of the DNA-binding activity of EWS-FLI1/FLI-1. Dominant-negative CBP sensitizes Ewing sarcoma cells to apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, dominant-negative CBP expression, apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"15273724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fli1, Elf1, and Ets1 directly bind to three conserved ETS sites in the LMO2 proximal promoter and activate its transcription in hematopoietic progenitor and endothelial cells. In vivo, the LMO2 proximal promoter is sufficient for endothelial but not hematopoietic expression in transgenic mice.\",\n      \"method\": \"ChIP, transient/stable transfection reporter assays, transgenic mouse analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with in vivo transgenic validation, single lab\",\n      \"pmids\": [\"15994290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNA helicase A (RHA) binds directly to EWS-FLI1 (specifically to RHA amino acids 630-1020 containing the region identified by phage display). Endogenous RHA forms a protein complex with EWS-FLI1 in ESFT cells; both co-occupy EWS-FLI1 target gene promoters by ChIP. RHA stimulates transcriptional activity of EWS-FLI1 regulated promoters including Id2 and enhances anchorage-independent growth of EWS-FLI1-expressing cells.\",\n      \"method\": \"Phage display, GST pull-down, ELISA, co-immunoprecipitation, ChIP, transcriptional reporter assays, anchorage-independent growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (phage display, GST pull-down, co-IP, ChIP, functional assays) in single study\",\n      \"pmids\": [\"16740692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Gata2, Fli1, and Scl/Tal1 form a recursively wired gene-regulatory circuit during hematopoiesis. All three transcription factors bind to each other's enhancers (Gata2-3, Fli1+12, Scl+19) in embryonic hematopoietic tissues, forming a fully connected triad. The Fli1+12 enhancer relies on a combination of Ets, Gata, and E-Box motifs and targets hematopoietic stem cells.\",\n      \"method\": \"ChIP, enhancer reporter assays, transgenic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirmed binding at all three enhancers in multiple tissue types plus transgenic validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17962413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FLI-1 interacts directly with RUNX-1 in a differentiation-dependent manner during megakaryocyte development, synergistically activating the c-mpl promoter. This interaction is absent in uninduced megakaryoblastic cells and correlates with dephosphorylation of FLI-1 at serine 10. Substitution of Ser10 with phosphomimetic aspartate impairs RUNX-1 binding and abrogates synergy; alanine substitution (blocking phosphorylation) augments primary megakaryocyte differentiation.\",\n      \"method\": \"Protein complex purification, co-immunoprecipitation, gel filtration chromatography, reporter assays, phosphorylation analysis, point mutation studies, primary fetal liver megakaryocyte differentiation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical purification plus reciprocal co-IP, gel filtration, phosphomimetic mutagenesis, and primary cell functional assays in single study\",\n      \"pmids\": [\"19470763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fli-1 directly binds to promoters of ribosome biogenesis genes (containing conserved ETS binding sites) in Friend erythroleukemic cells and contributes to their transcriptional activation. Fli-1 and Spi-1 additively regulate this common set of targets. Fli-1 knockdown contributes to proliferation arrest, apoptosis induction, and differentiation of erythroleukemic cells.\",\n      \"method\": \"Inducible shRNA knockdown, ChIP, transcriptome profiling, clonal analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming promoter binding plus functional knockdown, single lab\",\n      \"pmids\": [\"19289502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FLI-1 inhibitors decrease Fli-1 DNA binding to target genes (SHIP-1, GATA-1) and reveal a positive relationship between loss of Fli-1 DNA binding activity and increased Fli-1 phosphorylation. Fli-1 represses its own expression via a Fli-1-miR-145 autoregulatory loop (Fli-1 normally represses the miR-145 promoter; loss of Fli-1 allows miR-145 upregulation which further suppresses Fli-1).\",\n      \"method\": \"Drug screening, DNA binding assays, ChIP, miRNA expression analysis, promoter reporter assays\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and DNA binding assays with functional correlation, single lab\",\n      \"pmids\": [\"22829238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal transcriptional activation domain (CTA) of Fli-1 negatively regulates mononuclear phagocyte (monocyte, macrophage, dendritic cell) development. Fli-1 protein directly binds the Flt3L gene promoter, suppressing Flt3L expression in multipotent progenitors.\",\n      \"method\": \"Truncated Fli-1 CTA-deletion knock-in mice, bone marrow reconstitution, flow cytometry, ChIP\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus in vivo genetic model, single lab, two orthogonal methods\",\n      \"pmids\": [\"23320737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fli-1 directly binds ETS binding sites in the distal region of the CCL5/RANTES promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain significantly reduces this activation. Ets1 competes with Fli-1 for binding, acting as a dominant-negative for Fli-1-driven CCL5 transcription.\",\n      \"method\": \"ChIP, transient transfection reporter assays, promoter deletion/mutation analysis, siRNA knockdown\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays with domain mutation, single lab\",\n      \"pmids\": [\"25098295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EWS-FLI1 reprograms gene regulatory circuits by two mechanisms: (1) at GGAA repeat elements lacking evolutionary conservation, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters; (2) at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors to inactivate enhancers.\",\n      \"method\": \"ChIP-seq, ATAC-seq, 3C/chromatin interaction assays, gene expression analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, chromatin accessibility, and 3D chromatin interaction data with mechanistic model validated across multiple approaches\",\n      \"pmids\": [\"25453903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EWS-FLI1 regulates alternative splicing by interacting with spliceosomal complex partners including DDX5, hnRNP K, and PRPF6. In CLIP-seq, EWS-FLI1 RNA-binding motifs occur most frequently adjacent to intron-exon boundaries. EWS-FLI1 alters splicing of oncogenesis-related genes including CLK1, CASP3, PPFIBP1, and TERT.\",\n      \"method\": \"CLIP-seq, exon array, RNA-seq, co-immunoprecipitation, small molecule inhibitor (YK-4-279) validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CLIP-seq, co-IP for direct binding partners, exon array and RNA-seq, validated by small-molecule disruption\",\n      \"pmids\": [\"25737553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the FLI1 DNA-binding domain (ETS/DBD) alone and in complex with cognate GGAA-containing DNA reveal a previously unrecognized homodimer, with a helix-swapped dimerization interface dominated by hydrophobic interactions including Phe362. Mutation of Phe362 to alanine disrupts dimerization without perturbing structure or DNA binding function, supporting a role for DBD dimerization in transcriptional regulation at promoters with multiple FLI1 binding sites.\",\n      \"method\": \"X-ray crystallography, solution dimerization assays, site-directed mutagenesis (F362A)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of apo and DNA-bound forms plus mutagenesis validation, rigorous structural study\",\n      \"pmids\": [\"26618620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fli-1 directly binds the G-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in 94% loss of transcriptional activation. Mutation of a known acetylation site within Fli-1 leads to increased G-CSF promoter activation; p300/CBP and PCAF acetyltransferases decrease Fli-1-specific activation of the G-CSF promoter, indicating acetylation negatively regulates Fli-1 activity at this promoter.\",\n      \"method\": \"ChIP, transient transfection reporter assays, site-directed mutagenesis, siRNA knockdown\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter assays with mutagenesis, single lab\",\n      \"pmids\": [\"27431361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fli1 directly regulates AIRE expression in thymic epithelial cells; keratinocyte/epithelial-specific Fli1 knockout mice develop thymic defects with AIRE downregulation, systemic autoimmunity, and organ fibrosis. Fli1 occupancy of the AIRE promoter was demonstrated by ChIP.\",\n      \"method\": \"Conditional Keratin14-Cre Fli1 knockout mice, ChIP, gene expression analysis, histology\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with ChIP validation, single lab\",\n      \"pmids\": [\"28232470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLI-1 deficiency in human dermal microvascular endothelial cells promotes migration, proliferation, and cell survival while impairing tube formation on Matrigel, demonstrating that FLI-1 normally limits angiogenic sprouting behavior.\",\n      \"method\": \"siRNA knockdown, scratch assay, transwell migration, BrdU proliferation assay, flow cytometry apoptosis assay, Matrigel tube formation assay\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cellular assays, single lab, clean siRNA knockdown\",\n      \"pmids\": [\"28370536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLI1 haploinsufficiency impairs megakaryocyte yield, proplatelet formation, and platelet half-life/function. FLI1 overexpression in iPSC-derived megakaryocytes increases iMeg yield and improves in vivo platelet yield, half-life, and functionality. FLI1 appears to negatively regulate ETS1 expression during megakaryopoiesis.\",\n      \"method\": \"iPSC-derived megakaryocytes (Paris-Trousseau patient and FLI1+/- targeted iPSCs), in vivo platelet infusion and survival studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic iPSC system with in vivo platelet function validation, single lab\",\n      \"pmids\": [\"28432223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Combined knockdown of ERG and FLI1 in endothelial cells induces endothelial-to-mesenchymal transition (EndMT) accompanied by dynamic epigenomic changes. ERG and FLI1 act as critical transcriptional activators for EC-specific genes; their loss reduces microRNA-126 expression, which partially contributes to EndMT induction.\",\n      \"method\": \"siRNA double knockdown, RNA-seq, ChIP-seq, genome-wide chromatin analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq and RNA-seq with functional knockdown, single lab\",\n      \"pmids\": [\"30500808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLI1 deficiency in Foxd1-derived pericytes prevents CLP-induced pericyte loss, vascular leak, and improves survival in sepsis. FLI-1 transcriptionally regulates inflammatory cytokines and chemokines in pericytes, and CLP-induced pericyte pyroptosis is mitigated by pericyte-specific Fli-1 knockout.\",\n      \"method\": \"Foxd1-Cre conditional Fli-1 knockout mice, CLP sepsis model, siRNA knockdown in cultured pericytes, gene expression analysis\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo plus siRNA in vitro, single lab\",\n      \"pmids\": [\"30053030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fli-1 directly occupies the IL33 and IL6 promoters in dermal fibroblasts (demonstrated by ChIP). Fli-1 haploinsufficiency leads to overproduction of IL-33 and IL-6 in fibroblasts, and IL-33 from Fli-1-deficient fibroblasts drives Th2-like Treg transdifferentiation in skin.\",\n      \"method\": \"ChIP, co-culture experiments with neutralizing antibodies, flow cytometry, qRT-PCR in Fli-1+/- mice\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter occupancy plus functional co-culture validation, single lab\",\n      \"pmids\": [\"29415756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EWS-FLI1 increases transcription at target loci, causing accumulation of R-loops that block BRCA1 repair. BRCA1 is enriched in interaction with the elongating transcription machinery in Ewing sarcoma cells, impairing homologous recombination. Wild-type EWSR1 normally suppresses R-loops and promotes homologous recombination.\",\n      \"method\": \"R-loop detection, co-immunoprecipitation, DNA damage response assays, replication stress markers, PARP inhibitor sensitivity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods in high-impact study; mechanistic model validated by multiple assays including co-IP, R-loop mapping, and PARP inhibitor sensitivity\",\n      \"pmids\": [\"29513652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP19 deubiquitinase stabilizes EWS-FLI1 by binding to the N-terminal EWS region and deubiquitinating it. Depletion of USP19 reduces EWS-FLI1 protein levels and Ewing sarcoma cell growth in vitro and in vivo. Notably, USP19 does not stabilize wild-type FLI1 protein, despite binding to the EWS domain present in both EWS-FLI1 and EWSR1.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, Western blot of protein levels after modulation, shRNA stable depletion, xenograft mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"30700749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Diterpenoid compounds inhibit Fli-1 transcriptional activity by binding to nucleotide residues in a pocket near the major groove of the Fli-1 DNA-binding domain (computational docking). Functional inhibition of Fli-1 triggers a Fli-1-miR145 autoregulatory loop: loss of Fli-1 activity upregulates miR-145 (whose promoter is normally repressed by Fli-1), which further suppresses Fli-1 translation.\",\n      \"method\": \"High-content transcriptional reporter screen, apoptosis/differentiation assays, computational docking, miR-145 expression analysis, leukemia mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — computational docking (Tier 4) supported by functional assays and in vivo model, autoregulatory loop demonstrated by expression data\",\n      \"pmids\": [\"30741932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fli-1 directly binds caspase-1 promoter regions (demonstrated by ChIP and luciferase reporter assay) and drives caspase-1 and IL-18 expression in lung pericytes. Overexpressed Fli-1 increases caspase-1 and IL-18; Fli-1 siRNA blocks outer membrane vesicle-induced caspase-1, caspase-11, and IL-18 expression.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, bacterial OMV model of pyroptosis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay confirming direct promoter binding, single lab\",\n      \"pmids\": [\"30739075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fli-1 in CD8+ T cells binds to cis-regulatory elements of effector-associated genes to restrain effector T cell (TEFF) lineage differentiation. Loss of Fli-1 increases chromatin accessibility at ETS:RUNX motifs, enabling more efficient Runx3-driven TEFF biology. Genetic deletion of Fli-1 enhances TEFF responses without compromising memory or exhaustion precursor populations.\",\n      \"method\": \"In vivo CRISPR screen, conditional genetic deletion, ATAC-seq, ChIP-seq, viral infection and tumor protection models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin and binding studies with in vivo CRISPR genetic validation across multiple infection and tumor models\",\n      \"pmids\": [\"33636129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FLI1 controls expression of CCND1 (cyclin D1) and E2F2, regulating G1/S cell cycle progression. FLI1 depletion causes G1/S arrest and reduced cell proliferation in pancreatic cancer cells. FLI1 preferentially binds the mutant hTERT core promoter and regulates hTERT expression.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, protein microarray of transcription factor DNA-binding domains, gene expression analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockdown with cell cycle analysis, single lab, mechanistic connection to CCND1/E2F2 established by expression but limited direct promoter data\",\n      \"pmids\": [\"31846072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fli-1 directly binds the GM-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in significant loss of activation. Mutation of a phosphorylation site within Fli-1 leads to increased GM-CSF promoter activation, indicating that phosphorylation negatively regulates Fli-1 activity at this promoter. Fli-1 acts additively with Sp1 in regulating GM-CSF expression.\",\n      \"method\": \"ChIP, transient transfection reporter assays, site-directed mutagenesis (DNA-binding domain and phosphorylation site), siRNA knockdown\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays with mutagenesis, single lab\",\n      \"pmids\": [\"33268481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of ERG/FLI1 DNA-binding domain in complex with Runx2, core-binding factor beta (Cbfβ), and mithramycin (MTM) on a DNA enhancer site reveal that MTM allosterically inhibits ERG and FLI1 transactions by disrupting the FLI1-DBD/Runx2/DNA complex rather than directly blocking DNA binding.\",\n      \"method\": \"X-ray crystallography (series of crystal structures), DNA binding assays with MTM and analogues\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional DNA binding validation across multiple drug analogues in single study\",\n      \"pmids\": [\"33275876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPOP (E3 ubiquitin ligase) and OTUD7A (deubiquitinase) are the bona fide regulators of EWS-FLI1 protein stability. Casein kinase 1-mediated phosphorylation of the VTSSS degron in the FLI1 domain of EWS-FLI1 enhances SPOP-mediated degradation. OTUD7A counteracts SPOP by deubiquitinating and stabilizing EWS-FLI1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, phosphorylation mapping, siRNA/shRNA depletion, xenograft mouse model, AI-based virtual drug screen\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of ubiquitination, phosphodegron identification, reciprocal co-IP, functional in vivo validation\",\n      \"pmids\": [\"34060252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EWS-FLI1 incorporates into a protein granule/assembly in cells through its low-complexity (LC) domain. Cross-linking studies show the LC domain is required for the observed protein assemblies. EWS-FLI1 can bind RNA polymerase II and self-assemble through its LC domain, potentially enabling interaction with its wide network of protein partners.\",\n      \"method\": \"siRNA knockdown, RNA-seq, cross-linking-based protein assembly detection, co-immunoprecipitation\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-linking assembly assays plus functional RNA-seq, single lab, mechanistic insights from LC domain studies\",\n      \"pmids\": [\"34035145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP interacts with TEAD1, and this complex inhibits FLI1 expression during endothelial differentiation from pluripotent stem cells. Luciferase assay confirms TEAD1-mediated inhibition of the FLI1 promoter. FLI1 overexpression rescues the inhibition of endothelial differentiation caused by YAP overexpression.\",\n      \"method\": \"Luciferase reporter assay, siRNA/overexpression, microarray analysis, rescue experiments\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay plus functional rescue experiments, single lab\",\n      \"pmids\": [\"34666000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fli-1 promotes the transcription of Th1/Th17 pathways and TCR-inducible transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells, as revealed by single-cell RNA-seq analysis of heterozygous and homozygous Fli1-deficient T cells.\",\n      \"method\": \"Genetic Fli-1 deletion (hetero- and homozygous), single-cell RNA-seq, GVHD allogeneic models, xenograft model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq in genetic model with in vivo disease validation, single lab\",\n      \"pmids\": [\"36074578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ETV6 competes with EWS-FLI1 for binding to DNA elements enriched for short GGAA repeat sequences. Inactivation of ETV6 allows EWS-FLI1 to overtake and hyper-activate these cis-elements, promoting mesenchymal differentiation with SOX11 as a key downstream target. A dominant-interfering peptide that squelches ETV6 phenocopies these effects and suppresses Ewing sarcoma growth in vivo.\",\n      \"method\": \"Domain-focused CRISPR screen, biochemical DNA binding assays, ChIP-seq/epigenomics, dominant-interfering peptide, in vivo xenograft\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide epigenomic studies, biochemical competition assays, and in vivo functional validation with mechanistic peptide approach\",\n      \"pmids\": [\"36658219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FLI1 orchestrates IDO1 transcriptional activation in response to IFN-γ by regulating expression of CBP and STAT1, facilitating chromatin accessibility at the IDO1 locus. This leads to kynurenine production, CD8+ T cell exhaustion, and Treg differentiation, enabling immune evasion in nasopharyngeal carcinoma.\",\n      \"method\": \"siRNA knockdown, ChIP assays, chromatin accessibility assays, gene expression analysis, T cell co-culture functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and chromatin accessibility assays plus functional immune assays, single lab\",\n      \"pmids\": [\"38816360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FLI1 directly upregulates TIE1 transcription by binding to the TIE1 promoter (demonstrated by ChIP and dual luciferase reporter assay), thereby activating the PI3K/AKT signaling pathway to promote radiotherapy resistance in nasopharyngeal carcinoma.\",\n      \"method\": \"ChIP, dual luciferase reporter assay, RNA-seq, loss/gain-of-function in vitro and in vivo\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay confirming direct promoter binding, single lab\",\n      \"pmids\": [\"36814284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLI1 variants (c.1010G>A and c.1033A>G) cause macrothrombocytopenia with dense granule deficiency. Carrier platelets show defects in aggregation, ATP secretion, and mepacrine uptake/release. In vitro megakaryocyte studies reveal maturation defect and reduced proplatelet formation. The FLI1 variants show significantly reduced nuclear accumulation and transcriptional activity.\",\n      \"method\": \"High-throughput gene sequencing, electron microscopy, flow cytometry, megakaryocyte differentiation from CD34+ cells, transcriptional activity assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional variant characterization in patient cells with in vitro megakaryocyte modeling, single lab\",\n      \"pmids\": [\"28255014\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLI1 is an ETS family transcription factor that binds GGAA-containing DNA sequences through its C-terminal ETS domain (which can homodimerize), activates or represses target gene transcription through context-dependent interactions with co-factors including RUNX1, GATA-1, EKLF, CBP, Sp1, and RHA, directly regulates genes controlling hematopoiesis (BCL-2, c-mpl, GATA-1, SHIP-1), vascular homeostasis (Tek/Tie-2, TIE1), immunity (CCL5, G-CSF, GM-CSF, caspase-1, IDO1), and collagen production (COL1A2); its protein stability is controlled by SPOP-mediated ubiquitination (enhanced by CK1 phosphorylation of a VTSSS degron) opposed by the deubiquitinase OTUD7A; and it participates in a recursive gene-regulatory network with GATA2 and SCL during hematopoietic stem cell specification, while in CD8+ T cells it restrains effector differentiation by occupying cis-regulatory elements that otherwise allow Runx3-driven effector programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FLI1 is an ETS-family sequence-specific transcription factor that orchestrates hematopoietic, megakaryocytic, vascular, and immune gene-regulatory programs through a C-terminal ETS DNA-binding domain that recognizes GGAA-core elements [#2, #5, #14]. Its DNA-binding domain can form a helix-swapped homodimer (disrupted by the F362A mutation), enabling regulation at promoters bearing multiple FLI1 sites [#22]. FLI1 acts in a context-dependent manner—as an activator or repressor—through both autonomous activation domains and combinatorial protein partnerships: it interacts with RUNX1 in a phosphorylation-controlled (Ser10) switch to synergistically drive megakaryocytic genes such as c-mpl [#15], with EKLF and GATA-1 to balance erythroid versus megakaryocytic fate [#9], and with Sp1 to repress collagen COL1A2 production in fibroblasts [#6]. It participates in a recursively wired triad with GATA2 and SCL/TAL1 during hematopoietic stem cell specification and autoregulates its own locus, including through a Fli-1–miR-145 repressive loop [#14, #8, #17]. FLI1 directly binds and transactivates survival and lineage genes including BCL-2 [#7], and is required in vivo for vascular integrity via Tek/Tie-2, with its loss causing embryonic vascular failure and dysmegakaryopoiesis [#5]. It broadly governs inflammatory and immune gene expression—directly occupying CCL5, G-CSF, GM-CSF, caspase-1, IL33/IL6, and IDO1 regulatory regions—where its output is tuned by phosphorylation and acetylation [#19, #23, #36, #33, #29, #43]. In CD8+ T cells FLI1 restrains effector differentiation by occupying ETS:RUNX cis-elements that otherwise license Runx3-driven effector programs [#34]. FLI1 protein stability is set by SPOP-mediated ubiquitination, enhanced by CK1 phosphorylation of a VTSSS degron and opposed by the deubiquitinase OTUD7A [#38]. The oncogenic EWS-FLI1 fusion repurposes these activities, creating de novo enhancers at non-conserved GGAA microsatellites while displacing wild-type ETS factors at conserved enhancers [#20], with competition from ETV6 and ETS1 shaping its genomic occupancy [#42]. FLI1 missense variants cause autosomal macrothrombocytopenia with platelet granule and secretion defects [#45].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that FLI1 encodes an ETS-family protein with a conserved DNA-binding domain framed it as a candidate sequence-specific transcription factor and placed it within a defined ETS subset.\",\n      \"evidence\": \"cDNA cloning and structural domain mapping of the 452-residue human protein\",\n      \"pmids\": [\"1394211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration of DNA-binding specificity or target genes at this stage\", \"Functional role of the 5'-ETS homology region undefined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining the ETS domain as necessary and sufficient for binding a specific GGAA-core consensus established the molecular grammar of FLI1 target-site recognition.\",\n      \"evidence\": \"Binding-site selection and truncation analysis with in vitro DNA binding assays\",\n      \"pmids\": [\"7517940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro consensus does not establish in vivo occupancy\", \"Does not address cofactor-dependent target selection\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping two autonomous activation domains and showing the EWS fusion potentiates the C-terminal domain distinguished wild-type transcriptional output from the stronger oncogenic fusion.\",\n      \"evidence\": \"Deletion analysis and transcriptional activation assays in cell lines\",\n      \"pmids\": [\"7503813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors mediating activation not identified\", \"Native target genes not yet defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The Fli-1 knockout showed FLI1 is required in vivo for vascular integrity (via Tek/Tie-2) and normal megakaryopoiesis, anchoring its physiological role beyond in vitro transcription.\",\n      \"evidence\": \"Targeted null mouse with histology and gene expression analysis\",\n      \"pmids\": [\"10981960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality limits analysis of later/tissue-specific roles\", \"Direct versus indirect regulation of Tek not resolved at the chromatin level\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reciprocal interactions with EKLF and GATA-1 revealed FLI1 as a bifunctional regulator that balances erythroid versus megakaryocytic fate through both intrinsic repression and partner recruitment.\",\n      \"evidence\": \"Co-IP, Gal4 domain mapping, and promoter reporter assays across cell types\",\n      \"pmids\": [\"12556498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of direct repression versus tethering not separated in vivo\", \"Switch controlling activator versus repressor mode not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying BCL-2 as a directly bound, functionally required FLI1 target linked FLI1 transcriptional activity to survival of transformed erythroblasts.\",\n      \"evidence\": \"ChIP, in vitro binding, mutant rescue, and BCL-2 inhibitor studies\",\n      \"pmids\": [\"11847117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of the survival program to normal cells unclear\", \"Cofactors at the BCL-2 promoter not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating a fully connected GATA2–FLI1–SCL enhancer triad established FLI1 as a node in a recursive regulatory network specifying hematopoietic stem cells.\",\n      \"evidence\": \"ChIP, enhancer reporter assays, and transgenic analysis\",\n      \"pmids\": [\"17962413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of triad assembly over differentiation not resolved\", \"Quantitative weight of each input on Fli1+12 enhancer undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that Ser10 dephosphorylation gates FLI1–RUNX1 interaction during megakaryocyte differentiation revealed a phospho-switch coupling signaling to combinatorial transcription.\",\n      \"evidence\": \"Complex purification, reciprocal co-IP, gel filtration, and phosphomimetic mutagenesis in primary megakaryocytes\",\n      \"pmids\": [\"19470763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase acting on Ser10 not identified\", \"Whether the switch operates at other FLI1 targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of the apo and DNA-bound FLI1 DBD revealed a helix-swapped homodimer, providing a structural basis for cooperative regulation at multi-site promoters.\",\n      \"evidence\": \"X-ray crystallography with F362A dimer-disrupting mutagenesis\",\n      \"pmids\": [\"26618620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of DBD dimerization not directly tested at native loci\", \"Which target promoters require dimerization unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping direct FLI1 occupancy of inflammatory cytokine/chemokine promoters (CCL5, G-CSF, GM-CSF) showed FLI1 is a dose-dependent transcriptional driver whose output is tuned by acetylation and phosphorylation.\",\n      \"evidence\": \"ChIP, reporter assays, and site-directed mutagenesis of DNA-binding and modification sites\",\n      \"pmids\": [\"25098295\", \"27431361\", \"33268481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymes responsible for the modifications not all identified\", \"Cell-type specificity of these promoter programs not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockouts and human variant/iPSC studies extended FLI1 function to thymic AIRE control, fibroblast cytokine restraint, megakaryocyte maturation, and human macrothrombocytopenia.\",\n      \"evidence\": \"Tissue-specific Cre knockouts, ChIP, patient/isogenic iPSC megakaryocytes, and variant transcriptional assays\",\n      \"pmids\": [\"28232470\", \"29415756\", \"28432223\", \"28255014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between haploinsufficiency dosage and distinct phenotypes incompletely resolved\", \"Direct targets driving autoimmunity/fibrosis not fully enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide chromatin and in vivo CRISPR studies in CD8+ T cells defined FLI1 as a brake on effector differentiation by occupying ETS:RUNX cis-elements competing with Runx3.\",\n      \"evidence\": \"In vivo CRISPR screen, conditional deletion, ATAC-seq/ChIP-seq, and infection/tumor models\",\n      \"pmids\": [\"33636129\", \"36074578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FLI1 occupancy reduces accessibility not fully resolved\", \"Lineage-specific cofactors distinguishing CD4 versus CD8 effects undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying SPOP/CK1/OTUD7A control of the VTSSS degron established the post-translational machinery setting FLI1 (and EWS-FLI1) protein abundance.\",\n      \"evidence\": \"Ubiquitination assays, phospho-degron mapping, reciprocal co-IP, and xenograft validation\",\n      \"pmids\": [\"34060252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling CK1 activity on the degron not defined\", \"Whether degron control is differentiation-stage-regulated unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking FLI1 to IDO1/TIE1 transcriptional programs connected FLI1 to immune evasion and therapy resistance in carcinoma, broadening its role into the tumor immune microenvironment.\",\n      \"evidence\": \"ChIP, chromatin accessibility, RNA-seq, and T-cell co-culture functional assays\",\n      \"pmids\": [\"38816360\", \"36814284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal hierarchy between FLI1, CBP/STAT1, and IDO1 not fully dissected\", \"Generalizability beyond nasopharyngeal carcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FLI1's mode-switching between activation and repression is selected at individual loci—integrating partner identity, post-translational modification, DBD dimerization, and chromatin state—remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phospho/acetyl state to activator-versus-repressor output genome-wide\", \"Stoichiometry of cofactor competition (ETS1, ETV6, EKLF) at native loci unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 6, 7, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 9, 6, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [45]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 6, 9, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 14, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [34, 41, 43]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RUNX1\", \"GATA1\", \"EKLF\", \"SP1\", \"CBP\", \"ERG\", \"GATA2\", \"SCL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}