{"gene":"YY1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate enhancer-promoter looping. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression, establishing YY1 as a structural regulator of enhancer-promoter interactions analogous to CTCF.","method":"ChIP-seq, HiChIP, CRISPR deletion of binding sites, auxin-inducible degron protein depletion, chromosome conformation capture","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP-seq, looping assays, protein depletion, site deletion), rigorous controls, broadly replicated concept","pmids":["29224777"],"is_preprint":false},{"year":2024,"finding":"Acute degradation of YY1 in erythroid cells revealed its requirement for maintenance of enhancer-promoter loops but not compartments or TADs. YY1-dependent enhancer-promoter loop formation does not involve stalling of cohesin-mediated loop extrusion. YY1 is partially retained on mitotic chromatin at gene promoters and rapidly rebinds during mitotic exit coinciding with enhancer-promoter loop establishment; cell cycle stage influences YY1's architectural function.","method":"Auxin-inducible degron acute degradation, Hi-C, ChIP-seq, mitosis-to-G1 cell synchronization","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — acute degradation with multiple orthogonal genomic methods, cell-cycle-resolved experiments, rigorous controls","pmids":["39210046"],"is_preprint":false},{"year":1993,"finding":"YY1 physically associates with c-Myc (but not Max), and c-Myc inhibits both the repressor and activator functions of YY1 in cotransfection experiments, establishing c-Myc as a negative regulator of YY1 transcriptional activity.","method":"Yeast two-hybrid screen, affinity chromatography, cotransfection reporter assays","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by affinity chromatography and functional reporter assays, single lab","pmids":["8266081"],"is_preprint":false},{"year":1993,"finding":"YY1 (identified as CF1) directly binds two sites in the murine c-myc promoter (-260 and -390 bp from P1) and strongly activates c-myc transcription; overexpression of YY1 in erythroleukemia cells increases endogenous c-myc mRNA from both major initiation sites.","method":"Protein purification, immunological cross-reactivity, recombinant protein binding assays, cotransfection reporter assays, Northern blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical purification, recombinant protein validation, functional reporter assays, endogenous gene analysis, multiple orthogonal methods","pmids":["8246966"],"is_preprint":false},{"year":2023,"finding":"YY1 is lactylated at lysine 183 (K183) by the acetyltransferase p300; hyperlactylated YY1 directly enhances FGF2 transcription and promotes angiogenesis. YY1 K183 mutation eliminates these effects, and p300 overexpression increases YY1 lactylation and angiogenesis.","method":"Mass spectrometry identification of lactylation sites, site-directed mutagenesis (K183), ChIP, luciferase reporter assays, p300 inhibitor A485 in vivo/in vitro","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — PTM identified by MS, writer identified (p300), mutagenesis confirms function, in vivo validation, multiple orthogonal methods in single lab","pmids":["37085894"],"is_preprint":false},{"year":2024,"finding":"YY1 is lactylated at an unspecified site(s) by p300 in microglia; this lactylation promotes microglial activation by upregulating transcription of inflammatory genes including STAT3, CCL5, IRF1, IDO1, and SEMA4D. Inhibition of p300 decreases YY1 lactylation and suppresses microglial inflammation.","method":"CUT&Tag analysis, p300 inhibitor treatment, in vivo/in vitro inflammation assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — CUT&Tag confirms transcriptional targets of lactylated YY1, p300 identified as writer, in vivo/in vitro validation, single lab","pmids":["38493498"],"is_preprint":false},{"year":2007,"finding":"Conditional ablation of YY1 in mouse B cells caused a defect in somatic V(H)D(H)J(H) rearrangement, a block in pro-B to pre-B cell transition, and impaired IgH locus contraction. YY1 binds the intronic Eµ enhancer within the IgH locus, indicating a direct role in controlling long-distance DNA interactions required for V(H)D(H)J(H) recombination.","method":"Conditional knockout (Cre-loxP), 3D DNA FISH, ChIP, B-cell development assays, IgH transgene rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined developmental phenotype rescued by transgene, direct YY1 binding shown by ChIP, 3D FISH for locus contraction","pmids":["17504937"],"is_preprint":false},{"year":2004,"finding":"In Drosophila, YY1 can recruit Polycomb group (PcG) proteins to Polycomb response elements, leading to deacetylation and methylation of histone H3. This PcG recruitment and concomitant histone modification require CtBP; in a CtBP mutant background, YY1 DNA binding in vivo is also ablated without YY1 degradation or nuclear export, suggesting CtBP controls YY1 DNA-binding ability.","method":"In vivo Drosophila genetics (CtBP mutant), ChIP, histone modification assays, immunostaining","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in Drosophila with ChIP validation of histone modifications and DNA binding, multiple orthogonal readouts","pmids":["15520279"],"is_preprint":false},{"year":2013,"finding":"YY1 physically interacts with YAF2, which bridges YY1 to the PRC1 complex. YAF2 is responsible for PcG recruitment to DNA mediated by YY1 DNA binding; knockdown of YY1 abolishes PcG recruitment and is not compensated by exogenous YAF2, demonstrating YY1 DNA binding is required for Polycomb chromatin assembly.","method":"Biochemical pulldown, Co-IP, ChIP assays in HeLa cells, Drosophila complementation genetics, siRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, genetic rescue across species, multiple orthogonal approaches, single lab","pmids":["24285299"],"is_preprint":false},{"year":2014,"finding":"YY1 assembles into homo-oligomeric species built from a bell-shaped dimer, characterized by electron microscopy. YY1 self-association occurs in vivo (bimolecular fluorescence complementation). YY1 oligomers bind DNA substrates lacking the consensus YY1 sequence in vitro, and DNA binding is enhanced by RuvBL1-RuvBL2 ATPases. YY1 oligomers bind RuvBL1-RuvBL2, preferentially interacting with RuvBL1. YY1 and the ATPase activity of RuvBL2 are required for RAD51 foci formation during homologous recombination.","method":"Electron microscopy, bimolecular fluorescence complementation, in vitro DNA binding assays, Co-IP/pulldown, RAD51 foci assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — EM structure, in vitro reconstitution, in vivo validation, multiple orthogonal methods in single study","pmids":["24990942"],"is_preprint":false},{"year":2016,"finding":"SET7/9 (KMT7) methylates YY1 at K173 and K411; this methylation regulates YY1 DNA-binding activity both in vitro and at specific genomic loci in cells, and affects YY1-regulated gene transcription and cell proliferation.","method":"In vitro methyltransferase assay, site-directed mutagenesis, ChIP, reporter assays, cell proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay, mutagenesis, in vivo ChIP validation, single lab","pmids":["26902152"],"is_preprint":false},{"year":2015,"finding":"YY1 is tyrosine-phosphorylated by multiple Src family kinases in vitro and in vivo. Phosphorylation at tyrosine 383 interferes with DNA and RNA binding, leading to downregulation of YY1 transcriptional activity. YY1 is also a downstream target of EGFR signaling in vivo.","method":"Pharmacological kinase inhibition, kinase overexpression, kinase knockout, site-directed mutagenesis (Y383), DNA/RNA binding assays, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple kinase approaches (inhibition, OE, KO), mutagenesis of phosphosite, functional binding assays, single lab with multiple orthogonal methods","pmids":["26198631"],"is_preprint":false},{"year":2014,"finding":"Smurf2 E3 ubiquitin ligase physically interacts with YY1 via a PPxY motif on YY1, induces poly-ubiquitination of YY1, and shortens YY1 protein half-life via the ubiquitin-proteasome pathway. Smurf2 reduces YY1-mediated transcriptional activation and relieves YY1-mediated suppression of p53 activity.","method":"Co-IP, ubiquitination assay, half-life assay (cycloheximide chase), PPxY mutant analysis, reporter assays, siRNA knockdown","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, half-life measurement, mutagenesis, functional reporter assays, single lab","pmids":["24803334"],"is_preprint":false},{"year":2016,"finding":"YY1 promotes AKT phosphorylation at S473 through direct physical interaction with AKT; the AKT-binding site maps to residues G201-S226 (designated the OPB domain) on YY1. YY1-promoted AKT phosphorylation is mediated through mTORC2, is independent of PI3K activity and YY1 transcriptional activity. A peptide based on the OPB domain blocks YY1-AKT interaction and reduces AKT phosphorylation and cell proliferation.","method":"Co-IP, domain mapping, mTORC2 interaction assays, pharmacological PI3K inhibition, peptide competition, cell proliferation assays, tissue microarray","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping, peptide competition, functional rescue experiments, single lab","pmids":["26762111"],"is_preprint":false},{"year":2009,"finding":"YY1 physically interacts with androgen receptor (AR) both in cell-free systems and in cultured cells. YY1 is required for optimal AR transcriptional activity at the PSA promoter and is a necessary component of the complex binding the androgen response element. YY1 depletion reduces endogenous PSA levels in LNCaP cells.","method":"Co-IP, cell-free binding assay, ChIP, luciferase reporter assay, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP in cell-free and cellular systems, ChIP confirms complex at target promoter, functional reporter assay, single lab","pmids":["19668226"],"is_preprint":false},{"year":2020,"finding":"YAP interacts with YY1 and EZH2 to function as a transcriptional repressor. YAP colocalization with YY1 and EZH2 on the genome represses genes including the cell-cycle inhibitor p27, contributing to loss of contact inhibition.","method":"Genome-wide ChIP-seq, Co-IP, transcriptome profiling, loss-of-function experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP confirmed interaction, genome-wide ChIP-seq, functional gene expression analysis, single lab","pmids":["32409309"],"is_preprint":false},{"year":2020,"finding":"Endothelial cell-specific YY1 deletion causes embryonic lethality due to vascular defects. YY1 functions as a repressor of Notch signaling by binding to the N-terminal domain of RBPJ and competing with MAML1 for RBPJ binding, thereby impairing NICD/MAML1/RBPJ complex formation and Notch target gene expression to control endothelial tip-stalk fate determination.","method":"Conditional endothelial-specific KO (Cre-loxP), retinal sprouting angiogenesis assay, Co-IP, domain-mapping binding assays, Notch target gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo vascular phenotype, direct protein-protein interaction mapped, mechanistic competition assay, multiple orthogonal methods, single lab","pmids":["32075915"],"is_preprint":false},{"year":2021,"finding":"Disturbed flow induces phosphorylation of YY1 at serine 118 (phospho-YY1-S118) in endothelial cells via direct interaction with CK2α (casein kinase 2α). Phospho-YY1-S118 directly binds ZKSCAN4, inducing HDM2 promoter activity and gene expression, which promotes EC proliferation through downregulation of p53 and p21. EC-specific expression of a S118-nonphosphorylatable YY1 mutant in ApoE-deficient mice reduces atherosclerosis formation.","method":"Phosphoproteomics, yeast 2-hybrid screening, in situ proximity ligation, Co-IP, transgenic mouse model (EC-specific S118A mutant), ApoE-KO atherosclerosis model, CK2 inhibitor treatment","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphoproteomics identifies site, kinase identified by direct interaction, mutagenesis in transgenic mice confirms function in vivo, multiple orthogonal methods","pmids":["34747636"],"is_preprint":false},{"year":2013,"finding":"YY1 interacts with Smad7, and this interaction is attenuated by TGF-β signaling. YY1 and Smad7 act in concert to inhibit TGF-β-induced transcription in the nucleus. Smad7 enhances YY1's interaction with HDAC1, and YY1 and HDAC1 augment the transcriptional repression activity of Smad7.","method":"Co-IP, reporter assays, target gene expression analysis, Gal4-luciferase reporter","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP demonstrates interaction, functional reporter assays with multiple components, single lab","pmids":["24369345"],"is_preprint":false},{"year":2019,"finding":"YY1 binds the TGFB1 promoter and represses TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 overexpression attenuates glomerulosclerosis and YY1 knockdown aggravates it, establishing YY1 as a potent transcriptional repressor of TGFB1.","method":"Mass spectrometry-based DNA-protein interaction screen, ChIP, luciferase reporter, siRNA knockdown/adenoviral overexpression in mouse models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — MS-based screen, direct ChIP binding, functional reporter, in vivo mouse model rescue/aggravation, multiple orthogonal methods","pmids":["31534017"],"is_preprint":false},{"year":2008,"finding":"YY1 recognizes longer DNA-binding motifs (GGCGCCATnTT and CCGCCATnTT) beyond the known consensus (CGCCATnTT). Gel shift assays demonstrate higher affinity for the longer motif. Substitutions in the first zinc finger unit weaken DNA-binding specificity at both 5'- and 3'-flanks of the longer motif, indicating the first zinc finger is required for recognition of the extended motif and that DNA recognition involves concerted contribution of all four zinc finger units.","method":"Gel shift assays (EMSA), in vitro DNA-binding motif studies, zinc finger mutagenesis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical binding assays with mutagenesis, single lab","pmids":["18950698"],"is_preprint":false},{"year":2015,"finding":"YY1 is a transcriptional repressor of FEN1; YY1 binds the FEN1 promoter and suppresses FEN1 expression. In response to chemotherapeutic drugs (MMC, Taxol), YY1 is dissociated from the FEN1 promoter, leading to FEN1 overexpression. Overexpression of YY1 in cancer cells downregulates FEN1 and sensitizes cells to these drugs.","method":"ChIP, luciferase reporter assay, siRNA knockdown/overexpression, drug sensitivity assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP demonstrates direct binding, functional reporter and drug sensitivity assays, single lab","pmids":["25885449"],"is_preprint":false},{"year":2019,"finding":"YY1 regulates Bmp7 and Ctgf reporter activities and modulates their gene expression in cardiomyocytes. Upregulation of YY1 suppresses LMNA-deficiency-induced dilated cardiomyopathy and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf, which in turn downregulates TGF-β/Smad signaling.","method":"shRNA-induced Lmna DCM mouse model, adenoviral YY1 overexpression, Bmp7 knockdown, Ctgf silencing, reporter assays, gene expression analysis","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo mouse model with multiple genetic interventions, reporter assays for Bmp7/Ctgf, epistasis experiments, single lab","pmids":["31495264"],"is_preprint":false},{"year":2010,"finding":"TGF-β induces YY1 expression in lung fibroblasts via NF-κB (blocked by IκB degradation inhibitor). YY1 upregulates α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/-) mice are significantly protected from lung fibrosis with attenuated α-SMA and collagen expression; conditional YY1 deletion via adenovirus-Cre reduced lung fibrosis in floxed mice.","method":"Conditional knockout mice (Cre-loxP, partial heterozygous), NF-κB inhibition, α-SMA promoter reporter, siRNA knockdown, bleomycin/silica fibrosis models","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models, conditional KO, reporter assays linking YY1 to α-SMA promoter, pharmacological epistasis, single lab","pmids":["21169469"],"is_preprint":false},{"year":2012,"finding":"YY1 promotes hepatic gluconeogenesis by transcriptionally upregulating glucocorticoid receptor (GR) expression. Liver-specific ablation of YY1 via adenoviral shRNA ameliorates hyperglycemia in wild-type and diabetic db/db mice; YY1 overexpression in liver augments gluconeogenesis and raises fasting blood glucose.","method":"Adenoviral shRNA knockdown, adenoviral overexpression, liver-specific genetic manipulation, blood glucose measurement, gene expression analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo liver-specific gain/loss of function, GR as downstream mechanism identified, single lab","pmids":["23193188"],"is_preprint":false},{"year":2009,"finding":"YY1 knockdown during oogenesis results in loss of DNA methylation on Peg3 and Xist DMRs but not Nespas or H19. Continued YY1 knockdown from oogenesis to blastocyst causes further loss of DNA methylation on Peg3, and high incidence of embryonic lethality follows, indicating YY1 plays a role in de novo DNA methylation of these imprinted loci during oogenesis.","method":"Conditional YY1 knockdown (stage-specific), bisulfite sequencing of DMRs, embryo phenotyping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — stage-specific knockdown with direct methylation readout, single lab, specific DMR effects","pmids":["19628663"],"is_preprint":false},{"year":2016,"finding":"YY1 promotes thymocyte survival by suppressing p53 expression; YY1-deficient thymocytes show increased apoptosis and developmental block, which is completely rescued by concurrent loss of p53, placing YY1 upstream of p53 in thymocyte survival pathway.","method":"Conditional KO (Cre-loxP at two developmental stages), double KO (YY1/p53), flow cytometry, apoptosis assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis (double KO rescue), stage-specific conditional KO, defined phenotypic readout, replicates YY1-p53 regulatory axis","pmids":["26843327"],"is_preprint":false},{"year":2018,"finding":"YY1 directly binds the PLZF gene promoter (shown by ChIP-seq) and activates PLZF transcription; YY1-deficient thymocytes undergo normal Vα14-Jα18 rearrangements but display impaired survival and fail to develop iNKT cells due to absent PLZF induction.","method":"Conditional KO (Cre-loxP), ChIP-seq, deep sequencing of Vα14-Jα18 rearrangements, flow cytometry, apoptosis assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined developmental phenotype, ChIP-seq directly demonstrates YY1 binding to PLZF promoter, multiple orthogonal methods","pmids":["29500401"],"is_preprint":false},{"year":2007,"finding":"YY1 and E2F1 physically interact in the nucleus and synergistically activate p73 promoter activity. Both factors are required for doxorubicin-induced p73 promoter activation; YY1 silencing reduces endogenous p73 expression, while YY1 overexpression induces p73 promoter activity.","method":"Co-IP, immunofluorescence, luciferase reporter assay, siRNA knockdown, doxorubicin treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP demonstrates physical interaction, reporter assays with gain/loss of function, single lab","pmids":["17980704"],"is_preprint":false},{"year":2016,"finding":"YY1 directly binds the BAX promoter (shown by luciferase reporter, EMSA, and ChIP assays) and transcriptionally activates Bax, promoting its mitochondrial localization, cytochrome c release, and caspase activation in pancreatic cancer cells.","method":"Luciferase reporter assay, EMSA, ChIP, Western blotting, mitochondrial fractionation, caspase activation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct DNA binding by EMSA and ChIP, functional reporter, downstream apoptotic pathway validated, single lab","pmids":["27074573"],"is_preprint":false},{"year":2022,"finding":"In pancreatic β-cells, YY1 directly binds enhancer regions in exon 2 of Ins1 and Ins2 genes and activates insulin transcription. YY1 also directly interacts with RNA polymerase II, potentially stabilizing enhancer-promoter interactions during transcription initiation. β-cell-specific Yy1 ablation causes rapid-onset hyperglycemia and reduced β-cell mass.","method":"Conditional KO, ChIP assays (YY1, H3K4me1, H3K27ac, H3K27me3), RNA-seq, luciferase reporter assays, Co-IP (YY1-Pol II)","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo phenotype, direct ChIP binding at target enhancers, Co-IP with Pol II, reporter assays, multiple orthogonal methods","pmids":["35113157"],"is_preprint":false},{"year":2001,"finding":"YY1 binds to the myelin PLP promoter in vitro and in vivo (via yeast one-hybrid and gel shift/supershift with YY1 antibody). Overexpression of YY1 in oligodendrocyte cell lines enhances PLP promoter transcription; a truncated YY1 containing only the four zinc finger domains has little effect, indicating the non-zinc-finger domains are required for transactivation.","method":"Yeast one-hybrid, gel shift assay, antibody supershift, cotransfection reporter assay, promoter mutation analysis","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast one-hybrid confirmed by EMSA and in vivo binding, functional reporter with domain truncation, single lab","pmids":["11331422"],"is_preprint":false},{"year":2014,"finding":"YY1 regulates SQSTM1 expression through epigenetic modulation of MIR372 transcription; YY1 suppresses MIR372 expression during nutrient starvation, leading to increased SQSTM1 (p62) and autophagy flux activation. YY1 knockdown inhibits cell viability and autophagy flux through SQSTM1 downregulation.","method":"siRNA knockdown, miRNA overexpression, luciferase reporter assay, autophagy flux assays (LC3-II, electron microscopy), in vivo tumor growth","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis between YY1, miR-372, and SQSTM1 established by gain/loss experiments, functional autophagy assays, single lab","pmids":["24991827"],"is_preprint":false},{"year":2017,"finding":"YY1 activates GLUT3 transcription by directly binding to its promoter, enhancing tumor cell aerobic glycolysis in a p53-independent manner. This regulation is critical for YY1-induced tumor cell proliferation and tumorigenesis. Oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis.","method":"ChIP, luciferase reporter assay, siRNA knockdown/overexpression, glycolysis assays, cell proliferation assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP demonstrates direct binding, reporter assay confirms promoter activation, functional metabolic and proliferation readouts, single lab","pmids":["29869834"],"is_preprint":false},{"year":2024,"finding":"PHF8 demethylates YY1 (at methylation sites established by SET7/9), functioning as a co-repressor with YY1 for nuclear-encoded ETC genes, driving mitochondrial ROS production and cancer cell growth. PHF8 pharmacological inhibition (iPHF8) regulates YY1 methylation, ETC gene transcription, mROS production, and suppresses tumor growth in xenograft models.","method":"PHF8 knockout/inhibition, YY1 methylation assays, ETC gene expression profiling, mROS measurement, cell-line and PDX xenograft models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — PHF8 identified as YY1 demethylase with functional consequences on target genes and in vivo tumor growth, single lab","pmids":["38165927"],"is_preprint":false},{"year":2024,"finding":"OTUD3 deubiquitinase physically interacts with YY1, inhibits its ubiquitin-proteasome-mediated degradation, and increases YY1 protein levels. PLK1 phosphorylates OTUD3 at S326, enhancing OTUD3 binding to and deubiquitination of YY1.","method":"DUB screen, Co-IP, ubiquitination assay, cycloheximide chase, PLK1 kinase assay, phospho-mutant analysis, CRC cell proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, phosphorylation-dependent mechanism, single lab","pmids":["38351178"],"is_preprint":false},{"year":2019,"finding":"In un-stimulated neurons, a YY1-Brd4 transcription factor complex assembled at the Senp1 promoter activates Senp1 transcription. Upon neuronal membrane depolarization, YY1 is dephosphorylated and the YY1-Brd4 complex is evicted from the Senp1 promoter, reducing Senp1 transcription and subsequently decreasing GluR1 expression.","method":"Co-IP, ChIP, in vitro DNA binding assay, luciferase reporter assay, siRNA knockdown, phosphatase inhibitor experiments, qRT-PCR/Western blot","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP confirms YY1-Brd4 interaction, ChIP confirms complex eviction, functional reporter and KD experiments, single lab","pmids":["31629407"],"is_preprint":false},{"year":2024,"finding":"YY1 is recruited by direct interaction with Neurogenin2 (Ngn2) to Ngn2 target sites during astrocyte-to-neuron reprogramming. Upon Yy1 deletion, activation of neuronal enhancers and genes and reprogramming efficiency are impaired without affecting Ngn2 binding, indicating YY1 acts as a required cofactor downstream of Ngn2 binding.","method":"Single-cell multiomics, ChIP-seq, genome-wide 3D nuclear architecture profiling, DNA methylation profiling, conditional Yy1 deletion, Ngn2 Co-IP","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed, conditional KO with defined reprogramming phenotype, multi-omics validation of epigenome remodeling, multiple orthogonal approaches","pmids":["38956165"],"is_preprint":false},{"year":2022,"finding":"YY1 depletion in extended pluripotent stem cells (EPSCs) triggers changes in DNA methylation, histone modifications, and high-order chromatin structures including disruption of enhancer-promoter interactions for EPSC-specific genes. YY1 loss results in DNA hypomethylation and reduced H3K4me3 and H3K27ac at EPSC-specific gene promoters (including Dnmt3l) by upregulating Kdm5c and Hdac6 through facilitation of CTCF-mediated EP interactions at their loci.","method":"siRNA knockdown, ChIP-seq (multiple histone marks), ATAC-seq, Hi-C, WGBS, scRNA-seq, luciferase reporter","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive multi-omics in single lab, loss-of-function with epigenetic mechanistic follow-up, single lab","pmids":["35425987"],"is_preprint":false},{"year":2017,"finding":"YY1 interacts with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression decreases. YY1 knockdown reduces phosphorylated TBK1 and pIRF3 (impairing IFN-β production), while YY1 overexpression upregulates pTBK1 and pIRF3 and promotes IFN-β induction. YY1 knockdown upregulates pSTAT1/pSTAT2 and antiviral ISGs and inhibits viral replication.","method":"Co-IP, siRNA knockdown, overexpression, immunoblotting, real-time PCR","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifies STAT1 interaction, reciprocal gain/loss experiments with defined signaling readouts, single lab","pmids":["29161701"],"is_preprint":false},{"year":2023,"finding":"YY1 directly binds the minimal promoter of TREM2 and activates its transcription in microglial cells; YY1 silencing reduces TREM2 promoter activity and protein levels in BV2 and Neuro2A cells.","method":"Luciferase assay, DNA pull-down, EMSA, shRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple direct binding methods (pull-down, EMSA), functional reporter assay, loss-of-function, single lab","pmids":["37044212"],"is_preprint":false},{"year":2023,"finding":"YY1 forms a phase-separated complex (LLPS) in M2 macrophages with p300, p65, and CEBPB as transcriptional cofactors; this complex upregulates IL-6 by promoting IL-6 enhancer-promoter interactions revealed by H3K27ac ChIP-seq and YY1 ChIP-seq.","method":"LLPS assay, H3K27ac ChIP-seq, YY1 ChIP-seq, CRISPR-Cas9 KO, RNA-seq, Co-IP","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP-seq establishes YY1 at M2-specific enhancers, LLPS assay, CRISPR KO, single lab","pmids":["37094986"],"is_preprint":false},{"year":2015,"finding":"YY1 N-terminal domain is an intrinsically disordered region with little residual secondary structure and no defined tertiary structure, as characterized by fluorescence, circular dichroism, gel filtration, and proteolytic susceptibility assays. The full-length YY1 protein belongs to the family of intrinsically disordered proteins.","method":"Fluorescence spectroscopy, circular dichroism, gel filtration chromatography, proteolytic susceptibility, bioinformatics","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods characterizing protein structure, but no functional consequence linked, single lab","pmids":["25963536"],"is_preprint":false},{"year":2019,"finding":"YY1 directly regulates Bmp7 and Ctgf promoter/reporter activities in cardiomyocytes; overexpression of YY1 maintains H3K9Ac, H3K27Ac, and H3K4Me3 at the Nkx2-5 cardiac enhancer along with enrichment of Pol II, p300, and Brg1, thereby maintaining cardiac progenitor cell state and preventing cardiomyogenic differentiation.","method":"ChIP (multiple histone marks), luciferase reporter assay, YY1 overexpression in cardiac progenitor cells, genome-wide transcriptional profiling","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP at target enhancer, reporter assays, functional phenotypic readout, single lab","pmids":["28580685"],"is_preprint":false}],"current_model":"YY1 is a multifunctional zinc finger transcription factor that acts as a structural organizer of enhancer-promoter chromatin loops (forming dimers at active regulatory elements, independent of cohesin-mediated loop extrusion), recruits Polycomb repressive complexes to chromatin via YAF2 and CtBP, activates or represses transcription of diverse target genes (including c-Myc, BRCA1, BAX, insulin, PLP, TREM2, GLUT3, PLZF, and TGFβ1) depending on cofactor context, and is regulated by multiple post-translational modifications including tyrosine phosphorylation (Src family kinases/EGFR; Y383 blocks DNA binding), serine phosphorylation (CK2α at S118 promotes atherosclerosis), lysine methylation (SET7/9 at K173/K411; demethylated by PHF8 to repress ETC genes), lysine lactylation (p300 at K183, activating transcription), and ubiquitin-mediated degradation (Smurf2 as E3 ligase; OTUD3 as stabilizing DUB); it also engages non-transcriptional functions including direct interaction with AKT to promote mTORC2-mediated AKT-S473 phosphorylation, interaction with STAT1 to modulate antiviral IFN signaling, and binding to RBPJ to compete with Notch coactivator MAML1 in endothelial cells."},"narrative":{"mechanistic_narrative":"YY1 is a multifunctional zinc finger transcription factor that acts as a structural organizer of the genome, binding active enhancers and promoter-proximal elements and forming dimers that establish and maintain enhancer-promoter loops in a manner analogous to CTCF [PMID:29224777]. Acute degradation studies show this architectural function is required for enhancer-promoter loop maintenance but not for compartments or TADs, operates independently of cohesin-mediated loop extrusion stalling, and is cell-cycle-regulated, with YY1 partially retained on mitotic chromatin and rapidly rebinding promoters during mitotic exit [PMID:39210046]. DNA recognition is achieved through concerted contributions of all four zinc fingers, with the first finger required for engaging an extended binding motif [PMID:18950698], while the N-terminal portion of the protein is an intrinsically disordered region [PMID:25963536]. YY1 directs both activating and repressive transcriptional outputs depending on cofactor context: it recruits Polycomb group proteins to chromatin in a manner requiring CtBP for its DNA binding [PMID:15520279] and is bridged to PRC1 through YAF2 [PMID:24285299], and it interacts with diverse partners including c-Myc [PMID:8266081], androgen receptor [PMID:19668226], E2F1 [PMID:17980704], YAP/EZH2 [PMID:32409309], Smad7/HDAC1 [PMID:24369345], and RNA polymerase II [PMID:35113157] to tune target gene expression. YY1 directly activates or represses a broad target repertoire including c-myc [PMID:8246966], BAX [PMID:27074573], insulin genes [PMID:35113157], GLUT3 [PMID:29869834], TREM2 [PMID:37044212], PLZF [PMID:29500401], and TGFB1 [PMID:31534017], and suppresses p53 to promote cell survival [PMID:26843327]. In vivo, YY1 is essential for V(H)D(H)J(H) recombination and IgH locus contraction in B cells [PMID:17504937], for endothelial development where it represses Notch signaling by competing with MAML1 for RBPJ binding [PMID:32075915], and for insulin gene expression and beta-cell mass [PMID:35113157]. YY1 activity is extensively controlled by post-translational modifications: tyrosine phosphorylation at Y383 by Src-family kinases blocks DNA/RNA binding downstream of EGFR [PMID:26198631], serine phosphorylation at S118 by CK2alpha drives endothelial proliferation and atherosclerosis [PMID:34747636], SET7/9 methylation at K173/K411 modulates DNA binding [PMID:26902152] with PHF8 acting as the demethylating co-repressor at ETC genes [PMID:38165927], p300-mediated lactylation at K183 activates angiogenic transcription [PMID:37085894], and protein stability is set by the opposing actions of the Smurf2 E3 ligase [PMID:24803334] and the OTUD3 deubiquitinase [PMID:38351178]. Beyond transcription, YY1 directly binds AKT to promote mTORC2-mediated AKT-S473 phosphorylation independently of its transcriptional activity [PMID:26762111] and modulates antiviral interferon signaling through interaction with STAT1 [PMID:29161701].","teleology":[{"year":1993,"claim":"Established YY1 as a sequence-specific transcriptional activator with defined endogenous targets and identified c-Myc as a direct interacting negative regulator, defining YY1 as a context-dependent transcription factor rather than a simple activator or repressor.","evidence":"Protein purification, recombinant binding and reporter assays at the c-myc promoter, plus yeast two-hybrid and affinity chromatography for the c-Myc interaction","pmids":["8246966","8266081"],"confidence":"High","gaps":["Did not establish how cofactor context switches YY1 between activation and repression","Mechanism of c-Myc inhibition of YY1 not resolved at the structural level"]},{"year":2001,"claim":"Showed that YY1 transactivation requires domains beyond the zinc fingers, demonstrating that DNA binding and activation are separable functions.","evidence":"Yeast one-hybrid, EMSA/supershift, and reporter assays with a zinc-finger-only truncation at the PLP promoter in oligodendrocyte lines","pmids":["11331422"],"confidence":"Medium","gaps":["Specific transactivation domain not mapped","Single cell-type context"]},{"year":2004,"claim":"Revealed that YY1 recruits Polycomb group proteins and directs repressive histone modifications, and that CtBP is required for YY1 DNA binding in vivo, linking YY1 to Polycomb silencing.","evidence":"Drosophila genetic epistasis in CtBP mutants with ChIP and histone modification readouts","pmids":["15520279"],"confidence":"High","gaps":["Molecular basis of CtBP control over DNA binding unresolved","Conservation of CtBP requirement in mammals not addressed here"]},{"year":2007,"claim":"Demonstrated a direct in vivo requirement for YY1 in long-range DNA interactions controlling antigen receptor diversification, providing early evidence for an architectural function.","evidence":"Conditional B-cell knockout with 3D DNA FISH, ChIP at the Emu enhancer, and IgH transgene rescue","pmids":["17504937"],"confidence":"High","gaps":["Did not distinguish architectural from purely transcriptional roles at the IgH locus","Looping partner proteins not defined"]},{"year":2008,"claim":"Defined the DNA-recognition logic of YY1, showing all four zinc fingers contribute and the first finger enables binding to an extended motif.","evidence":"EMSA and zinc-finger mutagenesis on consensus and extended motifs in vitro","pmids":["18950698"],"confidence":"Medium","gaps":["No co-crystal structure","Genomic relevance of extended motif not tested in cells"]},{"year":2013,"claim":"Identified YAF2 as the bridge connecting YY1 DNA binding to PRC1, establishing a molecular route for YY1-directed Polycomb assembly.","evidence":"Reciprocal Co-IP, ChIP, and cross-species genetic rescue with siRNA knockdown in HeLa cells","pmids":["24285299"],"confidence":"High","gaps":["Stoichiometry of YY1-YAF2-PRC1 complex not defined","Genome-wide scope of YY1/YAF2 Polycomb targets not mapped"]},{"year":2014,"claim":"Characterized YY1 self-association into a bell-shaped dimer/oligomer and linked it to homologous recombination via RuvBL1-RuvBL2, revealing a non-canonical DNA-repair function.","evidence":"Electron microscopy, bimolecular fluorescence complementation, in vitro DNA binding, pulldowns, and RAD51 foci assays","pmids":["24990942"],"confidence":"High","gaps":["Relationship of oligomerization to enhancer-promoter looping not directly tested","Physiological setting of HR function unclear"]},{"year":2016,"claim":"Resolved the YY1-p53 regulatory axis through clean genetic epistasis, showing YY1 promotes survival by suppressing p53.","evidence":"Stage-specific conditional KO and YY1/p53 double KO rescue in thymocytes with apoptosis assays","pmids":["26843327"],"confidence":"High","gaps":["Direct mechanism of p53 suppression by YY1 in thymocytes not detailed","Whether suppression is transcriptional or post-translational not resolved here"]},{"year":2016,"claim":"Uncovered a transcription-independent role for YY1 as a direct AKT-binding scaffold promoting mTORC2-mediated AKT-S473 phosphorylation, expanding YY1 beyond the nucleus.","evidence":"Co-IP, OPB-domain mapping (G201-S226), peptide competition, PI3K inhibition, and proliferation assays","pmids":["26762111"],"confidence":"Medium","gaps":["Subcellular site of YY1-AKT interaction not defined","Structural basis of OPB-AKT contact unknown"]},{"year":2016,"claim":"Established SET7/9 methylation of YY1 at K173/K411 as a direct regulator of its DNA-binding and transcriptional activity, opening the PTM dimension of YY1 control.","evidence":"In vitro methyltransferase assay, mutagenesis, ChIP, reporter and proliferation assays","pmids":["26902152"],"confidence":"Medium","gaps":["Genome-wide consequences of methylation not mapped","Reader of methylated YY1 not identified at the time"]},{"year":2015,"claim":"Defined tyrosine phosphorylation of YY1 at Y383 by Src-family kinases as a switch that blocks DNA/RNA binding downstream of EGFR, linking growth-factor signaling to YY1 inactivation.","evidence":"Kinase inhibition, overexpression and knockout, Y383 mutagenesis, and DNA/RNA binding and reporter assays","pmids":["26198631"],"confidence":"High","gaps":["In vivo physiological contexts of Y383 phosphorylation not defined","Phosphatase reversing the mark not identified"]},{"year":2014,"claim":"Identified Smurf2 as an E3 ligase that polyubiquitinates YY1 via a PPxY motif to control its half-life, defining the degradative arm of YY1 regulation.","evidence":"Co-IP, ubiquitination and cycloheximide-chase assays, PPxY mutant analysis, and reporter assays","pmids":["24803334"],"confidence":"Medium","gaps":["In vivo relevance of Smurf2-YY1 axis not established","Signals triggering YY1 degradation unknown"]},{"year":2017,"claim":"Defined YY1 as a genome-wide structural regulator of enhancer-promoter looping analogous to CTCF, the central architectural model for the protein.","evidence":"ChIP-seq, HiChIP, CRISPR binding-site deletion, auxin-inducible degron depletion, and chromosome conformation capture","pmids":["29224777"],"confidence":"High","gaps":["Did not resolve relationship to cohesin/loop extrusion","Cell-cycle dynamics of looping not addressed"]},{"year":2024,"claim":"Showed YY1-dependent looping is cohesin-extrusion-independent and cell-cycle-coupled, with mitotic bookmarking and rapid rebinding at mitotic exit refining the architectural model.","evidence":"Acute auxin-degron degradation with Hi-C, ChIP-seq, and mitosis-to-G1 synchronization in erythroid cells","pmids":["39210046"],"confidence":"High","gaps":["Mechanism distinguishing YY1 loops from CTCF/cohesin loops molecularly unresolved","How mitotic retention is established not defined"]},{"year":2020,"claim":"Established an essential in vivo developmental role for YY1 in endothelium and a precise mechanism: repression of Notch by competing with MAML1 for RBPJ binding.","evidence":"Endothelial-specific conditional KO with retinal angiogenesis, Co-IP, domain mapping, and Notch target analysis","pmids":["32075915"],"confidence":"High","gaps":["Whether this competition operates outside endothelium not addressed","Effect on YY1 architectural function during vascular development not tested"]},{"year":2021,"claim":"Linked CK2alpha-mediated S118 phosphorylation of YY1 to endothelial proliferation and atherosclerosis through a phospho-YY1/ZKSCAN4/HDM2/p53-p21 pathway, providing in vivo PTM-to-disease causality.","evidence":"Phosphoproteomics, yeast two-hybrid, proximity ligation, Co-IP, and EC-specific S118A transgenic mice in an ApoE-KO atherosclerosis model","pmids":["34747636"],"confidence":"High","gaps":["Interplay between S118 phosphorylation and architectural function unknown","Relevance to other vascular beds not tested"]},{"year":2023,"claim":"Identified p300-mediated lactylation of YY1 (at K183) as an activating PTM coupling metabolic state to angiogenic and inflammatory gene transcription.","evidence":"Mass spectrometry site mapping, K183 mutagenesis, ChIP/CUT&Tag, reporter assays, and p300 inhibition in vivo and in vitro","pmids":["37085894","38493498"],"confidence":"High","gaps":["Eraser of YY1 lactylation not identified","Microglial lactylation site(s) not mapped"]},{"year":2024,"claim":"Completed a methylation read-write-erase axis by identifying PHF8 as the YY1 demethylase acting as a co-repressor at ETC genes to drive mitochondrial ROS and tumor growth.","evidence":"PHF8 KO/inhibition, YY1 methylation assays, ETC gene profiling, mROS measurement, and PDX xenografts","pmids":["38165927"],"confidence":"Medium","gaps":["Direct demethylation of specific YY1 residues by PHF8 not fully resolved","Single-lab finding"]},{"year":2024,"claim":"Identified OTUD3 as a stabilizing deubiquitinase for YY1 regulated by PLK1 phosphorylation, defining the counterbalance to Smurf2-mediated turnover.","evidence":"DUB screen, Co-IP, ubiquitination and cycloheximide-chase assays, and PLK1 phospho-mutant analysis in CRC cells","pmids":["38351178"],"confidence":"Medium","gaps":["In vivo relevance of OTUD3-YY1 axis not established","Crosstalk with Smurf2 not directly tested"]},{"year":2024,"claim":"Demonstrated YY1 acts as a required cofactor downstream of a master transcription factor (Ngn2), activating neuronal enhancers and remodeling 3D architecture during cell-fate reprogramming.","evidence":"Single-cell multiomics, ChIP-seq, 3D architecture and DNA methylation profiling, conditional Yy1 deletion, and Ngn2 Co-IP","pmids":["38956165"],"confidence":"High","gaps":["Generality of the Ngn2-YY1 cofactor relationship to other lineage factors unknown","Whether YY1 looping function is the operative mechanism not isolated"]},{"year":null,"claim":"It remains unresolved how YY1's many post-translational modifications, oligomerization state, and diverse cofactor interactions are integrated to switch between its architectural looping function and its locus-specific activating versus repressive transcriptional outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM status to choice of architectural vs transcriptional mode","Structural basis of YY1 dimer/oligomer at loops not defined","Determinants of activator-versus-repressor cofactor selection at individual loci unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,7,19,27,29,30,33,40]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,20,29,30,40]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,16,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,16,39]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,28]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,7,18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,7,8,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,19,27,30,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,16,17,18,39]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,16,30,37]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,11,12,34,35]}],"complexes":["PRC1 (via YAF2)"],"partners":["YAF2","CTBP","C-MYC","RBPJ","AKT","STAT1","RUVBL1","SMAD7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25490","full_name":"Transcriptional repressor protein YY1","aliases":["Delta transcription factor","INO80 complex subunit S","NF-E1","Yin and yang 1","YY-1"],"length_aa":414,"mass_kda":44.7,"function":"Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). Binds to the consensus sequence 5'-CCGCCATNTT-3'; some genes have been shown to contain a longer binding motif allowing enhanced binding; the initial CG dinucleotide can be methylated greatly reducing the binding affinity (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). The effect on transcription regulation is depending upon the context in which it binds and diverse mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). Its activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression (PubMed:15329343, PubMed:17721549, PubMed:24326773, PubMed:25787250). For example, it acts as a repressor in absence of adenovirus E1A protein but as an activator in its presence (PubMed:1655281). Acts synergistically with the SMAD1 and SMAD4 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (PubMed:15329343). May play an important role in development and differentiation. Proposed to recruit the PRC2/EED-EZH2 complex to target genes that are transcriptional repressed (PubMed:11158321). Involved in DNA repair (PubMed:18026119, PubMed:28575647). In vitro, binds to DNA recombination intermediate structures (Holliday junctions). Plays a role in regulating enhancer activation (PubMed:28575647). Recruits the PR-DUB complex to specific gene-regulatory regions (PubMed:20805357) Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair; proposed to target the INO80 complex to YY1-responsive elements","subcellular_location":"Nucleus matrix","url":"https://www.uniprot.org/uniprotkb/P25490/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YY1","classification":"Common Essential","n_dependent_lines":1035,"n_total_lines":1208,"dependency_fraction":0.8567880794701986},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100811","cell_line_id":"CID001087","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":1}],"interactors":[{"gene":"INO80C","stoichiometry":4.0},{"gene":"RUVBL1","stoichiometry":4.0},{"gene":"RUVBL2","stoichiometry":4.0},{"gene":"ACTL6A","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"NFRKB","stoichiometry":0.2},{"gene":"POGZ","stoichiometry":0.2},{"gene":"BAP18;C17ORF49;RNASEK-C17ORF49","stoichiometry":0.2},{"gene":"UCHL5","stoichiometry":0.2},{"gene":"ZHX1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001087","total_profiled":1310},"omim":[{"mim_id":"621515","title":"UBIQUITIN-CONJUGATING ENZYME E2 D4; UBE2D4","url":"https://www.omim.org/entry/621515"},{"mim_id":"621221","title":"STX18 ANTISENSE RNA 1, NONCODING; STX18AS1","url":"https://www.omim.org/entry/621221"},{"mim_id":"620262","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 36; ANKRD36","url":"https://www.omim.org/entry/620262"},{"mim_id":"618192","title":"PROSTATE CANCER-ASSOCIATED TRANSCRIPT 19, NONCODING; PCAT19","url":"https://www.omim.org/entry/618192"},{"mim_id":"618155","title":"OPHTHALMOPLEGIA, EXTERNAL, WITH RIB AND VERTEBRAL ANOMALIES; EORVA","url":"https://www.omim.org/entry/618155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YY1"},"hgnc":{"alias_symbol":["NF-E1","DELTA","UCRBP","YIN-YANG-1","INO80S"],"prev_symbol":[]},"alphafold":{"accession":"P25490","domains":[{"cath_id":"3.30.160","chopping":"381-414","consensus_level":"medium","plddt":83.7268,"start":381,"end":414}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25490","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25490-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25490-F1-predicted_aligned_error_v6.png","plddt_mean":50.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YY1","jax_strain_url":"https://www.jax.org/strain/search?query=YY1"},"sequence":{"accession":"P25490","fasta_url":"https://rest.uniprot.org/uniprotkb/P25490.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25490/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25490"}},"corpus_meta":[{"pmid":"29224777","id":"PMC_29224777","title":"YY1 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Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression, establishing YY1 as a structural regulator of enhancer-promoter interactions analogous to CTCF.\",\n      \"method\": \"ChIP-seq, HiChIP, CRISPR deletion of binding sites, auxin-inducible degron protein depletion, chromosome conformation capture\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP-seq, looping assays, protein depletion, site deletion), rigorous controls, broadly replicated concept\",\n      \"pmids\": [\"29224777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Acute degradation of YY1 in erythroid cells revealed its requirement for maintenance of enhancer-promoter loops but not compartments or TADs. YY1-dependent enhancer-promoter loop formation does not involve stalling of cohesin-mediated loop extrusion. YY1 is partially retained on mitotic chromatin at gene promoters and rapidly rebinds during mitotic exit coinciding with enhancer-promoter loop establishment; cell cycle stage influences YY1's architectural function.\",\n      \"method\": \"Auxin-inducible degron acute degradation, Hi-C, ChIP-seq, mitosis-to-G1 cell synchronization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — acute degradation with multiple orthogonal genomic methods, cell-cycle-resolved experiments, rigorous controls\",\n      \"pmids\": [\"39210046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"YY1 physically associates with c-Myc (but not Max), and c-Myc inhibits both the repressor and activator functions of YY1 in cotransfection experiments, establishing c-Myc as a negative regulator of YY1 transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid screen, affinity chromatography, cotransfection reporter assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by affinity chromatography and functional reporter assays, single lab\",\n      \"pmids\": [\"8266081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"YY1 (identified as CF1) directly binds two sites in the murine c-myc promoter (-260 and -390 bp from P1) and strongly activates c-myc transcription; overexpression of YY1 in erythroleukemia cells increases endogenous c-myc mRNA from both major initiation sites.\",\n      \"method\": \"Protein purification, immunological cross-reactivity, recombinant protein binding assays, cotransfection reporter assays, Northern blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical purification, recombinant protein validation, functional reporter assays, endogenous gene analysis, multiple orthogonal methods\",\n      \"pmids\": [\"8246966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YY1 is lactylated at lysine 183 (K183) by the acetyltransferase p300; hyperlactylated YY1 directly enhances FGF2 transcription and promotes angiogenesis. YY1 K183 mutation eliminates these effects, and p300 overexpression increases YY1 lactylation and angiogenesis.\",\n      \"method\": \"Mass spectrometry identification of lactylation sites, site-directed mutagenesis (K183), ChIP, luciferase reporter assays, p300 inhibitor A485 in vivo/in vitro\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — PTM identified by MS, writer identified (p300), mutagenesis confirms function, in vivo validation, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"37085894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 is lactylated at an unspecified site(s) by p300 in microglia; this lactylation promotes microglial activation by upregulating transcription of inflammatory genes including STAT3, CCL5, IRF1, IDO1, and SEMA4D. Inhibition of p300 decreases YY1 lactylation and suppresses microglial inflammation.\",\n      \"method\": \"CUT&Tag analysis, p300 inhibitor treatment, in vivo/in vitro inflammation assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — CUT&Tag confirms transcriptional targets of lactylated YY1, p300 identified as writer, in vivo/in vitro validation, single lab\",\n      \"pmids\": [\"38493498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Conditional ablation of YY1 in mouse B cells caused a defect in somatic V(H)D(H)J(H) rearrangement, a block in pro-B to pre-B cell transition, and impaired IgH locus contraction. YY1 binds the intronic Eµ enhancer within the IgH locus, indicating a direct role in controlling long-distance DNA interactions required for V(H)D(H)J(H) recombination.\",\n      \"method\": \"Conditional knockout (Cre-loxP), 3D DNA FISH, ChIP, B-cell development assays, IgH transgene rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined developmental phenotype rescued by transgene, direct YY1 binding shown by ChIP, 3D FISH for locus contraction\",\n      \"pmids\": [\"17504937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Drosophila, YY1 can recruit Polycomb group (PcG) proteins to Polycomb response elements, leading to deacetylation and methylation of histone H3. This PcG recruitment and concomitant histone modification require CtBP; in a CtBP mutant background, YY1 DNA binding in vivo is also ablated without YY1 degradation or nuclear export, suggesting CtBP controls YY1 DNA-binding ability.\",\n      \"method\": \"In vivo Drosophila genetics (CtBP mutant), ChIP, histone modification assays, immunostaining\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in Drosophila with ChIP validation of histone modifications and DNA binding, multiple orthogonal readouts\",\n      \"pmids\": [\"15520279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YY1 physically interacts with YAF2, which bridges YY1 to the PRC1 complex. YAF2 is responsible for PcG recruitment to DNA mediated by YY1 DNA binding; knockdown of YY1 abolishes PcG recruitment and is not compensated by exogenous YAF2, demonstrating YY1 DNA binding is required for Polycomb chromatin assembly.\",\n      \"method\": \"Biochemical pulldown, Co-IP, ChIP assays in HeLa cells, Drosophila complementation genetics, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, genetic rescue across species, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"24285299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 assembles into homo-oligomeric species built from a bell-shaped dimer, characterized by electron microscopy. YY1 self-association occurs in vivo (bimolecular fluorescence complementation). YY1 oligomers bind DNA substrates lacking the consensus YY1 sequence in vitro, and DNA binding is enhanced by RuvBL1-RuvBL2 ATPases. YY1 oligomers bind RuvBL1-RuvBL2, preferentially interacting with RuvBL1. YY1 and the ATPase activity of RuvBL2 are required for RAD51 foci formation during homologous recombination.\",\n      \"method\": \"Electron microscopy, bimolecular fluorescence complementation, in vitro DNA binding assays, Co-IP/pulldown, RAD51 foci assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EM structure, in vitro reconstitution, in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24990942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7/9 (KMT7) methylates YY1 at K173 and K411; this methylation regulates YY1 DNA-binding activity both in vitro and at specific genomic loci in cells, and affects YY1-regulated gene transcription and cell proliferation.\",\n      \"method\": \"In vitro methyltransferase assay, site-directed mutagenesis, ChIP, reporter assays, cell proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay, mutagenesis, in vivo ChIP validation, single lab\",\n      \"pmids\": [\"26902152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 is tyrosine-phosphorylated by multiple Src family kinases in vitro and in vivo. Phosphorylation at tyrosine 383 interferes with DNA and RNA binding, leading to downregulation of YY1 transcriptional activity. YY1 is also a downstream target of EGFR signaling in vivo.\",\n      \"method\": \"Pharmacological kinase inhibition, kinase overexpression, kinase knockout, site-directed mutagenesis (Y383), DNA/RNA binding assays, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple kinase approaches (inhibition, OE, KO), mutagenesis of phosphosite, functional binding assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26198631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Smurf2 E3 ubiquitin ligase physically interacts with YY1 via a PPxY motif on YY1, induces poly-ubiquitination of YY1, and shortens YY1 protein half-life via the ubiquitin-proteasome pathway. Smurf2 reduces YY1-mediated transcriptional activation and relieves YY1-mediated suppression of p53 activity.\",\n      \"method\": \"Co-IP, ubiquitination assay, half-life assay (cycloheximide chase), PPxY mutant analysis, reporter assays, siRNA knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, half-life measurement, mutagenesis, functional reporter assays, single lab\",\n      \"pmids\": [\"24803334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YY1 promotes AKT phosphorylation at S473 through direct physical interaction with AKT; the AKT-binding site maps to residues G201-S226 (designated the OPB domain) on YY1. YY1-promoted AKT phosphorylation is mediated through mTORC2, is independent of PI3K activity and YY1 transcriptional activity. A peptide based on the OPB domain blocks YY1-AKT interaction and reduces AKT phosphorylation and cell proliferation.\",\n      \"method\": \"Co-IP, domain mapping, mTORC2 interaction assays, pharmacological PI3K inhibition, peptide competition, cell proliferation assays, tissue microarray\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping, peptide competition, functional rescue experiments, single lab\",\n      \"pmids\": [\"26762111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"YY1 physically interacts with androgen receptor (AR) both in cell-free systems and in cultured cells. YY1 is required for optimal AR transcriptional activity at the PSA promoter and is a necessary component of the complex binding the androgen response element. YY1 depletion reduces endogenous PSA levels in LNCaP cells.\",\n      \"method\": \"Co-IP, cell-free binding assay, ChIP, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP in cell-free and cellular systems, ChIP confirms complex at target promoter, functional reporter assay, single lab\",\n      \"pmids\": [\"19668226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YAP interacts with YY1 and EZH2 to function as a transcriptional repressor. YAP colocalization with YY1 and EZH2 on the genome represses genes including the cell-cycle inhibitor p27, contributing to loss of contact inhibition.\",\n      \"method\": \"Genome-wide ChIP-seq, Co-IP, transcriptome profiling, loss-of-function experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP confirmed interaction, genome-wide ChIP-seq, functional gene expression analysis, single lab\",\n      \"pmids\": [\"32409309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial cell-specific YY1 deletion causes embryonic lethality due to vascular defects. YY1 functions as a repressor of Notch signaling by binding to the N-terminal domain of RBPJ and competing with MAML1 for RBPJ binding, thereby impairing NICD/MAML1/RBPJ complex formation and Notch target gene expression to control endothelial tip-stalk fate determination.\",\n      \"method\": \"Conditional endothelial-specific KO (Cre-loxP), retinal sprouting angiogenesis assay, Co-IP, domain-mapping binding assays, Notch target gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo vascular phenotype, direct protein-protein interaction mapped, mechanistic competition assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32075915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Disturbed flow induces phosphorylation of YY1 at serine 118 (phospho-YY1-S118) in endothelial cells via direct interaction with CK2α (casein kinase 2α). Phospho-YY1-S118 directly binds ZKSCAN4, inducing HDM2 promoter activity and gene expression, which promotes EC proliferation through downregulation of p53 and p21. EC-specific expression of a S118-nonphosphorylatable YY1 mutant in ApoE-deficient mice reduces atherosclerosis formation.\",\n      \"method\": \"Phosphoproteomics, yeast 2-hybrid screening, in situ proximity ligation, Co-IP, transgenic mouse model (EC-specific S118A mutant), ApoE-KO atherosclerosis model, CK2 inhibitor treatment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphoproteomics identifies site, kinase identified by direct interaction, mutagenesis in transgenic mice confirms function in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"34747636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YY1 interacts with Smad7, and this interaction is attenuated by TGF-β signaling. YY1 and Smad7 act in concert to inhibit TGF-β-induced transcription in the nucleus. Smad7 enhances YY1's interaction with HDAC1, and YY1 and HDAC1 augment the transcriptional repression activity of Smad7.\",\n      \"method\": \"Co-IP, reporter assays, target gene expression analysis, Gal4-luciferase reporter\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP demonstrates interaction, functional reporter assays with multiple components, single lab\",\n      \"pmids\": [\"24369345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 binds the TGFB1 promoter and represses TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 overexpression attenuates glomerulosclerosis and YY1 knockdown aggravates it, establishing YY1 as a potent transcriptional repressor of TGFB1.\",\n      \"method\": \"Mass spectrometry-based DNA-protein interaction screen, ChIP, luciferase reporter, siRNA knockdown/adenoviral overexpression in mouse models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS-based screen, direct ChIP binding, functional reporter, in vivo mouse model rescue/aggravation, multiple orthogonal methods\",\n      \"pmids\": [\"31534017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"YY1 recognizes longer DNA-binding motifs (GGCGCCATnTT and CCGCCATnTT) beyond the known consensus (CGCCATnTT). Gel shift assays demonstrate higher affinity for the longer motif. Substitutions in the first zinc finger unit weaken DNA-binding specificity at both 5'- and 3'-flanks of the longer motif, indicating the first zinc finger is required for recognition of the extended motif and that DNA recognition involves concerted contribution of all four zinc finger units.\",\n      \"method\": \"Gel shift assays (EMSA), in vitro DNA-binding motif studies, zinc finger mutagenesis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical binding assays with mutagenesis, single lab\",\n      \"pmids\": [\"18950698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 is a transcriptional repressor of FEN1; YY1 binds the FEN1 promoter and suppresses FEN1 expression. In response to chemotherapeutic drugs (MMC, Taxol), YY1 is dissociated from the FEN1 promoter, leading to FEN1 overexpression. Overexpression of YY1 in cancer cells downregulates FEN1 and sensitizes cells to these drugs.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown/overexpression, drug sensitivity assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP demonstrates direct binding, functional reporter and drug sensitivity assays, single lab\",\n      \"pmids\": [\"25885449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 regulates Bmp7 and Ctgf reporter activities and modulates their gene expression in cardiomyocytes. Upregulation of YY1 suppresses LMNA-deficiency-induced dilated cardiomyopathy and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf, which in turn downregulates TGF-β/Smad signaling.\",\n      \"method\": \"shRNA-induced Lmna DCM mouse model, adenoviral YY1 overexpression, Bmp7 knockdown, Ctgf silencing, reporter assays, gene expression analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo mouse model with multiple genetic interventions, reporter assays for Bmp7/Ctgf, epistasis experiments, single lab\",\n      \"pmids\": [\"31495264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGF-β induces YY1 expression in lung fibroblasts via NF-κB (blocked by IκB degradation inhibitor). YY1 upregulates α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/-) mice are significantly protected from lung fibrosis with attenuated α-SMA and collagen expression; conditional YY1 deletion via adenovirus-Cre reduced lung fibrosis in floxed mice.\",\n      \"method\": \"Conditional knockout mice (Cre-loxP, partial heterozygous), NF-κB inhibition, α-SMA promoter reporter, siRNA knockdown, bleomycin/silica fibrosis models\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models, conditional KO, reporter assays linking YY1 to α-SMA promoter, pharmacological epistasis, single lab\",\n      \"pmids\": [\"21169469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"YY1 promotes hepatic gluconeogenesis by transcriptionally upregulating glucocorticoid receptor (GR) expression. Liver-specific ablation of YY1 via adenoviral shRNA ameliorates hyperglycemia in wild-type and diabetic db/db mice; YY1 overexpression in liver augments gluconeogenesis and raises fasting blood glucose.\",\n      \"method\": \"Adenoviral shRNA knockdown, adenoviral overexpression, liver-specific genetic manipulation, blood glucose measurement, gene expression analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo liver-specific gain/loss of function, GR as downstream mechanism identified, single lab\",\n      \"pmids\": [\"23193188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"YY1 knockdown during oogenesis results in loss of DNA methylation on Peg3 and Xist DMRs but not Nespas or H19. Continued YY1 knockdown from oogenesis to blastocyst causes further loss of DNA methylation on Peg3, and high incidence of embryonic lethality follows, indicating YY1 plays a role in de novo DNA methylation of these imprinted loci during oogenesis.\",\n      \"method\": \"Conditional YY1 knockdown (stage-specific), bisulfite sequencing of DMRs, embryo phenotyping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — stage-specific knockdown with direct methylation readout, single lab, specific DMR effects\",\n      \"pmids\": [\"19628663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YY1 promotes thymocyte survival by suppressing p53 expression; YY1-deficient thymocytes show increased apoptosis and developmental block, which is completely rescued by concurrent loss of p53, placing YY1 upstream of p53 in thymocyte survival pathway.\",\n      \"method\": \"Conditional KO (Cre-loxP at two developmental stages), double KO (YY1/p53), flow cytometry, apoptosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis (double KO rescue), stage-specific conditional KO, defined phenotypic readout, replicates YY1-p53 regulatory axis\",\n      \"pmids\": [\"26843327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YY1 directly binds the PLZF gene promoter (shown by ChIP-seq) and activates PLZF transcription; YY1-deficient thymocytes undergo normal Vα14-Jα18 rearrangements but display impaired survival and fail to develop iNKT cells due to absent PLZF induction.\",\n      \"method\": \"Conditional KO (Cre-loxP), ChIP-seq, deep sequencing of Vα14-Jα18 rearrangements, flow cytometry, apoptosis assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined developmental phenotype, ChIP-seq directly demonstrates YY1 binding to PLZF promoter, multiple orthogonal methods\",\n      \"pmids\": [\"29500401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"YY1 and E2F1 physically interact in the nucleus and synergistically activate p73 promoter activity. Both factors are required for doxorubicin-induced p73 promoter activation; YY1 silencing reduces endogenous p73 expression, while YY1 overexpression induces p73 promoter activity.\",\n      \"method\": \"Co-IP, immunofluorescence, luciferase reporter assay, siRNA knockdown, doxorubicin treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP demonstrates physical interaction, reporter assays with gain/loss of function, single lab\",\n      \"pmids\": [\"17980704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YY1 directly binds the BAX promoter (shown by luciferase reporter, EMSA, and ChIP assays) and transcriptionally activates Bax, promoting its mitochondrial localization, cytochrome c release, and caspase activation in pancreatic cancer cells.\",\n      \"method\": \"Luciferase reporter assay, EMSA, ChIP, Western blotting, mitochondrial fractionation, caspase activation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct DNA binding by EMSA and ChIP, functional reporter, downstream apoptotic pathway validated, single lab\",\n      \"pmids\": [\"27074573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pancreatic β-cells, YY1 directly binds enhancer regions in exon 2 of Ins1 and Ins2 genes and activates insulin transcription. YY1 also directly interacts with RNA polymerase II, potentially stabilizing enhancer-promoter interactions during transcription initiation. β-cell-specific Yy1 ablation causes rapid-onset hyperglycemia and reduced β-cell mass.\",\n      \"method\": \"Conditional KO, ChIP assays (YY1, H3K4me1, H3K27ac, H3K27me3), RNA-seq, luciferase reporter assays, Co-IP (YY1-Pol II)\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo phenotype, direct ChIP binding at target enhancers, Co-IP with Pol II, reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"35113157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"YY1 binds to the myelin PLP promoter in vitro and in vivo (via yeast one-hybrid and gel shift/supershift with YY1 antibody). Overexpression of YY1 in oligodendrocyte cell lines enhances PLP promoter transcription; a truncated YY1 containing only the four zinc finger domains has little effect, indicating the non-zinc-finger domains are required for transactivation.\",\n      \"method\": \"Yeast one-hybrid, gel shift assay, antibody supershift, cotransfection reporter assay, promoter mutation analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast one-hybrid confirmed by EMSA and in vivo binding, functional reporter with domain truncation, single lab\",\n      \"pmids\": [\"11331422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 regulates SQSTM1 expression through epigenetic modulation of MIR372 transcription; YY1 suppresses MIR372 expression during nutrient starvation, leading to increased SQSTM1 (p62) and autophagy flux activation. YY1 knockdown inhibits cell viability and autophagy flux through SQSTM1 downregulation.\",\n      \"method\": \"siRNA knockdown, miRNA overexpression, luciferase reporter assay, autophagy flux assays (LC3-II, electron microscopy), in vivo tumor growth\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis between YY1, miR-372, and SQSTM1 established by gain/loss experiments, functional autophagy assays, single lab\",\n      \"pmids\": [\"24991827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YY1 activates GLUT3 transcription by directly binding to its promoter, enhancing tumor cell aerobic glycolysis in a p53-independent manner. This regulation is critical for YY1-induced tumor cell proliferation and tumorigenesis. Oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown/overexpression, glycolysis assays, cell proliferation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP demonstrates direct binding, reporter assay confirms promoter activation, functional metabolic and proliferation readouts, single lab\",\n      \"pmids\": [\"29869834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHF8 demethylates YY1 (at methylation sites established by SET7/9), functioning as a co-repressor with YY1 for nuclear-encoded ETC genes, driving mitochondrial ROS production and cancer cell growth. PHF8 pharmacological inhibition (iPHF8) regulates YY1 methylation, ETC gene transcription, mROS production, and suppresses tumor growth in xenograft models.\",\n      \"method\": \"PHF8 knockout/inhibition, YY1 methylation assays, ETC gene expression profiling, mROS measurement, cell-line and PDX xenograft models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — PHF8 identified as YY1 demethylase with functional consequences on target genes and in vivo tumor growth, single lab\",\n      \"pmids\": [\"38165927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD3 deubiquitinase physically interacts with YY1, inhibits its ubiquitin-proteasome-mediated degradation, and increases YY1 protein levels. PLK1 phosphorylates OTUD3 at S326, enhancing OTUD3 binding to and deubiquitination of YY1.\",\n      \"method\": \"DUB screen, Co-IP, ubiquitination assay, cycloheximide chase, PLK1 kinase assay, phospho-mutant analysis, CRC cell proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, phosphorylation-dependent mechanism, single lab\",\n      \"pmids\": [\"38351178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In un-stimulated neurons, a YY1-Brd4 transcription factor complex assembled at the Senp1 promoter activates Senp1 transcription. Upon neuronal membrane depolarization, YY1 is dephosphorylated and the YY1-Brd4 complex is evicted from the Senp1 promoter, reducing Senp1 transcription and subsequently decreasing GluR1 expression.\",\n      \"method\": \"Co-IP, ChIP, in vitro DNA binding assay, luciferase reporter assay, siRNA knockdown, phosphatase inhibitor experiments, qRT-PCR/Western blot\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP confirms YY1-Brd4 interaction, ChIP confirms complex eviction, functional reporter and KD experiments, single lab\",\n      \"pmids\": [\"31629407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 is recruited by direct interaction with Neurogenin2 (Ngn2) to Ngn2 target sites during astrocyte-to-neuron reprogramming. Upon Yy1 deletion, activation of neuronal enhancers and genes and reprogramming efficiency are impaired without affecting Ngn2 binding, indicating YY1 acts as a required cofactor downstream of Ngn2 binding.\",\n      \"method\": \"Single-cell multiomics, ChIP-seq, genome-wide 3D nuclear architecture profiling, DNA methylation profiling, conditional Yy1 deletion, Ngn2 Co-IP\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed, conditional KO with defined reprogramming phenotype, multi-omics validation of epigenome remodeling, multiple orthogonal approaches\",\n      \"pmids\": [\"38956165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YY1 depletion in extended pluripotent stem cells (EPSCs) triggers changes in DNA methylation, histone modifications, and high-order chromatin structures including disruption of enhancer-promoter interactions for EPSC-specific genes. YY1 loss results in DNA hypomethylation and reduced H3K4me3 and H3K27ac at EPSC-specific gene promoters (including Dnmt3l) by upregulating Kdm5c and Hdac6 through facilitation of CTCF-mediated EP interactions at their loci.\",\n      \"method\": \"siRNA knockdown, ChIP-seq (multiple histone marks), ATAC-seq, Hi-C, WGBS, scRNA-seq, luciferase reporter\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive multi-omics in single lab, loss-of-function with epigenetic mechanistic follow-up, single lab\",\n      \"pmids\": [\"35425987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YY1 interacts with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression decreases. YY1 knockdown reduces phosphorylated TBK1 and pIRF3 (impairing IFN-β production), while YY1 overexpression upregulates pTBK1 and pIRF3 and promotes IFN-β induction. YY1 knockdown upregulates pSTAT1/pSTAT2 and antiviral ISGs and inhibits viral replication.\",\n      \"method\": \"Co-IP, siRNA knockdown, overexpression, immunoblotting, real-time PCR\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifies STAT1 interaction, reciprocal gain/loss experiments with defined signaling readouts, single lab\",\n      \"pmids\": [\"29161701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YY1 directly binds the minimal promoter of TREM2 and activates its transcription in microglial cells; YY1 silencing reduces TREM2 promoter activity and protein levels in BV2 and Neuro2A cells.\",\n      \"method\": \"Luciferase assay, DNA pull-down, EMSA, shRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple direct binding methods (pull-down, EMSA), functional reporter assay, loss-of-function, single lab\",\n      \"pmids\": [\"37044212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YY1 forms a phase-separated complex (LLPS) in M2 macrophages with p300, p65, and CEBPB as transcriptional cofactors; this complex upregulates IL-6 by promoting IL-6 enhancer-promoter interactions revealed by H3K27ac ChIP-seq and YY1 ChIP-seq.\",\n      \"method\": \"LLPS assay, H3K27ac ChIP-seq, YY1 ChIP-seq, CRISPR-Cas9 KO, RNA-seq, Co-IP\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP-seq establishes YY1 at M2-specific enhancers, LLPS assay, CRISPR KO, single lab\",\n      \"pmids\": [\"37094986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 N-terminal domain is an intrinsically disordered region with little residual secondary structure and no defined tertiary structure, as characterized by fluorescence, circular dichroism, gel filtration, and proteolytic susceptibility assays. The full-length YY1 protein belongs to the family of intrinsically disordered proteins.\",\n      \"method\": \"Fluorescence spectroscopy, circular dichroism, gel filtration chromatography, proteolytic susceptibility, bioinformatics\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods characterizing protein structure, but no functional consequence linked, single lab\",\n      \"pmids\": [\"25963536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 directly regulates Bmp7 and Ctgf promoter/reporter activities in cardiomyocytes; overexpression of YY1 maintains H3K9Ac, H3K27Ac, and H3K4Me3 at the Nkx2-5 cardiac enhancer along with enrichment of Pol II, p300, and Brg1, thereby maintaining cardiac progenitor cell state and preventing cardiomyogenic differentiation.\",\n      \"method\": \"ChIP (multiple histone marks), luciferase reporter assay, YY1 overexpression in cardiac progenitor cells, genome-wide transcriptional profiling\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP at target enhancer, reporter assays, functional phenotypic readout, single lab\",\n      \"pmids\": [\"28580685\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YY1 is a multifunctional zinc finger transcription factor that acts as a structural organizer of enhancer-promoter chromatin loops (forming dimers at active regulatory elements, independent of cohesin-mediated loop extrusion), recruits Polycomb repressive complexes to chromatin via YAF2 and CtBP, activates or represses transcription of diverse target genes (including c-Myc, BRCA1, BAX, insulin, PLP, TREM2, GLUT3, PLZF, and TGFβ1) depending on cofactor context, and is regulated by multiple post-translational modifications including tyrosine phosphorylation (Src family kinases/EGFR; Y383 blocks DNA binding), serine phosphorylation (CK2α at S118 promotes atherosclerosis), lysine methylation (SET7/9 at K173/K411; demethylated by PHF8 to repress ETC genes), lysine lactylation (p300 at K183, activating transcription), and ubiquitin-mediated degradation (Smurf2 as E3 ligase; OTUD3 as stabilizing DUB); it also engages non-transcriptional functions including direct interaction with AKT to promote mTORC2-mediated AKT-S473 phosphorylation, interaction with STAT1 to modulate antiviral IFN signaling, and binding to RBPJ to compete with Notch coactivator MAML1 in endothelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YY1 is a multifunctional zinc finger transcription factor that acts as a structural organizer of the genome, binding active enhancers and promoter-proximal elements and forming dimers that establish and maintain enhancer-promoter loops in a manner analogous to CTCF [#0]. Acute degradation studies show this architectural function is required for enhancer-promoter loop maintenance but not for compartments or TADs, operates independently of cohesin-mediated loop extrusion stalling, and is cell-cycle-regulated, with YY1 partially retained on mitotic chromatin and rapidly rebinding promoters during mitotic exit [#1]. DNA recognition is achieved through concerted contributions of all four zinc fingers, with the first finger required for engaging an extended binding motif [#20], while the N-terminal portion of the protein is an intrinsically disordered region [#42]. YY1 directs both activating and repressive transcriptional outputs depending on cofactor context: it recruits Polycomb group proteins to chromatin in a manner requiring CtBP for its DNA binding [#7] and is bridged to PRC1 through YAF2 [#8], and it interacts with diverse partners including c-Myc [#2], androgen receptor [#14], E2F1 [#28], YAP/EZH2 [#15], Smad7/HDAC1 [#18], and RNA polymerase II [#30] to tune target gene expression. YY1 directly activates or represses a broad target repertoire including c-myc [#3], BAX [#29], insulin genes [#30], GLUT3 [#33], TREM2 [#40], PLZF [#27], and TGFB1 [#19], and suppresses p53 to promote cell survival [#26]. In vivo, YY1 is essential for V(H)D(H)J(H) recombination and IgH locus contraction in B cells [#6], for endothelial development where it represses Notch signaling by competing with MAML1 for RBPJ binding [#16], and for insulin gene expression and beta-cell mass [#30]. YY1 activity is extensively controlled by post-translational modifications: tyrosine phosphorylation at Y383 by Src-family kinases blocks DNA/RNA binding downstream of EGFR [#11], serine phosphorylation at S118 by CK2alpha drives endothelial proliferation and atherosclerosis [#17], SET7/9 methylation at K173/K411 modulates DNA binding [#10] with PHF8 acting as the demethylating co-repressor at ETC genes [#34], p300-mediated lactylation at K183 activates angiogenic transcription [#4], and protein stability is set by the opposing actions of the Smurf2 E3 ligase [#12] and the OTUD3 deubiquitinase [#35]. Beyond transcription, YY1 directly binds AKT to promote mTORC2-mediated AKT-S473 phosphorylation independently of its transcriptional activity [#13] and modulates antiviral interferon signaling through interaction with STAT1 [#39].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established YY1 as a sequence-specific transcriptional activator with defined endogenous targets and identified c-Myc as a direct interacting negative regulator, defining YY1 as a context-dependent transcription factor rather than a simple activator or repressor.\",\n      \"evidence\": \"Protein purification, recombinant binding and reporter assays at the c-myc promoter, plus yeast two-hybrid and affinity chromatography for the c-Myc interaction\",\n      \"pmids\": [\"8246966\", \"8266081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how cofactor context switches YY1 between activation and repression\", \"Mechanism of c-Myc inhibition of YY1 not resolved at the structural level\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that YY1 transactivation requires domains beyond the zinc fingers, demonstrating that DNA binding and activation are separable functions.\",\n      \"evidence\": \"Yeast one-hybrid, EMSA/supershift, and reporter assays with a zinc-finger-only truncation at the PLP promoter in oligodendrocyte lines\",\n      \"pmids\": [\"11331422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific transactivation domain not mapped\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed that YY1 recruits Polycomb group proteins and directs repressive histone modifications, and that CtBP is required for YY1 DNA binding in vivo, linking YY1 to Polycomb silencing.\",\n      \"evidence\": \"Drosophila genetic epistasis in CtBP mutants with ChIP and histone modification readouts\",\n      \"pmids\": [\"15520279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CtBP control over DNA binding unresolved\", \"Conservation of CtBP requirement in mammals not addressed here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a direct in vivo requirement for YY1 in long-range DNA interactions controlling antigen receptor diversification, providing early evidence for an architectural function.\",\n      \"evidence\": \"Conditional B-cell knockout with 3D DNA FISH, ChIP at the Emu enhancer, and IgH transgene rescue\",\n      \"pmids\": [\"17504937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish architectural from purely transcriptional roles at the IgH locus\", \"Looping partner proteins not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the DNA-recognition logic of YY1, showing all four zinc fingers contribute and the first finger enables binding to an extended motif.\",\n      \"evidence\": \"EMSA and zinc-finger mutagenesis on consensus and extended motifs in vitro\",\n      \"pmids\": [\"18950698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure\", \"Genomic relevance of extended motif not tested in cells\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified YAF2 as the bridge connecting YY1 DNA binding to PRC1, establishing a molecular route for YY1-directed Polycomb assembly.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, and cross-species genetic rescue with siRNA knockdown in HeLa cells\",\n      \"pmids\": [\"24285299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of YY1-YAF2-PRC1 complex not defined\", \"Genome-wide scope of YY1/YAF2 Polycomb targets not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized YY1 self-association into a bell-shaped dimer/oligomer and linked it to homologous recombination via RuvBL1-RuvBL2, revealing a non-canonical DNA-repair function.\",\n      \"evidence\": \"Electron microscopy, bimolecular fluorescence complementation, in vitro DNA binding, pulldowns, and RAD51 foci assays\",\n      \"pmids\": [\"24990942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of oligomerization to enhancer-promoter looping not directly tested\", \"Physiological setting of HR function unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the YY1-p53 regulatory axis through clean genetic epistasis, showing YY1 promotes survival by suppressing p53.\",\n      \"evidence\": \"Stage-specific conditional KO and YY1/p53 double KO rescue in thymocytes with apoptosis assays\",\n      \"pmids\": [\"26843327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of p53 suppression by YY1 in thymocytes not detailed\", \"Whether suppression is transcriptional or post-translational not resolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a transcription-independent role for YY1 as a direct AKT-binding scaffold promoting mTORC2-mediated AKT-S473 phosphorylation, expanding YY1 beyond the nucleus.\",\n      \"evidence\": \"Co-IP, OPB-domain mapping (G201-S226), peptide competition, PI3K inhibition, and proliferation assays\",\n      \"pmids\": [\"26762111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular site of YY1-AKT interaction not defined\", \"Structural basis of OPB-AKT contact unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SET7/9 methylation of YY1 at K173/K411 as a direct regulator of its DNA-binding and transcriptional activity, opening the PTM dimension of YY1 control.\",\n      \"evidence\": \"In vitro methyltransferase assay, mutagenesis, ChIP, reporter and proliferation assays\",\n      \"pmids\": [\"26902152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide consequences of methylation not mapped\", \"Reader of methylated YY1 not identified at the time\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined tyrosine phosphorylation of YY1 at Y383 by Src-family kinases as a switch that blocks DNA/RNA binding downstream of EGFR, linking growth-factor signaling to YY1 inactivation.\",\n      \"evidence\": \"Kinase inhibition, overexpression and knockout, Y383 mutagenesis, and DNA/RNA binding and reporter assays\",\n      \"pmids\": [\"26198631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological contexts of Y383 phosphorylation not defined\", \"Phosphatase reversing the mark not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Smurf2 as an E3 ligase that polyubiquitinates YY1 via a PPxY motif to control its half-life, defining the degradative arm of YY1 regulation.\",\n      \"evidence\": \"Co-IP, ubiquitination and cycloheximide-chase assays, PPxY mutant analysis, and reporter assays\",\n      \"pmids\": [\"24803334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of Smurf2-YY1 axis not established\", \"Signals triggering YY1 degradation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined YY1 as a genome-wide structural regulator of enhancer-promoter looping analogous to CTCF, the central architectural model for the protein.\",\n      \"evidence\": \"ChIP-seq, HiChIP, CRISPR binding-site deletion, auxin-inducible degron depletion, and chromosome conformation capture\",\n      \"pmids\": [\"29224777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve relationship to cohesin/loop extrusion\", \"Cell-cycle dynamics of looping not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed YY1-dependent looping is cohesin-extrusion-independent and cell-cycle-coupled, with mitotic bookmarking and rapid rebinding at mitotic exit refining the architectural model.\",\n      \"evidence\": \"Acute auxin-degron degradation with Hi-C, ChIP-seq, and mitosis-to-G1 synchronization in erythroid cells\",\n      \"pmids\": [\"39210046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing YY1 loops from CTCF/cohesin loops molecularly unresolved\", \"How mitotic retention is established not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established an essential in vivo developmental role for YY1 in endothelium and a precise mechanism: repression of Notch by competing with MAML1 for RBPJ binding.\",\n      \"evidence\": \"Endothelial-specific conditional KO with retinal angiogenesis, Co-IP, domain mapping, and Notch target analysis\",\n      \"pmids\": [\"32075915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this competition operates outside endothelium not addressed\", \"Effect on YY1 architectural function during vascular development not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked CK2alpha-mediated S118 phosphorylation of YY1 to endothelial proliferation and atherosclerosis through a phospho-YY1/ZKSCAN4/HDM2/p53-p21 pathway, providing in vivo PTM-to-disease causality.\",\n      \"evidence\": \"Phosphoproteomics, yeast two-hybrid, proximity ligation, Co-IP, and EC-specific S118A transgenic mice in an ApoE-KO atherosclerosis model\",\n      \"pmids\": [\"34747636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between S118 phosphorylation and architectural function unknown\", \"Relevance to other vascular beds not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified p300-mediated lactylation of YY1 (at K183) as an activating PTM coupling metabolic state to angiogenic and inflammatory gene transcription.\",\n      \"evidence\": \"Mass spectrometry site mapping, K183 mutagenesis, ChIP/CUT&Tag, reporter assays, and p300 inhibition in vivo and in vitro\",\n      \"pmids\": [\"37085894\", \"38493498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Eraser of YY1 lactylation not identified\", \"Microglial lactylation site(s) not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Completed a methylation read-write-erase axis by identifying PHF8 as the YY1 demethylase acting as a co-repressor at ETC genes to drive mitochondrial ROS and tumor growth.\",\n      \"evidence\": \"PHF8 KO/inhibition, YY1 methylation assays, ETC gene profiling, mROS measurement, and PDX xenografts\",\n      \"pmids\": [\"38165927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demethylation of specific YY1 residues by PHF8 not fully resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified OTUD3 as a stabilizing deubiquitinase for YY1 regulated by PLK1 phosphorylation, defining the counterbalance to Smurf2-mediated turnover.\",\n      \"evidence\": \"DUB screen, Co-IP, ubiquitination and cycloheximide-chase assays, and PLK1 phospho-mutant analysis in CRC cells\",\n      \"pmids\": [\"38351178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of OTUD3-YY1 axis not established\", \"Crosstalk with Smurf2 not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated YY1 acts as a required cofactor downstream of a master transcription factor (Ngn2), activating neuronal enhancers and remodeling 3D architecture during cell-fate reprogramming.\",\n      \"evidence\": \"Single-cell multiomics, ChIP-seq, 3D architecture and DNA methylation profiling, conditional Yy1 deletion, and Ngn2 Co-IP\",\n      \"pmids\": [\"38956165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the Ngn2-YY1 cofactor relationship to other lineage factors unknown\", \"Whether YY1 looping function is the operative mechanism not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how YY1's many post-translational modifications, oligomerization state, and diverse cofactor interactions are integrated to switch between its architectural looping function and its locus-specific activating versus repressive transcriptional outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM status to choice of architectural vs transcriptional mode\", \"Structural basis of YY1 dimer/oligomer at loops not defined\", \"Determinants of activator-versus-repressor cofactor selection at individual loci unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 7, 19, 27, 29, 30, 33, 40]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 20, 29, 30, 40]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 16, 37]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 16, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 28]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 7, 18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 7, 8, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 19, 27, 30, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 16, 17, 18, 39]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 16, 30, 37]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 11, 12, 34, 35]}\n    ],\n    \"complexes\": [\"PRC1 (via YAF2)\"],\n    \"partners\": [\"YAF2\", \"CtBP\", \"c-Myc\", \"RBPJ\", \"AKT\", \"STAT1\", \"RuvBL1\", \"Smad7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}