{"gene":"YY1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2017,"finding":"YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate structural interactions between enhancers and promoters. 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 loops analogous to CTCF.","method":"ChIP-seq, Hi-C, CRISPR deletion of binding sites, protein depletion with dTAG system, 4C-seq","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (ChIP-seq, chromatin conformation, genetic deletion, protein depletion) in a single high-impact study; widely replicated concept","pmids":["29224777"],"is_preprint":false},{"year":2011,"finding":"YY1 acts as a bivalent adaptor protein capable of binding both RNA (Xist RNA through Repeat C) and DNA (through an epigenetically regulated trio of YY1 sites on the inactive X), thereby docking Xist particles onto the X chromosome nucleation center to initiate X-chromosome inactivation.","method":"RNA immunoprecipitation, ChIP, mutational analysis of YY1 RNA- and DNA-binding motifs, allele-specific assays, deletion of YY1 binding sites","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution of RNA-DNA bridging function with mutagenesis, multiple orthogonal methods in a high-impact study","pmids":["21729784"],"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, establishing c-Myc as a modulator of YY1 transcriptional activity.","method":"Yeast two-hybrid screen, affinity chromatography, cotransfection reporter assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by affinity chromatography and functional cotransfection; foundational paper with >250 citations","pmids":["8266081"],"is_preprint":false},{"year":2007,"finding":"YY1 acts as a lineage-specific transcriptional repressor in oligodendrocyte progenitors by recruiting histone deacetylase-1 (HDAC1) to the promoters of myelin gene expression inhibitors Tcf4 and Id4, thereby enabling oligodendrocyte progenitor differentiation.","method":"Conditional yy1 knockout in oligodendrocyte lineage, ChIP, co-immunoprecipitation, in vivo phenotypic analysis (myelination defects, ataxia)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotype, ChIP showing HDAC1 recruitment, multiple orthogonal methods","pmids":["17640524"],"is_preprint":false},{"year":2014,"finding":"YY1 activates Xist transcription by binding directly to the Xist 5' region, competing with the Xist repressor REX1; DNA methylation controls mono-allelic fixation of YY1 to the Xist locus at the onset of XCI, establishing YY1 as the first autosomal activating factor in Xist regulation.","method":"YY1 loss-of-function, ChIP, luciferase reporter assays, bisulfite sequencing, allele-specific analysis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal methods (ChIP, reporter, methylation analysis); replicated the Jeon & Lee finding with distinct mechanism","pmids":["25209548"],"is_preprint":false},{"year":2004,"finding":"YY1 DNA binding in vivo and its recruitment of Polycomb Group (PcG) proteins to DNA requires CtBP; in a CtBP mutant background, YY1 DNA binding is masked (without protein degradation or nuclear export) and PcG-dependent histone H3 deacetylation and methylation do not occur.","method":"Drosophila CtBP mutant genetic analysis, ChIP, histone modification assays, Western blot","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with ChIP and histone modification readouts; ortholog confirmed by functional conservation","pmids":["15520279"],"is_preprint":false},{"year":2013,"finding":"YY1 interacts with YAF2 (a RYBP homolog); YAF2 bridges YY1 to the PRC1 complex and is responsible for PcG recruitment to DNA, which requires prior YY1 DNA binding. Knockdown of YY1 abrogates PcG recruitment even when YAF2 is exogenously supplied.","method":"Co-immunoprecipitation, ChIP in HeLa cells, Drosophila phenotypic rescue, siRNA knockdown","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldowns, ChIP, genetic rescue across species; multiple orthogonal methods","pmids":["24285299"],"is_preprint":false},{"year":2007,"finding":"YY1 is sumoylated at lysine 288 by the SUMO E3 ligase PIASy both in vivo and in vitro. PIASy stimulates YY1 sumoylation through its interaction with YY1 (dependent on the PPxY motif in YY1) rather than through its RING finger domain, colocalizes with YY1 in the nucleus, stabilizes YY1, and differentially regulates YY1 transcriptional activity on different promoters.","method":"In vitro and in vivo sumoylation assays, mutagenesis of sumoylation site (K288R), PIASy interaction mapping, co-immunoprecipitation, reporter assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro sumoylation assay plus mutagenesis plus in vivo confirmation; multiple orthogonal methods","pmids":["17353273"],"is_preprint":false},{"year":1995,"finding":"Cyclophilin A (CyPA) and FK506-binding protein 12 (FKBP12) specifically interact with YY1 in both yeast and mammalian cells; cyclosporin A and FK506 disrupt these interactions, respectively; overexpression of CyPA and FKBP12 differentially and promoter-dependently alter YY1-regulated transcription.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, pharmacological disruption, cotransfection reporter assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid confirmed by mammalian Co-IP and functional reporter assays; single lab study","pmids":["7541038"],"is_preprint":false},{"year":2015,"finding":"YY1 is sumoylated and also subject to ubiquitin-proteasome–mediated degradation by the E3 ubiquitin ligase Smurf2, which interacts with YY1 via its PPxY motif, induces poly-ubiquitination of YY1, and shortens YY1 protein half-life. Smurf2-mediated degradation reduces YY1 transcriptional activity and relieves YY1-mediated suppression of p53.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase (half-life), Smurf2 knockdown, reporter assays","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods including ubiquitination assay and half-life measurement; single lab","pmids":["24803334"],"is_preprint":false},{"year":2005,"finding":"Nitric oxide (NO) inhibits YY1 DNA-binding activity through S-nitrosation of YY1 (detected at cysteine residues coordinated by Zn2+ in the zinc finger domain), which leads to upregulation of Fas expression and sensitization of prostate cancer cells to Fas-induced apoptosis.","method":"EMSA, S-nitrosation detection by DAN-based fluorometry and anti-SNO immunoprecipitation, siRNA knockdown of YY1, immunofluorescence","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — two independent S-nitrosation detection methods plus functional EMSA and siRNA validation; single lab","pmids":["16143308"],"is_preprint":false},{"year":2015,"finding":"YY1 is phosphorylated at multiple tyrosine residues by Src family kinases in vitro and in vivo; phosphorylation at tyrosine 383 specifically interferes with YY1 DNA and RNA binding, downregulating YY1 transcriptional activity. YY1 is also identified as a downstream target of EGFR signaling.","method":"Pharmacological inhibition, kinase overexpression, kinase knockout, site-directed mutagenesis (Y383), EMSA, in vitro kinase assay, reporter assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus mutagenesis plus in vivo pharmacological and genetic validation; multiple orthogonal approaches","pmids":["26198631"],"is_preprint":false},{"year":1995,"finding":"The nuclear matrix protein NMP-1 is identical to YY1; YY1/NMP-1 is localized in the nuclear matrix (principally associated with residual nucleoli) and binds sequence-specifically to histone H4 gene site IV, suggesting YY1 mediates gene-matrix interactions.","method":"Gel-shift assay, Western blot with YY1 antibody, nuclear matrix fractionation, in situ immunofluorescence, reconstitution with purified YY1","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 — protein purification/reconstitution combined with fractionation and in situ imaging; multiple orthogonal methods","pmids":["7479833"],"is_preprint":false},{"year":2014,"finding":"YY1 assembles into homo-oligomeric species built from a bell-shaped dimer (characterized by electron microscopy and bimolecular fluorescence complementation in vivo); these oligomers bind DNA substrates without canonical YY1 consensus sequences in vitro, and DNA binding is enhanced by interaction with RuvBL1-RuvBL2 AAA+ ATPases (YY1 interacts preferentially with RuvBL1). YY1 and RuvBL2 ATPase activity are required for RAD51 foci formation during homologous recombination.","method":"Electron microscopy, bimolecular fluorescence complementation, EMSA, co-immunoprecipitation, RAD51 foci assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — EM structural characterization plus in vivo BiFC plus functional HR assay; single lab","pmids":["24990942"],"is_preprint":false},{"year":2015,"finding":"YY1 binds directly to the promoter of Linc-YY1, and Linc-YY1 interacts with YY1 protein through its middle domain to evict YY1/PRC2 complexes from target promoters, activating gene expression in trans and promoting myogenic differentiation.","method":"RNA immunoprecipitation, gain/loss-of-function in C2C12 myoblasts and satellite cells, in vivo muscle regeneration assay, ChIP, RNA-protein interaction mapping","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of RNA-protein interaction, functional KD/OE with in vivo validation, ChIP; single lab but multiple methods","pmids":["26658965"],"is_preprint":false},{"year":2009,"finding":"YY1 autoregulates its own transcription through a cluster of YY1-binding sites within the first intron of the YY1 gene; overexpression of exogenous YY1 reduces endogenous YY1 transcription, and reverting to normal YY1 levels restores endogenous transcription, establishing YY1 as the first known autoregulating transcription factor in mammalian genomes.","method":"Inducible overexpression cell line, luciferase reporter with site mutations, gel shift assay","journal":"BMC Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 — inducible expression system with site-directed mutagenesis of binding sites and reporter assays; single lab","pmids":["19712462"],"is_preprint":false},{"year":2013,"finding":"YY1 binds to the LTR region of exogenous and endogenous retroviruses (ERVs) in embryonic cells and is required for their transcriptional silencing; deletion of the YY1-binding site causes major loss of silencing and loss of repressive histone marks. YY1 physically interacts with Trim28 in an embryonic cell–specific manner.","method":"ChIP, LTR binding site deletion, YY1 depletion (siRNA/shRNA), RT-qPCR of ERV expression, co-immunoprecipitation","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — genetic deletion of binding site, protein depletion, ChIP for repressive marks, and Co-IP all in same study; multiple orthogonal methods","pmids":["23810560"],"is_preprint":false},{"year":2018,"finding":"Characterization of Trim28-YY1 interaction domains: the RBCC domain of Trim28 is sufficient for interaction with YY1, and the acidic region 1 and zinc fingers of YY1 are necessary and sufficient for interaction with Trim28. Sumoylation and phosphorylation of Trim28 regulate M-MLV silencing, with residue K779 of Trim28 critical for silencing in embryonic cells.","method":"Domain mapping by deletion constructs, co-immunoprecipitation, retroviral silencing reporter assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain-mapping Co-IP with functional silencing assay; single lab","pmids":["29407374"],"is_preprint":false},{"year":2023,"finding":"YY1 is lactylated at lysine 183 (K183) by the writer p300; hyperlactylation at K183 directly enhances YY1 binding to the FGF2 promoter and increases FGF2 transcription, promoting angiogenesis. YY1 K183 mutation abolishes these effects.","method":"Mass spectrometry identification of lactylation sites, K183R mutagenesis, ChIP, luciferase reporter, p300 inhibitor (A485) in vitro and in vivo, p300 overexpression","journal":"Genome Biology","confidence":"High","confidence_rationale":"Tier 1–2 — PTM site identified by MS, confirmed by site mutagenesis, writer identified, functional ChIP and reporter assays, in vivo validation","pmids":["37085894"],"is_preprint":false},{"year":2024,"finding":"YY1 is also lactylated by p300 at retinal microglia during autoimmune uveitis; YY1 lactylation promotes microglial activation and transcription of inflammatory genes including STAT3, CCL5, IRF1, IDO1, and SEMA4D as shown by CUT&Tag analysis. p300 inhibition decreases YY1 lactylation and suppresses microglial inflammation.","method":"CUT&Tag sequencing, p300 inhibitor treatment, lactylation inhibition, in vivo autoimmune uveitis model, Co-IP","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 — CUT&Tag genome-wide profiling with in vivo validation and pharmacological inhibition; single lab","pmids":["38493498"],"is_preprint":false},{"year":2015,"finding":"Somatic T372R mutation in the DNA-binding zinc finger of YY1 (found in 14/43 insulinomas) changes the DNA motif recognized by YY1, leading to neo-morphic activation of ADCY1 and CACNA2D2, genes involved in cAMP and Ca2+ signaling that regulate insulin secretion.","method":"Exome sequencing, ChIP-seq comparing wild-type and T372R YY1, expression of mutant in INS-1 cells, insulin secretion assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq defining altered binding motif combined with functional expression assay demonstrating changed insulin secretion; multiple orthogonal methods","pmids":["25787250"],"is_preprint":false},{"year":2017,"finding":"YY1 haploinsufficiency in humans with de novo YY1 mutations/deletions leads to global loss of YY1 chromatin binding with preferential retention at high-occupancy sites, and a widespread loss of H3K27 acetylation particularly at YY1-bound enhancers, defining a clinical syndrome caused by dysregulation of key transcriptional regulators.","method":"ChIP with antibodies against both ends of YY1 from patient cells, H3K27ac ChIP-seq, clinical genomics of 23 individuals","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq from patient-derived cells with multiple antibodies demonstrating direct consequence of YY1 loss on enhancer acetylation; strong translational evidence","pmids":["28575647"],"is_preprint":false},{"year":2018,"finding":"YY1 directly activates transcription of G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzyme of the pentose phosphate pathway, in a p53-independent manner, thereby promoting nucleotide synthesis, NADPH production, ROS reduction, and tumor cell proliferation.","method":"ChIP, luciferase reporter assay with G6PD promoter, siRNA knockdown, metabolic assays (NADPH, nucleotide synthesis), xenograft tumor model","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter confirm direct binding/activation; metabolic and in vivo phenotype; single lab","pmids":["29921695"],"is_preprint":false},{"year":2020,"finding":"Endothelial YY1 deletion in mice causes embryonic lethality and impairs sprouting angiogenesis; mechanistically, YY1 binds the N-terminal domain of RBPJ and competes with MAML1 for RBPJ binding, thereby blocking NICD/MAML1/RBPJ complex formation and repressing Notch-dependent gene expression to control endothelial tip cell fate.","method":"EC-specific conditional knockout mice, retinal angiogenesis assay, aortic ring assay, co-immunoprecipitation of YY1-RBPJ, competition assay with MAML1, Notch target gene expression analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined vascular phenotype, Co-IP defining direct YY1-RBPJ interaction, competition with MAML1; multiple orthogonal methods","pmids":["32075915"],"is_preprint":false},{"year":2021,"finding":"YY1 co-occupies gene-regulatory elements with bromodomain-containing proteins BRD2/4 in prostate cancer; YY1 directly binds and activates PFKP (phosphofructokinase, platelet type), the rate-limiting enzyme for glycolysis, establishing a YY1:BRD2/4-PFKP oncogenic axis contributing to the Warburg effect.","method":"ChIP-seq, interactome profiling (mass spectrometry), gene loss-of-function and rescue, mutagenesis of YY1-bound cis-elements, metabolic assays, xenograft","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq cistrome plus MS interactome plus cis-element mutagenesis plus functional rescue; multiple orthogonal methods","pmids":["33849067"],"is_preprint":false},{"year":2021,"finding":"YY1 physically interacts with EZH2 through a specific 'oncoprotein binding' (OPB) domain on YY1; disruption of the YY1-EZH2 interaction using synthetic peptides targeting either the OPB domain on YY1 or the YY1-protein binding (YPB) domain on EZH2 alters H3K27me3 at hundreds of genomic loci and inhibits breast cancer cell growth.","method":"Domain mapping, synthetic peptide competition assay, ChIP-seq (H3K27me3), cell viability, xenograft tumor model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain mapping plus ChIP-seq readout; functional validation in vitro and in vivo; single lab","pmids":["34065631"],"is_preprint":false},{"year":2021,"finding":"PHF8 demethylates YY1 (functioning as a co-repressor of nuclear-encoded ETC genes) to drive mitochondrial ROS production; PHF8 acts as a demethylase not on histones but on the transcription factor YY1 itself to repress ETC gene transcription and promote cancer cell growth.","method":"PHF8 KO, PHF8 inhibitor (iPHF8), YY1 methylation assay, ETC gene expression profiling, xenograft and PDX models, genetic ablation","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 — direct demethylation of YY1 demonstrated, pharmacological and genetic validation in vivo; single lab","pmids":["38165927"],"is_preprint":false},{"year":2021,"finding":"CK2α (casein kinase 2α) directly phosphorylates YY1 at serine 118 (S118) in endothelial cells under disturbed/oscillatory flow; phospho-YY1S118 directly binds ZKSCAN4, inducing HDM2 promoter activity and gene expression, which downregulates p53 and p21CIP1 to promote EC proliferation and atherosclerosis.","method":"Quantitative phosphoproteomics, in situ proximity ligation assay, yeast two-hybrid for ZKSCAN4 interaction, S118 non-phosphorylatable transgenic mice, luciferase reporter, CK2 inhibitor in ApoE-/- mice","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 1–2 — phosphoproteomics site identification, kinase-substrate validation, transgenic mouse model, multiple orthogonal methods","pmids":["34747636"],"is_preprint":false},{"year":2024,"finding":"OTUD3 is a deubiquitinase for YY1 that stabilizes YY1 protein; PLK1 phosphorylates OTUD3 at S326, enhancing OTUD3 binding to and deubiquitination of YY1, thereby increasing YY1 protein levels and promoting colorectal cancer cell proliferation.","method":"DUB screening, co-immunoprecipitation, ubiquitination assay, OTUD3 KD/KO, phosphorylation assay, PLK1 inhibition, clinical CRC tissue analysis","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, phosphorylation demonstrated; single lab but multiple biochemical methods","pmids":["38351178"],"is_preprint":false},{"year":2009,"finding":"YY1 binding sites within differentially methylated regions (DMRs) of Peg3 and Xist are required for de novo DNA methylation of these loci during oogenesis; YY1 knockdown during oogenesis causes loss of DNA methylation on Peg3 and Xist DMRs, while YY1 knockdown during spermatogenesis maintains unmethylation status.","method":"Conditional YY1 knockdown during oogenesis and spermatogenesis, bisulfite sequencing of DMRs","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 — conditional knockdown with stage-specific methylation readout; single lab but clean genetic approach","pmids":["19628663"],"is_preprint":false},{"year":2024,"finding":"YY1 maintains numerous enhancer-promoter loops in erythroid cells independent of cohesin-mediated loop extrusion; YY1 is partially retained on mitotic chromatin (predominantly at gene promoters) and rapidly rebinds during mitotic exit, coinciding with enhancer-promoter loop re-establishment. Some YY1-dependent loops require YY1 for establishment at G1-phase entry but not for maintenance in interphase, demonstrating cell-cycle stage–dependent architectural function.","method":"Acute YY1 degradation (dTAG), Hi-C, ChIP-seq, cell-cycle synchronization, 4C-seq, cohesin depletion comparison","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 1–2 — acute protein degradation system combined with Hi-C and cell-cycle dynamics; multiple orthogonal methods; rigorous controls","pmids":["39210046"],"is_preprint":false},{"year":2012,"finding":"YY1 physically interacts with M-MITF (Waardenburg Syndrome IIA gene product) in melanocytes and cooperates with M-MITF to regulate expression of pigmentation genes including KIT; genome-wide ChIP-seq identified YY1 targets in the melanocyte lineage, demonstrating how a ubiquitous factor (YY1) gains lineage-specific functions through co-regulation with a lineage-restricted factor (M-MITF).","method":"Conditional yy1 KO in melanocyte lineage, co-immunoprecipitation of YY1-MITF, ChIP-seq, reporter assays, coat color phenotype analysis","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with in vivo phenotype, Co-IP, and genome-wide ChIP-seq; multiple orthogonal methods","pmids":["22570637"],"is_preprint":false},{"year":2008,"finding":"YY1 recognizes a longer consensus DNA-binding motif (GCCGCCATTTTG) beyond the previously known core sequence, requiring intact contribution of its first zinc finger unit; a three–amino acid substitution mimicking Drosophila Pho in the first zinc finger weakens DNA-binding specificity and shortens the recognized motif to GCCAT.","method":"Gel shift assay (EMSA), systematic DNA motif analysis, zinc finger mutagenesis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro biochemical assay with site-directed mutagenesis; single lab","pmids":["18950698"],"is_preprint":false},{"year":2021,"finding":"YY1 and YY2 bind competitively to the same DNA-binding site in the SLC7A11 promoter and antagonistically regulate ferroptosis: YY1 activates SLC7A11 to promote glutathione biosynthesis and suppress ferroptosis, while YY2 represses SLC7A11 to induce ferroptosis and suppress tumorigenesis.","method":"ChIP, luciferase reporter assay, site-directed mutagenesis of zinc finger domains, siRNA knockdown, ferroptosis assays (lipid peroxidation, cell death), clinical mutation analysis","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 — competitive ChIP at shared binding site, mutagenesis, and functional ferroptosis assays; single lab","pmids":["35246964"],"is_preprint":false},{"year":2021,"finding":"3-Hydroxyanthranilic acid (3-HAA), a kynurenine derivative, directly binds YY1 as an agonist ligand, inducing YY1 phosphorylation at Thr398 by PKCζ and enhancing YY1 chromatin binding activity to increase expression of target genes including apoptotic genes in hepatocellular carcinoma.","method":"Ligand-binding assay, co-immunoprecipitation, phosphorylation assay, ChIP, cell viability assay","journal":"Journal of Hematology & Oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited structural validation of ligand binding, mechanism partially characterized","pmids":["34563230"],"is_preprint":false},{"year":2019,"finding":"YY1 forms an active complex with HIF-1α at VEGF gene promoters and increases VEGF transcription; CXCR4/SDF-1 inhibition causes YY1 cytoplasmic accumulation by reducing YY1 phosphorylation through AKT downregulation.","method":"Co-immunoprecipitation of YY1-HIF-1α, ChIP at VEGF promoter, RT-PCR, ELISA, in vitro angiogenesis assay, phosphorylation analysis","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus ChIP plus functional angiogenesis assay; single lab","pmids":["20660740"],"is_preprint":false},{"year":2024,"finding":"YY1 is recruited by direct protein-protein interaction with Neurogenin2 (Ngn2) to neuronal enhancer sites in astrocyte-to-neuron reprogramming; YY1 deletion impairs activation of neuronal enhancers and genes and reduces reprogramming efficiency without affecting Ngn2 chromatin binding, establishing YY1 as a required co-factor for Ngn2-mediated epigenome remodeling.","method":"Single-cell multiomics, ChIP-seq, ATAC-seq, co-immunoprecipitation of YY1-Ngn2, Yy1 conditional deletion, direct neuronal reprogramming assay","journal":"Nature Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — Co-IP confirming direct interaction, genetic deletion, genome-wide profiling; multiple orthogonal methods","pmids":["38956165"],"is_preprint":false},{"year":2019,"finding":"In M2 macrophages in prostate cancer, YY1 undergoes liquid-liquid phase separation (LLPS) with transcriptional cofactors p300, p65, and CEBPB; the YY1 phase separation complex upregulates IL-6 by promoting IL-6 enhancer-promoter chromatin interactions, facilitating prostate cancer progression.","method":"LLPS assay, H3K27ac-ChIP-seq, YY1 ChIP-seq, CRISPR-Cas9 KO, RNA-seq, chromatin interaction assay, transgenic YY1-overexpressing mice","journal":"Journal for Immunotherapy of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq, LLPS, and functional KO with in vivo validation; single lab but multiple orthogonal methods","pmids":["37094986"],"is_preprint":false},{"year":2016,"finding":"GON4L interacts with YY1 and promotes YY1's association with the androgen receptor, forming a GON4L-YY1-androgen receptor complex that drives CD24 expression and cancer cell growth.","method":"shRNA library screen, co-immunoprecipitation of GON4L-YY1 and YY1-AR, gene silencing with proliferation/tumor growth assays, clinical tissue analysis","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP establishing ternary complex, functional shRNA validation in vivo; single lab","pmids":["27312530"],"is_preprint":false},{"year":2019,"finding":"YY1 directly binds to and represses the TGFB1 promoter in human renal mesangial cells; YY1 overexpression attenuates glomerulosclerosis in mouse DN models, and YY1 knockdown aggravates renal lesions, establishing YY1 as a potent transcriptional repressor of TGFβ1 in diabetic nephropathy.","method":"Mass spectrometry-based DNA-protein interaction screen, ChIP, luciferase reporter, in vitro and in vivo YY1 manipulation (knockdown and overexpression), mouse DN models","journal":"Science Translational Medicine","confidence":"High","confidence_rationale":"Tier 2 — unbiased proteomics identification confirmed by ChIP and reporter, plus in vivo genetic gain/loss-of-function; multiple orthogonal methods","pmids":["31534017"],"is_preprint":false},{"year":2019,"finding":"YY1 is a substrate of CARM1-mediated arginine methylation; CARM1 co-activates YY1-mediated reporter gene activation in vivo and the two proteins regulate each other in a positive feedback loop in oral cancer.","method":"In vivo arginine methylation assay, reporter assay with CARM1 co-expression, siRNA knockdown, qRT-PCR, xenograft","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 — arginine methylation of YY1 demonstrated in vivo but mechanistic resolution limited; single lab, partial follow-up","pmids":["31217904"],"is_preprint":false}],"current_model":"YY1 is a multifunctional zinc-finger transcription factor that forms dimers and oligomers to bridge enhancer-promoter DNA loops, recruits Polycomb repressive complexes (via YAF2/RYBP and CtBP), acts as a bivalent RNA-DNA adaptor to tether Xist RNA to the inactive X chromosome, and can either activate or repress target gene transcription depending on its interacting partners (including c-Myc, HDAC1, EZH2, HIF-1α, RBPJ, MITF, and BRD2/4); its activity is regulated by multiple post-translational modifications including tyrosine phosphorylation (by Src/EGFR; Y383 inhibits DNA binding), serine phosphorylation (CK2α at S118 promotes atherosclerosis), S-nitrosation (inhibits DNA binding), sumoylation (by PIASy at K288), lactylation (by p300 at K183 enhancing chromatin binding), demethylation (by PHF8 converting YY1 to a co-repressor of ETC genes), and ubiquitin-proteasome–mediated degradation (by Smurf2 E3 ligase, reversed by OTUD3 deubiquitinase)."},"narrative":{"teleology":[{"year":1993,"claim":"The discovery that YY1 physically associates with c-Myc—which inhibits both YY1's activator and repressor functions—established that YY1 is not an autonomous switch but a partner-dependent transcription factor whose output is modulated by oncoproteins.","evidence":"Yeast two-hybrid, affinity chromatography, and cotransfection reporter assays in mammalian cells","pmids":["8266081"],"confidence":"High","gaps":["Structural basis of c-Myc–YY1 interaction unknown","Which YY1 target genes are regulated by c-Myc modulation not defined"]},{"year":1995,"claim":"Identification of YY1 as a nuclear matrix protein (NMP-1) associated with residual nucleoli, and the finding that immunophilins CyPA and FKBP12 interact with YY1 and modulate its transcriptional activity, revealed that YY1 functions within a defined subnuclear scaffold and is subject to regulation by peptidyl-prolyl isomerases.","evidence":"Nuclear matrix fractionation, gel-shift, in situ immunofluorescence (NMP-1); yeast two-hybrid, mammalian Co-IP, pharmacological disruption with CsA/FK506 (immunophilins)","pmids":["7479833","7541038"],"confidence":"High","gaps":["Physiological relevance of immunophilin–YY1 interaction in vivo not established","Whether CyPA/FKBP12 catalytically isomerize YY1 not tested"]},{"year":2004,"claim":"Genetic epistasis in Drosophila demonstrated that CtBP is required for YY1 (Pho) DNA binding in vivo and for subsequent Polycomb group protein recruitment and histone modification, establishing the first essential cofactor for YY1-mediated Polycomb silencing.","evidence":"Drosophila CtBP mutant analysis, ChIP for PcG occupancy and histone marks","pmids":["15520279"],"confidence":"High","gaps":["Mechanism by which CtBP unmasks YY1 DNA binding not resolved","Whether CtBP dependence is conserved in mammalian PcG targeting not shown"]},{"year":2007,"claim":"Conditional YY1 knockout in the oligodendrocyte lineage revealed that YY1 recruits HDAC1 to repress differentiation inhibitors Tcf4 and Id4, establishing YY1 as a lineage-specific differentiation regulator, while identification of K288 sumoylation by PIASy showed that SUMO modification stabilizes YY1 and modulates its transcriptional output in a promoter-dependent manner.","evidence":"Conditional KO with myelination phenotype, ChIP/Co-IP for HDAC1 (oligodendrocytes); in vitro sumoylation, K288R mutagenesis, reporter assays (sumoylation)","pmids":["17640524","17353273"],"confidence":"High","gaps":["Whether sumoylation alters YY1-HDAC1 interaction not tested","Full repertoire of YY1 target genes in OPC differentiation not mapped"]},{"year":2008,"claim":"Systematic motif and zinc-finger mutagenesis extended YY1's DNA recognition to a longer consensus (GCCGCCATTTTG) requiring the first zinc finger, refining the understanding of how YY1 selects genomic targets.","evidence":"EMSA with systematic DNA motif variants and zinc-finger substitution mutants","pmids":["18950698"],"confidence":"Medium","gaps":["In vivo validation of the extended motif's functional significance not provided","Contribution of flanking sequence context to binding affinity not addressed"]},{"year":2009,"claim":"Two studies revealed YY1's role in epigenetic memory: YY1 binding sites in DMRs of Peg3 and Xist are required for de novo DNA methylation during oogenesis, and YY1 autoregulates its own transcription through intronic binding sites, demonstrating both trans-regulatory imprinting control and a self-buffering feedback loop.","evidence":"Conditional YY1 KD during oogenesis/spermatogenesis with bisulfite sequencing; inducible overexpression with reporter mutagenesis","pmids":["19628663","19712462"],"confidence":"Medium","gaps":["Whether YY1 recruits specific DNMTs to DMRs not identified","Autoregulation kinetics and quantitative buffering capacity not measured"]},{"year":2011,"claim":"Demonstration that YY1 simultaneously binds Xist RNA (via Repeat C) and DNA (via an epigenetically regulated trio of sites) to dock Xist onto the X chromosome nucleation center established YY1 as a bivalent RNA-DNA adaptor critical for X-chromosome inactivation.","evidence":"RNA immunoprecipitation, ChIP, mutational dissection of RNA- and DNA-binding motifs, allele-specific assays","pmids":["21729784"],"confidence":"High","gaps":["Structural basis of simultaneous RNA and DNA binding not resolved","Whether YY1 bridges other lncRNAs to chromatin genome-wide not explored"]},{"year":2012,"claim":"Conditional YY1 knockout in melanocytes combined with Co-IP and ChIP-seq showed that YY1 physically interacts with the lineage-restricted factor MITF to co-regulate pigmentation genes, explaining how a ubiquitous factor achieves lineage-specific transcriptional output.","evidence":"Melanocyte-specific Yy1 KO, Co-IP of YY1-MITF, ChIP-seq, coat color phenotype","pmids":["22570637"],"confidence":"High","gaps":["Whether YY1-MITF form a stable complex or transient interaction not determined","Genome-wide partitioning of MITF-dependent versus -independent YY1 targets not complete"]},{"year":2013,"claim":"Two studies clarified YY1's role in Polycomb recruitment and retroviral silencing: YAF2 bridges YY1 to PRC1 in a YY1 DNA-binding-dependent manner, and YY1 binds ERV LTRs in embryonic cells through interaction with Trim28 to recruit repressive histone marks, defining distinct PRC1 and Trim28/KRAB pathways for YY1-mediated silencing.","evidence":"Reciprocal Co-IP, ChIP, siRNA, Drosophila rescue (YAF2-PRC1); LTR binding-site deletion, YY1 depletion, Trim28 Co-IP (ERV silencing)","pmids":["24285299","23810560"],"confidence":"High","gaps":["Whether YAF2 and Trim28 pathways operate on overlapping or distinct target sets not resolved","Structural basis of YAF2-YY1 and Trim28-YY1 interfaces only partially mapped"]},{"year":2014,"claim":"YY1 was shown to activate Xist transcription by competing with the repressor REX1 for binding at the Xist promoter, while structural studies revealed YY1 forms bell-shaped dimers that oligomerize and interact with RuvBL1/2 ATPases to participate in homologous recombination, expanding YY1's functions beyond transcription to DNA repair.","evidence":"ChIP, reporter, bisulfite sequencing (Xist activation); electron microscopy, BiFC, EMSA, RAD51 foci assay (oligomers/HR)","pmids":["25209548","24990942"],"confidence":"High","gaps":["Whether oligomerization is required for enhancer-promoter looping not tested","Mechanism of YY1/RuvBL1-2 cooperation in RAD51 loading not defined"]},{"year":2015,"claim":"Multiple regulatory mechanisms were defined: Src/EGFR-mediated Y383 phosphorylation inhibits YY1 DNA/RNA binding, Smurf2-mediated ubiquitination targets YY1 for proteasomal degradation, S-nitrosation of zinc-finger cysteines blocks DNA binding, a somatic T372R zinc-finger mutation in insulinomas creates a neomorphic binding specificity activating cAMP/Ca²⁺ signaling genes, and Linc-YY1 evicts YY1/PRC2 from target promoters to promote myogenic differentiation.","evidence":"In vitro kinase assay with Y383 mutagenesis (Src); ubiquitination/CHX chase (Smurf2); S-nitrosation detection and EMSA (NO); exome sequencing with ChIP-seq of WT vs T372R (insulinoma); RIP and ChIP with in vivo muscle regeneration (Linc-YY1)","pmids":["26198631","24803334","16143308","25787250","26658965"],"confidence":"High","gaps":["Phosphatase(s) reversing Y383 phosphorylation unknown","Whether Smurf2 ubiquitinates YY1 at specific lysines not mapped","Linc-YY1 mechanism of PRC2 eviction not structurally resolved"]},{"year":2017,"claim":"ChIP-seq, Hi-C, and acute protein depletion established YY1 as a general structural regulator of enhancer-promoter loops analogous to CTCF, while patient-derived cells with YY1 haploinsufficiency showed global loss of YY1 chromatin binding and H3K27ac at enhancers, linking YY1 architectural function to a neurodevelopmental syndrome.","evidence":"dTAG depletion, CRISPR deletion of binding sites, 4C-seq, Hi-C (looping); ChIP-seq from cells of 23 patients with de novo YY1 mutations (disease)","pmids":["29224777","28575647"],"confidence":"High","gaps":["Whether YY1-mediated loops require specific cofactors or are solely dimer-driven not resolved","Genotype-phenotype correlations across different YY1 mutations not fully characterized"]},{"year":2019,"claim":"Context-specific transcriptional programs were delineated: YY1 represses TGFB1 in renal mesangial cells to protect against diabetic nephropathy, forms an active complex with HIF-1α at VEGF promoters for angiogenesis, and undergoes liquid-liquid phase separation with p300/p65/CEBPB to activate IL-6 enhancer-promoter interactions in M2 macrophages.","evidence":"MS-based DNA-protein screen, ChIP, mouse DN models (TGFB1); Co-IP of YY1-HIF-1α, ChIP at VEGF (angiogenesis); LLPS assay, ChIP-seq, CRISPR KO (phase separation)","pmids":["31534017","20660740","37094986"],"confidence":"High","gaps":["Whether phase separation is required for all YY1-dependent enhancer-promoter contacts unknown","Structural determinants of YY1 LLPS not defined"]},{"year":2021,"claim":"Multiple studies converged on YY1's metabolic and signaling roles: YY1 cooperates with BRD2/4 to activate glycolytic PFKP, YY1's interaction with EZH2 through the OPB domain controls H3K27me3 deposition, PHF8 demethylates YY1 itself to convert it into a co-repressor of ETC genes, CK2α phosphorylates YY1 at S118 to drive endothelial proliferation and atherosclerosis, and YY1 activates SLC7A11 to suppress ferroptosis.","evidence":"ChIP-seq/MS interactome with cis-element mutagenesis (BRD2/4-PFKP); peptide competition, ChIP-seq for H3K27me3 (EZH2); PHF8 KO/inhibitor with YY1 methylation assay (PHF8); phosphoproteomics, S118A transgenic mice (CK2α); competitive ChIP and ferroptosis assays (SLC7A11)","pmids":["33849067","34065631","38165927","34747636","35246964"],"confidence":"High","gaps":["Specific methylation site(s) on YY1 targeted by PHF8 not identified","Whether BRD2/4-YY1 co-occupancy is a general phenomenon across cancer types unclear","Direct structural data for YY1-EZH2 OPB/YPB interface lacking"]},{"year":2023,"claim":"Identification of p300-mediated lactylation at YY1 K183 that enhances chromatin binding and FGF2 transcription established lactylation as a metabolically responsive PTM tuning YY1 activity, later extended to microglial inflammatory gene regulation in autoimmune uveitis.","evidence":"Mass spectrometry, K183R mutagenesis, ChIP, p300 inhibition in vitro/in vivo (FGF2); CUT&Tag, p300 inhibitor in uveitis model (microglia)","pmids":["37085894","38493498"],"confidence":"High","gaps":["Delactylase(s) that reverse K183 lactylation not identified","Genome-wide scope of lactylation-dependent versus -independent YY1 targets not defined"]},{"year":2024,"claim":"Advanced chromatin conformation and acute degradation studies showed that YY1 maintains enhancer-promoter loops independently of cohesin and is partially bookmarked on mitotic chromatin, re-establishing loops at G1 entry; separately, YY1 was identified as a required cofactor for Ngn2-mediated neuronal enhancer activation during astrocyte-to-neuron reprogramming, and OTUD3 was characterized as a PLK1-regulated deubiquitinase stabilizing YY1.","evidence":"dTAG degradation, Hi-C, cell-cycle synchronization, cohesin depletion (looping); single-cell multiomics, Yy1 cKO, Co-IP of YY1-Ngn2 (reprogramming); DUB screen, ubiquitination assay, PLK1 phosphorylation of OTUD3 (stability)","pmids":["39210046","38956165","38351178"],"confidence":"High","gaps":["Molecular determinants distinguishing YY1-bookmarked from non-bookmarked sites unknown","Whether Ngn2-YY1 cooperation is unique to reprogramming or also operates in developmental neurogenesis not addressed","Full ubiquitin site map on YY1 not determined"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis of YY1 simultaneous RNA and DNA binding, (2) how YY1 phase separation, oligomerization, and dimerization relate to each other and to enhancer-promoter loop formation in vivo, (3) the full combinatorial code of post-translational modifications that switch YY1 between activator and repressor states, and (4) whether YY1's cohesin-independent architectural function operates genome-wide or at a specialized subset of loci.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of YY1 bound simultaneously to RNA and DNA","Quantitative in vivo PTM crosstalk map absent","Genome-wide assignment of cohesin-dependent versus YY1-dependent loops incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,4,10,11,12,20,32]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,14,16,22,23,24,33,39]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,37]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,12,35]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,21,30]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,30]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,14,16,22,23,24,33,39]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,6,21,25,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,4,31,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[23,27,35]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13]}],"complexes":["PRC1 (via YAF2/RYBP)","PRC2 (via EZH2)","Trim28-YY1 silencing complex"],"partners":["EZH2","HDAC1","YAF2","TRIM28","RBPJ","MITF","BRD2","BRD4"],"other_free_text":[]},"mechanistic_narrative":"YY1 is a multifunctional zinc-finger transcription factor that serves as a structural organizer of enhancer-promoter chromatin loops and a context-dependent transcriptional activator or repressor. YY1 dimerizes and oligomerizes to bridge enhancers and promoters in a cohesin-independent manner, with some loops requiring YY1 specifically at mitotic exit for re-establishment [PMID:29224777, PMID:39210046]; it also functions as a bivalent RNA-DNA adaptor that tethers Xist RNA to the inactive X chromosome to initiate X-chromosome inactivation [PMID:21729784]. Its transcriptional output is determined by lineage-specific partners—recruiting HDAC1 to repress differentiation inhibitors in oligodendrocyte progenitors [PMID:17640524], cooperating with MITF in melanocytes [PMID:22570637], competing with the Notch co-activator MAML1 for RBPJ binding in endothelial cells [PMID:32075915], and recruiting PRC1 via YAF2/RYBP and PRC2 via EZH2 for Polycomb-mediated silencing [PMID:24285299, PMID:34065631]—while its activity is extensively regulated by post-translational modifications including Src-mediated Y383 phosphorylation that inhibits DNA/RNA binding [PMID:26198631], CK2α-mediated S118 phosphorylation that promotes atherosclerosis [PMID:34747636], p300-mediated K183 lactylation that enhances chromatin binding [PMID:37085894], and Smurf2/OTUD3-controlled ubiquitin-proteasome turnover [PMID:24803334, PMID:38351178]. De novo heterozygous YY1 mutations cause a neurodevelopmental syndrome characterized by global loss of YY1 chromatin occupancy and H3K27 acetylation at enhancers [PMID:28575647]."},"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 loops analogous to CTCF.\",\n      \"method\": \"ChIP-seq, Hi-C, CRISPR deletion of binding sites, protein depletion with dTAG system, 4C-seq\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (ChIP-seq, chromatin conformation, genetic deletion, protein depletion) in a single high-impact study; widely replicated concept\",\n      \"pmids\": [\"29224777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"YY1 acts as a bivalent adaptor protein capable of binding both RNA (Xist RNA through Repeat C) and DNA (through an epigenetically regulated trio of YY1 sites on the inactive X), thereby docking Xist particles onto the X chromosome nucleation center to initiate X-chromosome inactivation.\",\n      \"method\": \"RNA immunoprecipitation, ChIP, mutational analysis of YY1 RNA- and DNA-binding motifs, allele-specific assays, deletion of YY1 binding sites\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of RNA-DNA bridging function with mutagenesis, multiple orthogonal methods in a high-impact study\",\n      \"pmids\": [\"21729784\"],\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, establishing c-Myc as a modulator of YY1 transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid screen, affinity chromatography, cotransfection reporter assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by affinity chromatography and functional cotransfection; foundational paper with >250 citations\",\n      \"pmids\": [\"8266081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"YY1 acts as a lineage-specific transcriptional repressor in oligodendrocyte progenitors by recruiting histone deacetylase-1 (HDAC1) to the promoters of myelin gene expression inhibitors Tcf4 and Id4, thereby enabling oligodendrocyte progenitor differentiation.\",\n      \"method\": \"Conditional yy1 knockout in oligodendrocyte lineage, ChIP, co-immunoprecipitation, in vivo phenotypic analysis (myelination defects, ataxia)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype, ChIP showing HDAC1 recruitment, multiple orthogonal methods\",\n      \"pmids\": [\"17640524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 activates Xist transcription by binding directly to the Xist 5' region, competing with the Xist repressor REX1; DNA methylation controls mono-allelic fixation of YY1 to the Xist locus at the onset of XCI, establishing YY1 as the first autosomal activating factor in Xist regulation.\",\n      \"method\": \"YY1 loss-of-function, ChIP, luciferase reporter assays, bisulfite sequencing, allele-specific analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal methods (ChIP, reporter, methylation analysis); replicated the Jeon & Lee finding with distinct mechanism\",\n      \"pmids\": [\"25209548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"YY1 DNA binding in vivo and its recruitment of Polycomb Group (PcG) proteins to DNA requires CtBP; in a CtBP mutant background, YY1 DNA binding is masked (without protein degradation or nuclear export) and PcG-dependent histone H3 deacetylation and methylation do not occur.\",\n      \"method\": \"Drosophila CtBP mutant genetic analysis, ChIP, histone modification assays, Western blot\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with ChIP and histone modification readouts; ortholog confirmed by functional conservation\",\n      \"pmids\": [\"15520279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YY1 interacts with YAF2 (a RYBP homolog); YAF2 bridges YY1 to the PRC1 complex and is responsible for PcG recruitment to DNA, which requires prior YY1 DNA binding. Knockdown of YY1 abrogates PcG recruitment even when YAF2 is exogenously supplied.\",\n      \"method\": \"Co-immunoprecipitation, ChIP in HeLa cells, Drosophila phenotypic rescue, siRNA knockdown\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldowns, ChIP, genetic rescue across species; multiple orthogonal methods\",\n      \"pmids\": [\"24285299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"YY1 is sumoylated at lysine 288 by the SUMO E3 ligase PIASy both in vivo and in vitro. PIASy stimulates YY1 sumoylation through its interaction with YY1 (dependent on the PPxY motif in YY1) rather than through its RING finger domain, colocalizes with YY1 in the nucleus, stabilizes YY1, and differentially regulates YY1 transcriptional activity on different promoters.\",\n      \"method\": \"In vitro and in vivo sumoylation assays, mutagenesis of sumoylation site (K288R), PIASy interaction mapping, co-immunoprecipitation, reporter assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro sumoylation assay plus mutagenesis plus in vivo confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"17353273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cyclophilin A (CyPA) and FK506-binding protein 12 (FKBP12) specifically interact with YY1 in both yeast and mammalian cells; cyclosporin A and FK506 disrupt these interactions, respectively; overexpression of CyPA and FKBP12 differentially and promoter-dependently alter YY1-regulated transcription.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, pharmacological disruption, cotransfection reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid confirmed by mammalian Co-IP and functional reporter assays; single lab study\",\n      \"pmids\": [\"7541038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 is sumoylated and also subject to ubiquitin-proteasome–mediated degradation by the E3 ubiquitin ligase Smurf2, which interacts with YY1 via its PPxY motif, induces poly-ubiquitination of YY1, and shortens YY1 protein half-life. Smurf2-mediated degradation reduces YY1 transcriptional activity and relieves YY1-mediated suppression of p53.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase (half-life), Smurf2 knockdown, reporter assays\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods including ubiquitination assay and half-life measurement; single lab\",\n      \"pmids\": [\"24803334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nitric oxide (NO) inhibits YY1 DNA-binding activity through S-nitrosation of YY1 (detected at cysteine residues coordinated by Zn2+ in the zinc finger domain), which leads to upregulation of Fas expression and sensitization of prostate cancer cells to Fas-induced apoptosis.\",\n      \"method\": \"EMSA, S-nitrosation detection by DAN-based fluorometry and anti-SNO immunoprecipitation, siRNA knockdown of YY1, immunofluorescence\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent S-nitrosation detection methods plus functional EMSA and siRNA validation; single lab\",\n      \"pmids\": [\"16143308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 is phosphorylated at multiple tyrosine residues by Src family kinases in vitro and in vivo; phosphorylation at tyrosine 383 specifically interferes with YY1 DNA and RNA binding, downregulating YY1 transcriptional activity. YY1 is also identified as a downstream target of EGFR signaling.\",\n      \"method\": \"Pharmacological inhibition, kinase overexpression, kinase knockout, site-directed mutagenesis (Y383), EMSA, in vitro kinase assay, reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutagenesis plus in vivo pharmacological and genetic validation; multiple orthogonal approaches\",\n      \"pmids\": [\"26198631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The nuclear matrix protein NMP-1 is identical to YY1; YY1/NMP-1 is localized in the nuclear matrix (principally associated with residual nucleoli) and binds sequence-specifically to histone H4 gene site IV, suggesting YY1 mediates gene-matrix interactions.\",\n      \"method\": \"Gel-shift assay, Western blot with YY1 antibody, nuclear matrix fractionation, in situ immunofluorescence, reconstitution with purified YY1\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — protein purification/reconstitution combined with fractionation and in situ imaging; multiple orthogonal methods\",\n      \"pmids\": [\"7479833\"],\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 and bimolecular fluorescence complementation in vivo); these oligomers bind DNA substrates without canonical YY1 consensus sequences in vitro, and DNA binding is enhanced by interaction with RuvBL1-RuvBL2 AAA+ ATPases (YY1 interacts preferentially with RuvBL1). YY1 and RuvBL2 ATPase activity are required for RAD51 foci formation during homologous recombination.\",\n      \"method\": \"Electron microscopy, bimolecular fluorescence complementation, EMSA, co-immunoprecipitation, RAD51 foci assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — EM structural characterization plus in vivo BiFC plus functional HR assay; single lab\",\n      \"pmids\": [\"24990942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1 binds directly to the promoter of Linc-YY1, and Linc-YY1 interacts with YY1 protein through its middle domain to evict YY1/PRC2 complexes from target promoters, activating gene expression in trans and promoting myogenic differentiation.\",\n      \"method\": \"RNA immunoprecipitation, gain/loss-of-function in C2C12 myoblasts and satellite cells, in vivo muscle regeneration assay, ChIP, RNA-protein interaction mapping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of RNA-protein interaction, functional KD/OE with in vivo validation, ChIP; single lab but multiple methods\",\n      \"pmids\": [\"26658965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"YY1 autoregulates its own transcription through a cluster of YY1-binding sites within the first intron of the YY1 gene; overexpression of exogenous YY1 reduces endogenous YY1 transcription, and reverting to normal YY1 levels restores endogenous transcription, establishing YY1 as the first known autoregulating transcription factor in mammalian genomes.\",\n      \"method\": \"Inducible overexpression cell line, luciferase reporter with site mutations, gel shift assay\",\n      \"journal\": \"BMC Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible expression system with site-directed mutagenesis of binding sites and reporter assays; single lab\",\n      \"pmids\": [\"19712462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YY1 binds to the LTR region of exogenous and endogenous retroviruses (ERVs) in embryonic cells and is required for their transcriptional silencing; deletion of the YY1-binding site causes major loss of silencing and loss of repressive histone marks. YY1 physically interacts with Trim28 in an embryonic cell–specific manner.\",\n      \"method\": \"ChIP, LTR binding site deletion, YY1 depletion (siRNA/shRNA), RT-qPCR of ERV expression, co-immunoprecipitation\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion of binding site, protein depletion, ChIP for repressive marks, and Co-IP all in same study; multiple orthogonal methods\",\n      \"pmids\": [\"23810560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Characterization of Trim28-YY1 interaction domains: the RBCC domain of Trim28 is sufficient for interaction with YY1, and the acidic region 1 and zinc fingers of YY1 are necessary and sufficient for interaction with Trim28. Sumoylation and phosphorylation of Trim28 regulate M-MLV silencing, with residue K779 of Trim28 critical for silencing in embryonic cells.\",\n      \"method\": \"Domain mapping by deletion constructs, co-immunoprecipitation, retroviral silencing reporter assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain-mapping Co-IP with functional silencing assay; single lab\",\n      \"pmids\": [\"29407374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YY1 is lactylated at lysine 183 (K183) by the writer p300; hyperlactylation at K183 directly enhances YY1 binding to the FGF2 promoter and increases FGF2 transcription, promoting angiogenesis. YY1 K183 mutation abolishes these effects.\",\n      \"method\": \"Mass spectrometry identification of lactylation sites, K183R mutagenesis, ChIP, luciferase reporter, p300 inhibitor (A485) in vitro and in vivo, p300 overexpression\",\n      \"journal\": \"Genome Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — PTM site identified by MS, confirmed by site mutagenesis, writer identified, functional ChIP and reporter assays, in vivo validation\",\n      \"pmids\": [\"37085894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 is also lactylated by p300 at retinal microglia during autoimmune uveitis; YY1 lactylation promotes microglial activation and transcription of inflammatory genes including STAT3, CCL5, IRF1, IDO1, and SEMA4D as shown by CUT&Tag analysis. p300 inhibition decreases YY1 lactylation and suppresses microglial inflammation.\",\n      \"method\": \"CUT&Tag sequencing, p300 inhibitor treatment, lactylation inhibition, in vivo autoimmune uveitis model, Co-IP\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CUT&Tag genome-wide profiling with in vivo validation and pharmacological inhibition; single lab\",\n      \"pmids\": [\"38493498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Somatic T372R mutation in the DNA-binding zinc finger of YY1 (found in 14/43 insulinomas) changes the DNA motif recognized by YY1, leading to neo-morphic activation of ADCY1 and CACNA2D2, genes involved in cAMP and Ca2+ signaling that regulate insulin secretion.\",\n      \"method\": \"Exome sequencing, ChIP-seq comparing wild-type and T372R YY1, expression of mutant in INS-1 cells, insulin secretion assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq defining altered binding motif combined with functional expression assay demonstrating changed insulin secretion; multiple orthogonal methods\",\n      \"pmids\": [\"25787250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YY1 haploinsufficiency in humans with de novo YY1 mutations/deletions leads to global loss of YY1 chromatin binding with preferential retention at high-occupancy sites, and a widespread loss of H3K27 acetylation particularly at YY1-bound enhancers, defining a clinical syndrome caused by dysregulation of key transcriptional regulators.\",\n      \"method\": \"ChIP with antibodies against both ends of YY1 from patient cells, H3K27ac ChIP-seq, clinical genomics of 23 individuals\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq from patient-derived cells with multiple antibodies demonstrating direct consequence of YY1 loss on enhancer acetylation; strong translational evidence\",\n      \"pmids\": [\"28575647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YY1 directly activates transcription of G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzyme of the pentose phosphate pathway, in a p53-independent manner, thereby promoting nucleotide synthesis, NADPH production, ROS reduction, and tumor cell proliferation.\",\n      \"method\": \"ChIP, luciferase reporter assay with G6PD promoter, siRNA knockdown, metabolic assays (NADPH, nucleotide synthesis), xenograft tumor model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter confirm direct binding/activation; metabolic and in vivo phenotype; single lab\",\n      \"pmids\": [\"29921695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial YY1 deletion in mice causes embryonic lethality and impairs sprouting angiogenesis; mechanistically, YY1 binds the N-terminal domain of RBPJ and competes with MAML1 for RBPJ binding, thereby blocking NICD/MAML1/RBPJ complex formation and repressing Notch-dependent gene expression to control endothelial tip cell fate.\",\n      \"method\": \"EC-specific conditional knockout mice, retinal angiogenesis assay, aortic ring assay, co-immunoprecipitation of YY1-RBPJ, competition assay with MAML1, Notch target gene expression analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined vascular phenotype, Co-IP defining direct YY1-RBPJ interaction, competition with MAML1; multiple orthogonal methods\",\n      \"pmids\": [\"32075915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YY1 co-occupies gene-regulatory elements with bromodomain-containing proteins BRD2/4 in prostate cancer; YY1 directly binds and activates PFKP (phosphofructokinase, platelet type), the rate-limiting enzyme for glycolysis, establishing a YY1:BRD2/4-PFKP oncogenic axis contributing to the Warburg effect.\",\n      \"method\": \"ChIP-seq, interactome profiling (mass spectrometry), gene loss-of-function and rescue, mutagenesis of YY1-bound cis-elements, metabolic assays, xenograft\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq cistrome plus MS interactome plus cis-element mutagenesis plus functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"33849067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YY1 physically interacts with EZH2 through a specific 'oncoprotein binding' (OPB) domain on YY1; disruption of the YY1-EZH2 interaction using synthetic peptides targeting either the OPB domain on YY1 or the YY1-protein binding (YPB) domain on EZH2 alters H3K27me3 at hundreds of genomic loci and inhibits breast cancer cell growth.\",\n      \"method\": \"Domain mapping, synthetic peptide competition assay, ChIP-seq (H3K27me3), cell viability, xenograft tumor model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain mapping plus ChIP-seq readout; functional validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"34065631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHF8 demethylates YY1 (functioning as a co-repressor of nuclear-encoded ETC genes) to drive mitochondrial ROS production; PHF8 acts as a demethylase not on histones but on the transcription factor YY1 itself to repress ETC gene transcription and promote cancer cell growth.\",\n      \"method\": \"PHF8 KO, PHF8 inhibitor (iPHF8), YY1 methylation assay, ETC gene expression profiling, xenograft and PDX models, genetic ablation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct demethylation of YY1 demonstrated, pharmacological and genetic validation in vivo; single lab\",\n      \"pmids\": [\"38165927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CK2α (casein kinase 2α) directly phosphorylates YY1 at serine 118 (S118) in endothelial cells under disturbed/oscillatory flow; phospho-YY1S118 directly binds ZKSCAN4, inducing HDM2 promoter activity and gene expression, which downregulates p53 and p21CIP1 to promote EC proliferation and atherosclerosis.\",\n      \"method\": \"Quantitative phosphoproteomics, in situ proximity ligation assay, yeast two-hybrid for ZKSCAN4 interaction, S118 non-phosphorylatable transgenic mice, luciferase reporter, CK2 inhibitor in ApoE-/- mice\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphoproteomics site identification, kinase-substrate validation, transgenic mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"34747636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD3 is a deubiquitinase for YY1 that stabilizes YY1 protein; PLK1 phosphorylates OTUD3 at S326, enhancing OTUD3 binding to and deubiquitination of YY1, thereby increasing YY1 protein levels and promoting colorectal cancer cell proliferation.\",\n      \"method\": \"DUB screening, co-immunoprecipitation, ubiquitination assay, OTUD3 KD/KO, phosphorylation assay, PLK1 inhibition, clinical CRC tissue analysis\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, phosphorylation demonstrated; single lab but multiple biochemical methods\",\n      \"pmids\": [\"38351178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"YY1 binding sites within differentially methylated regions (DMRs) of Peg3 and Xist are required for de novo DNA methylation of these loci during oogenesis; YY1 knockdown during oogenesis causes loss of DNA methylation on Peg3 and Xist DMRs, while YY1 knockdown during spermatogenesis maintains unmethylation status.\",\n      \"method\": \"Conditional YY1 knockdown during oogenesis and spermatogenesis, bisulfite sequencing of DMRs\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockdown with stage-specific methylation readout; single lab but clean genetic approach\",\n      \"pmids\": [\"19628663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 maintains numerous enhancer-promoter loops in erythroid cells independent of cohesin-mediated loop extrusion; YY1 is partially retained on mitotic chromatin (predominantly at gene promoters) and rapidly rebinds during mitotic exit, coinciding with enhancer-promoter loop re-establishment. Some YY1-dependent loops require YY1 for establishment at G1-phase entry but not for maintenance in interphase, demonstrating cell-cycle stage–dependent architectural function.\",\n      \"method\": \"Acute YY1 degradation (dTAG), Hi-C, ChIP-seq, cell-cycle synchronization, 4C-seq, cohesin depletion comparison\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — acute protein degradation system combined with Hi-C and cell-cycle dynamics; multiple orthogonal methods; rigorous controls\",\n      \"pmids\": [\"39210046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"YY1 physically interacts with M-MITF (Waardenburg Syndrome IIA gene product) in melanocytes and cooperates with M-MITF to regulate expression of pigmentation genes including KIT; genome-wide ChIP-seq identified YY1 targets in the melanocyte lineage, demonstrating how a ubiquitous factor (YY1) gains lineage-specific functions through co-regulation with a lineage-restricted factor (M-MITF).\",\n      \"method\": \"Conditional yy1 KO in melanocyte lineage, co-immunoprecipitation of YY1-MITF, ChIP-seq, reporter assays, coat color phenotype analysis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vivo phenotype, Co-IP, and genome-wide ChIP-seq; multiple orthogonal methods\",\n      \"pmids\": [\"22570637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"YY1 recognizes a longer consensus DNA-binding motif (GCCGCCATTTTG) beyond the previously known core sequence, requiring intact contribution of its first zinc finger unit; a three–amino acid substitution mimicking Drosophila Pho in the first zinc finger weakens DNA-binding specificity and shortens the recognized motif to GCCAT.\",\n      \"method\": \"Gel shift assay (EMSA), systematic DNA motif analysis, zinc finger mutagenesis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with site-directed mutagenesis; single lab\",\n      \"pmids\": [\"18950698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YY1 and YY2 bind competitively to the same DNA-binding site in the SLC7A11 promoter and antagonistically regulate ferroptosis: YY1 activates SLC7A11 to promote glutathione biosynthesis and suppress ferroptosis, while YY2 represses SLC7A11 to induce ferroptosis and suppress tumorigenesis.\",\n      \"method\": \"ChIP, luciferase reporter assay, site-directed mutagenesis of zinc finger domains, siRNA knockdown, ferroptosis assays (lipid peroxidation, cell death), clinical mutation analysis\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — competitive ChIP at shared binding site, mutagenesis, and functional ferroptosis assays; single lab\",\n      \"pmids\": [\"35246964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"3-Hydroxyanthranilic acid (3-HAA), a kynurenine derivative, directly binds YY1 as an agonist ligand, inducing YY1 phosphorylation at Thr398 by PKCζ and enhancing YY1 chromatin binding activity to increase expression of target genes including apoptotic genes in hepatocellular carcinoma.\",\n      \"method\": \"Ligand-binding assay, co-immunoprecipitation, phosphorylation assay, ChIP, cell viability assay\",\n      \"journal\": \"Journal of Hematology & Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited structural validation of ligand binding, mechanism partially characterized\",\n      \"pmids\": [\"34563230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 forms an active complex with HIF-1α at VEGF gene promoters and increases VEGF transcription; CXCR4/SDF-1 inhibition causes YY1 cytoplasmic accumulation by reducing YY1 phosphorylation through AKT downregulation.\",\n      \"method\": \"Co-immunoprecipitation of YY1-HIF-1α, ChIP at VEGF promoter, RT-PCR, ELISA, in vitro angiogenesis assay, phosphorylation analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus ChIP plus functional angiogenesis assay; single lab\",\n      \"pmids\": [\"20660740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 is recruited by direct protein-protein interaction with Neurogenin2 (Ngn2) to neuronal enhancer sites in astrocyte-to-neuron reprogramming; YY1 deletion impairs activation of neuronal enhancers and genes and reduces reprogramming efficiency without affecting Ngn2 chromatin binding, establishing YY1 as a required co-factor for Ngn2-mediated epigenome remodeling.\",\n      \"method\": \"Single-cell multiomics, ChIP-seq, ATAC-seq, co-immunoprecipitation of YY1-Ngn2, Yy1 conditional deletion, direct neuronal reprogramming assay\",\n      \"journal\": \"Nature Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP confirming direct interaction, genetic deletion, genome-wide profiling; multiple orthogonal methods\",\n      \"pmids\": [\"38956165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In M2 macrophages in prostate cancer, YY1 undergoes liquid-liquid phase separation (LLPS) with transcriptional cofactors p300, p65, and CEBPB; the YY1 phase separation complex upregulates IL-6 by promoting IL-6 enhancer-promoter chromatin interactions, facilitating prostate cancer progression.\",\n      \"method\": \"LLPS assay, H3K27ac-ChIP-seq, YY1 ChIP-seq, CRISPR-Cas9 KO, RNA-seq, chromatin interaction assay, transgenic YY1-overexpressing mice\",\n      \"journal\": \"Journal for Immunotherapy of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, LLPS, and functional KO with in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37094986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GON4L interacts with YY1 and promotes YY1's association with the androgen receptor, forming a GON4L-YY1-androgen receptor complex that drives CD24 expression and cancer cell growth.\",\n      \"method\": \"shRNA library screen, co-immunoprecipitation of GON4L-YY1 and YY1-AR, gene silencing with proliferation/tumor growth assays, clinical tissue analysis\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP establishing ternary complex, functional shRNA validation in vivo; single lab\",\n      \"pmids\": [\"27312530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 directly binds to and represses the TGFB1 promoter in human renal mesangial cells; YY1 overexpression attenuates glomerulosclerosis in mouse DN models, and YY1 knockdown aggravates renal lesions, establishing YY1 as a potent transcriptional repressor of TGFβ1 in diabetic nephropathy.\",\n      \"method\": \"Mass spectrometry-based DNA-protein interaction screen, ChIP, luciferase reporter, in vitro and in vivo YY1 manipulation (knockdown and overexpression), mouse DN models\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomics identification confirmed by ChIP and reporter, plus in vivo genetic gain/loss-of-function; multiple orthogonal methods\",\n      \"pmids\": [\"31534017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YY1 is a substrate of CARM1-mediated arginine methylation; CARM1 co-activates YY1-mediated reporter gene activation in vivo and the two proteins regulate each other in a positive feedback loop in oral cancer.\",\n      \"method\": \"In vivo arginine methylation assay, reporter assay with CARM1 co-expression, siRNA knockdown, qRT-PCR, xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — arginine methylation of YY1 demonstrated in vivo but mechanistic resolution limited; single lab, partial follow-up\",\n      \"pmids\": [\"31217904\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YY1 is a multifunctional zinc-finger transcription factor that forms dimers and oligomers to bridge enhancer-promoter DNA loops, recruits Polycomb repressive complexes (via YAF2/RYBP and CtBP), acts as a bivalent RNA-DNA adaptor to tether Xist RNA to the inactive X chromosome, and can either activate or repress target gene transcription depending on its interacting partners (including c-Myc, HDAC1, EZH2, HIF-1α, RBPJ, MITF, and BRD2/4); its activity is regulated by multiple post-translational modifications including tyrosine phosphorylation (by Src/EGFR; Y383 inhibits DNA binding), serine phosphorylation (CK2α at S118 promotes atherosclerosis), S-nitrosation (inhibits DNA binding), sumoylation (by PIASy at K288), lactylation (by p300 at K183 enhancing chromatin binding), demethylation (by PHF8 converting YY1 to a co-repressor of ETC genes), and ubiquitin-proteasome–mediated degradation (by Smurf2 E3 ligase, reversed by OTUD3 deubiquitinase).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YY1 is a multifunctional zinc-finger transcription factor that serves as a structural organizer of enhancer-promoter chromatin loops and a context-dependent transcriptional activator or repressor. YY1 dimerizes and oligomerizes to bridge enhancers and promoters in a cohesin-independent manner, with some loops requiring YY1 specifically at mitotic exit for re-establishment [PMID:29224777, PMID:39210046]; it also functions as a bivalent RNA-DNA adaptor that tethers Xist RNA to the inactive X chromosome to initiate X-chromosome inactivation [PMID:21729784]. Its transcriptional output is determined by lineage-specific partners—recruiting HDAC1 to repress differentiation inhibitors in oligodendrocyte progenitors [PMID:17640524], cooperating with MITF in melanocytes [PMID:22570637], competing with the Notch co-activator MAML1 for RBPJ binding in endothelial cells [PMID:32075915], and recruiting PRC1 via YAF2/RYBP and PRC2 via EZH2 for Polycomb-mediated silencing [PMID:24285299, PMID:34065631]—while its activity is extensively regulated by post-translational modifications including Src-mediated Y383 phosphorylation that inhibits DNA/RNA binding [PMID:26198631], CK2α-mediated S118 phosphorylation that promotes atherosclerosis [PMID:34747636], p300-mediated K183 lactylation that enhances chromatin binding [PMID:37085894], and Smurf2/OTUD3-controlled ubiquitin-proteasome turnover [PMID:24803334, PMID:38351178]. De novo heterozygous YY1 mutations cause a neurodevelopmental syndrome characterized by global loss of YY1 chromatin occupancy and H3K27 acetylation at enhancers [PMID:28575647].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"The discovery that YY1 physically associates with c-Myc—which inhibits both YY1's activator and repressor functions—established that YY1 is not an autonomous switch but a partner-dependent transcription factor whose output is modulated by oncoproteins.\",\n      \"evidence\": \"Yeast two-hybrid, affinity chromatography, and cotransfection reporter assays in mammalian cells\",\n      \"pmids\": [\"8266081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of c-Myc–YY1 interaction unknown\", \"Which YY1 target genes are regulated by c-Myc modulation not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of YY1 as a nuclear matrix protein (NMP-1) associated with residual nucleoli, and the finding that immunophilins CyPA and FKBP12 interact with YY1 and modulate its transcriptional activity, revealed that YY1 functions within a defined subnuclear scaffold and is subject to regulation by peptidyl-prolyl isomerases.\",\n      \"evidence\": \"Nuclear matrix fractionation, gel-shift, in situ immunofluorescence (NMP-1); yeast two-hybrid, mammalian Co-IP, pharmacological disruption with CsA/FK506 (immunophilins)\",\n      \"pmids\": [\"7479833\", \"7541038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of immunophilin–YY1 interaction in vivo not established\", \"Whether CyPA/FKBP12 catalytically isomerize YY1 not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic epistasis in Drosophila demonstrated that CtBP is required for YY1 (Pho) DNA binding in vivo and for subsequent Polycomb group protein recruitment and histone modification, establishing the first essential cofactor for YY1-mediated Polycomb silencing.\",\n      \"evidence\": \"Drosophila CtBP mutant analysis, ChIP for PcG occupancy and histone marks\",\n      \"pmids\": [\"15520279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CtBP unmasks YY1 DNA binding not resolved\", \"Whether CtBP dependence is conserved in mammalian PcG targeting not shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Conditional YY1 knockout in the oligodendrocyte lineage revealed that YY1 recruits HDAC1 to repress differentiation inhibitors Tcf4 and Id4, establishing YY1 as a lineage-specific differentiation regulator, while identification of K288 sumoylation by PIASy showed that SUMO modification stabilizes YY1 and modulates its transcriptional output in a promoter-dependent manner.\",\n      \"evidence\": \"Conditional KO with myelination phenotype, ChIP/Co-IP for HDAC1 (oligodendrocytes); in vitro sumoylation, K288R mutagenesis, reporter assays (sumoylation)\",\n      \"pmids\": [\"17640524\", \"17353273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sumoylation alters YY1-HDAC1 interaction not tested\", \"Full repertoire of YY1 target genes in OPC differentiation not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Systematic motif and zinc-finger mutagenesis extended YY1's DNA recognition to a longer consensus (GCCGCCATTTTG) requiring the first zinc finger, refining the understanding of how YY1 selects genomic targets.\",\n      \"evidence\": \"EMSA with systematic DNA motif variants and zinc-finger substitution mutants\",\n      \"pmids\": [\"18950698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of the extended motif's functional significance not provided\", \"Contribution of flanking sequence context to binding affinity not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two studies revealed YY1's role in epigenetic memory: YY1 binding sites in DMRs of Peg3 and Xist are required for de novo DNA methylation during oogenesis, and YY1 autoregulates its own transcription through intronic binding sites, demonstrating both trans-regulatory imprinting control and a self-buffering feedback loop.\",\n      \"evidence\": \"Conditional YY1 KD during oogenesis/spermatogenesis with bisulfite sequencing; inducible overexpression with reporter mutagenesis\",\n      \"pmids\": [\"19628663\", \"19712462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YY1 recruits specific DNMTs to DMRs not identified\", \"Autoregulation kinetics and quantitative buffering capacity not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that YY1 simultaneously binds Xist RNA (via Repeat C) and DNA (via an epigenetically regulated trio of sites) to dock Xist onto the X chromosome nucleation center established YY1 as a bivalent RNA-DNA adaptor critical for X-chromosome inactivation.\",\n      \"evidence\": \"RNA immunoprecipitation, ChIP, mutational dissection of RNA- and DNA-binding motifs, allele-specific assays\",\n      \"pmids\": [\"21729784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of simultaneous RNA and DNA binding not resolved\", \"Whether YY1 bridges other lncRNAs to chromatin genome-wide not explored\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Conditional YY1 knockout in melanocytes combined with Co-IP and ChIP-seq showed that YY1 physically interacts with the lineage-restricted factor MITF to co-regulate pigmentation genes, explaining how a ubiquitous factor achieves lineage-specific transcriptional output.\",\n      \"evidence\": \"Melanocyte-specific Yy1 KO, Co-IP of YY1-MITF, ChIP-seq, coat color phenotype\",\n      \"pmids\": [\"22570637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YY1-MITF form a stable complex or transient interaction not determined\", \"Genome-wide partitioning of MITF-dependent versus -independent YY1 targets not complete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies clarified YY1's role in Polycomb recruitment and retroviral silencing: YAF2 bridges YY1 to PRC1 in a YY1 DNA-binding-dependent manner, and YY1 binds ERV LTRs in embryonic cells through interaction with Trim28 to recruit repressive histone marks, defining distinct PRC1 and Trim28/KRAB pathways for YY1-mediated silencing.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, siRNA, Drosophila rescue (YAF2-PRC1); LTR binding-site deletion, YY1 depletion, Trim28 Co-IP (ERV silencing)\",\n      \"pmids\": [\"24285299\", \"23810560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YAF2 and Trim28 pathways operate on overlapping or distinct target sets not resolved\", \"Structural basis of YAF2-YY1 and Trim28-YY1 interfaces only partially mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"YY1 was shown to activate Xist transcription by competing with the repressor REX1 for binding at the Xist promoter, while structural studies revealed YY1 forms bell-shaped dimers that oligomerize and interact with RuvBL1/2 ATPases to participate in homologous recombination, expanding YY1's functions beyond transcription to DNA repair.\",\n      \"evidence\": \"ChIP, reporter, bisulfite sequencing (Xist activation); electron microscopy, BiFC, EMSA, RAD51 foci assay (oligomers/HR)\",\n      \"pmids\": [\"25209548\", \"24990942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether oligomerization is required for enhancer-promoter looping not tested\", \"Mechanism of YY1/RuvBL1-2 cooperation in RAD51 loading not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple regulatory mechanisms were defined: Src/EGFR-mediated Y383 phosphorylation inhibits YY1 DNA/RNA binding, Smurf2-mediated ubiquitination targets YY1 for proteasomal degradation, S-nitrosation of zinc-finger cysteines blocks DNA binding, a somatic T372R zinc-finger mutation in insulinomas creates a neomorphic binding specificity activating cAMP/Ca²⁺ signaling genes, and Linc-YY1 evicts YY1/PRC2 from target promoters to promote myogenic differentiation.\",\n      \"evidence\": \"In vitro kinase assay with Y383 mutagenesis (Src); ubiquitination/CHX chase (Smurf2); S-nitrosation detection and EMSA (NO); exome sequencing with ChIP-seq of WT vs T372R (insulinoma); RIP and ChIP with in vivo muscle regeneration (Linc-YY1)\",\n      \"pmids\": [\"26198631\", \"24803334\", \"16143308\", \"25787250\", \"26658965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase(s) reversing Y383 phosphorylation unknown\", \"Whether Smurf2 ubiquitinates YY1 at specific lysines not mapped\", \"Linc-YY1 mechanism of PRC2 eviction not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ChIP-seq, Hi-C, and acute protein depletion established YY1 as a general structural regulator of enhancer-promoter loops analogous to CTCF, while patient-derived cells with YY1 haploinsufficiency showed global loss of YY1 chromatin binding and H3K27ac at enhancers, linking YY1 architectural function to a neurodevelopmental syndrome.\",\n      \"evidence\": \"dTAG depletion, CRISPR deletion of binding sites, 4C-seq, Hi-C (looping); ChIP-seq from cells of 23 patients with de novo YY1 mutations (disease)\",\n      \"pmids\": [\"29224777\", \"28575647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YY1-mediated loops require specific cofactors or are solely dimer-driven not resolved\", \"Genotype-phenotype correlations across different YY1 mutations not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Context-specific transcriptional programs were delineated: YY1 represses TGFB1 in renal mesangial cells to protect against diabetic nephropathy, forms an active complex with HIF-1α at VEGF promoters for angiogenesis, and undergoes liquid-liquid phase separation with p300/p65/CEBPB to activate IL-6 enhancer-promoter interactions in M2 macrophages.\",\n      \"evidence\": \"MS-based DNA-protein screen, ChIP, mouse DN models (TGFB1); Co-IP of YY1-HIF-1α, ChIP at VEGF (angiogenesis); LLPS assay, ChIP-seq, CRISPR KO (phase separation)\",\n      \"pmids\": [\"31534017\", \"20660740\", \"37094986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phase separation is required for all YY1-dependent enhancer-promoter contacts unknown\", \"Structural determinants of YY1 LLPS not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies converged on YY1's metabolic and signaling roles: YY1 cooperates with BRD2/4 to activate glycolytic PFKP, YY1's interaction with EZH2 through the OPB domain controls H3K27me3 deposition, PHF8 demethylates YY1 itself to convert it into a co-repressor of ETC genes, CK2α phosphorylates YY1 at S118 to drive endothelial proliferation and atherosclerosis, and YY1 activates SLC7A11 to suppress ferroptosis.\",\n      \"evidence\": \"ChIP-seq/MS interactome with cis-element mutagenesis (BRD2/4-PFKP); peptide competition, ChIP-seq for H3K27me3 (EZH2); PHF8 KO/inhibitor with YY1 methylation assay (PHF8); phosphoproteomics, S118A transgenic mice (CK2α); competitive ChIP and ferroptosis assays (SLC7A11)\",\n      \"pmids\": [\"33849067\", \"34065631\", \"38165927\", \"34747636\", \"35246964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific methylation site(s) on YY1 targeted by PHF8 not identified\", \"Whether BRD2/4-YY1 co-occupancy is a general phenomenon across cancer types unclear\", \"Direct structural data for YY1-EZH2 OPB/YPB interface lacking\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of p300-mediated lactylation at YY1 K183 that enhances chromatin binding and FGF2 transcription established lactylation as a metabolically responsive PTM tuning YY1 activity, later extended to microglial inflammatory gene regulation in autoimmune uveitis.\",\n      \"evidence\": \"Mass spectrometry, K183R mutagenesis, ChIP, p300 inhibition in vitro/in vivo (FGF2); CUT&Tag, p300 inhibitor in uveitis model (microglia)\",\n      \"pmids\": [\"37085894\", \"38493498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Delactylase(s) that reverse K183 lactylation not identified\", \"Genome-wide scope of lactylation-dependent versus -independent YY1 targets not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Advanced chromatin conformation and acute degradation studies showed that YY1 maintains enhancer-promoter loops independently of cohesin and is partially bookmarked on mitotic chromatin, re-establishing loops at G1 entry; separately, YY1 was identified as a required cofactor for Ngn2-mediated neuronal enhancer activation during astrocyte-to-neuron reprogramming, and OTUD3 was characterized as a PLK1-regulated deubiquitinase stabilizing YY1.\",\n      \"evidence\": \"dTAG degradation, Hi-C, cell-cycle synchronization, cohesin depletion (looping); single-cell multiomics, Yy1 cKO, Co-IP of YY1-Ngn2 (reprogramming); DUB screen, ubiquitination assay, PLK1 phosphorylation of OTUD3 (stability)\",\n      \"pmids\": [\"39210046\", \"38956165\", \"38351178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants distinguishing YY1-bookmarked from non-bookmarked sites unknown\", \"Whether Ngn2-YY1 cooperation is unique to reprogramming or also operates in developmental neurogenesis not addressed\", \"Full ubiquitin site map on YY1 not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis of YY1 simultaneous RNA and DNA binding, (2) how YY1 phase separation, oligomerization, and dimerization relate to each other and to enhancer-promoter loop formation in vivo, (3) the full combinatorial code of post-translational modifications that switch YY1 between activator and repressor states, and (4) whether YY1's cohesin-independent architectural function operates genome-wide or at a specialized subset of loci.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of YY1 bound simultaneously to RNA and DNA\", \"Quantitative in vivo PTM crosstalk map absent\", \"Genome-wide assignment of cohesin-dependent versus YY1-dependent loops incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 4, 10, 11, 12, 20, 32]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 14, 16, 22, 23, 24, 33, 39]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 12, 35]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 21, 30]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 14, 16, 22, 23, 24, 33, 39]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 6, 21, 25, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 4, 31, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [23, 27, 35]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"PRC1 (via YAF2/RYBP)\",\n      \"PRC2 (via EZH2)\",\n      \"Trim28-YY1 silencing complex\"\n    ],\n    \"partners\": [\n      \"EZH2\",\n      \"HDAC1\",\n      \"YAF2\",\n      \"TRIM28\",\n      \"RBPJ\",\n      \"MITF\",\n      \"BRD2\",\n      \"BRD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}