{"gene":"ZBTB38","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"ZBTB38 (CIBZ) physically associates with the transcriptional corepressor CtBP via a conserved PLDLR motif. CIBZ represses transcription through two independent repression domains: an N-terminal BTB domain (HDAC-independent) and a PLDLR-containing RD2 region (HDAC-dependent). CIBZ redistributes CtBP from diffuse nuclear localization to pericentromeric foci; mutation of the PLDLR motif abolishes CtBP interaction, RD2 repression activity, and pericentromeric targeting of CtBP, but not CIBZ's own localization to pericentromeric foci.","method":"Co-immunoprecipitation, site-directed mutagenesis of PLDLR motif, heterologous DNA-targeting transcriptional repression assay, immunofluorescence localization","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal interaction confirmed by Co-IP, mutagenesis of binding motif with functional readout, multiple orthogonal methods in single study","pmids":["16115196"],"is_preprint":false},{"year":2008,"finding":"ZBTB38 (CIBZ) is a direct substrate of caspase-3: in vitro caspase cleavage assays with mutagenesis identified two caspase-3 recognition sites in CIBZ. Knockdown of CIBZ induces apoptosis through the mitochondrial pathway (activating caspases-3, -7, and -9 and PARP cleavage) in a p53-independent manner.","method":"In vitro caspase-3 cleavage assay, site-directed mutagenesis of caspase recognition sites, siRNA knockdown, annexin V/PI flow cytometry, caspase activation assays in p53-/- cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay plus mutagenesis of recognition sites, combined with functional knockdown phenotype using multiple orthogonal readouts","pmids":["18375381"],"is_preprint":false},{"year":2011,"finding":"ZBTB38 (CIBZ) binds to a methylated CpG-containing proximal region of the Myogenin (Myog) promoter and represses Myog transcription in a DNA methylation-dependent manner, thereby suppressing myogenic differentiation. Loss of CIBZ promotes myogenic differentiation; ectopic CIBZ expression impairs it. Importantly, CIBZ-mediated repression does not require demethylation of the Myog promoter CpGs.","method":"siRNA knockdown and ectopic overexpression in C2C12 cells, chromatin immunoprecipitation (ChIP), luciferase reporter assay, myogenic differentiation assays in vitro and in vivo","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, combined with loss- and gain-of-function experiments showing concordant phenotype","pmids":["21625269"],"is_preprint":false},{"year":2012,"finding":"ZBTB38 (CIBZ) promotes ESC proliferation and G1/S transition at least in part by post-transcriptionally maintaining Nanog protein levels. CIBZ deletion or siRNA knockdown inhibits ESC proliferation and delays G1/S transition; ectopic CIBZ expression accelerates it. Constitutive overexpression of Nanog partially rescues the proliferation defect caused by CIBZ knockdown.","method":"siRNA knockdown, CIBZ deletion, ectopic overexpression in ESCs, cell cycle analysis, Nanog rescue experiment, western blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via Nanog rescue, loss- and gain-of-function, single lab but multiple orthogonal approaches","pmids":["22315219"],"is_preprint":false},{"year":2014,"finding":"RBBP6 (an E3 ubiquitin ligase) ubiquitinates ZBTB38, destabilizing it. ZBTB38 in turn negatively regulates transcription and chromatin-associated levels of the MCM10 replication factor. Cells lacking RBBP6 accumulate ZBTB38, which causes MCM10 downregulation, reduced replication fork progression, and increased DNA damage at common fragile sites.","method":"Ubiquitination assays, siRNA knockdown of RBBP6 and ZBTB38, ChIP, DNA fiber assay for replication fork speed, FISH for common fragile site stability","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ubiquitination assay establishing enzymatic relationship, combined with functional epistasis and multiple orthogonal cellular readouts","pmids":["24726359"],"is_preprint":false},{"year":2016,"finding":"ZBTB38 (CIBZ) binds directly to the promoters of Brachyury (T) and Mesp1 in undifferentiated ESCs, repressing their transcription and thereby suppressing mesodermal and cardiac differentiation. Loss of CIBZ induces mesoderm specification and cardiomyocyte differentiation; overexpression delays these processes.","method":"ChIP assay, luciferase reporter assay, CIBZ knockout and overexpression in ESCs, differentiation assays toward cardiomyocytes","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP, luciferase assay for transcriptional repression, concordant loss- and gain-of-function phenotypes","pmids":["27659197"],"is_preprint":false},{"year":2017,"finding":"ZBTB38's C-terminal zinc fingers (ZFs 6–9) exhibit high-affinity, methyl-CpG-selective DNA binding to a consensus sequence distinct from the N-terminal ZF consensus. These C-terminal ZFs can directly occupy promoters containing this motif in cells in a DNA methylation-dependent manner and modulate transcriptional responses at those loci.","method":"Fluorescence polarization DNA binding assays, small-angle X-ray scattering (SAXS) structural modeling, ChIP in cell lines, gene expression analysis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assays plus ChIP in cells, hybrid structural modeling; single lab","pmids":["29287967"],"is_preprint":false},{"year":2017,"finding":"ATF4 (an ER-stress-inducible transcription factor) directly activates ZBTB38 transcription by binding to the ZBTB38 promoter under normal conditions; this binding is significantly reduced following spinal cord injury, causing decreased ZBTB38 expression and increased ER stress-associated apoptosis.","method":"ChIP-qPCR, lentiviral overexpression of ZBTB38 in SCI mouse model, apoptosis assays, motor function assessment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly demonstrating ATF4 binding to ZBTB38 promoter, supported by in vivo rescue experiment","pmids":["28514761"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of ZBTB38 C-terminal zinc fingers 6–9 in complex with a methylated consensus DNA sequence (1.75 Å resolution) reveals that methyl-selective binding is mediated by base-specific interactions from residues in the α-helices of ZF7 and ZF8 at the 5' mCpG site, while ZF6 and ZF9 serve structural stabilization roles. This represents a mode of mCpG recognition distinct from other ZF methyl-CpG binding proteins.","method":"X-ray crystallography (1.75 Å), solution NMR spectroscopy, electrophoretic mobility shift assay (EMSA)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with NMR and EMSA validating methylated DNA recognition mechanism","pmids":["30355731"],"is_preprint":false},{"year":2018,"finding":"The deubiquitinase USP9X interacts with ZBTB38, deubiquitinates it, and stabilizes it. USP9X is itself stabilized by oxidative stress. The USP9X/ZBTB38 axis limits basal ROS production and is required for the cellular response to acute oxidative stress; loss of either protein increases ROS toxicity.","method":"Co-immunoprecipitation, ubiquitination assay, mass spectrometry identification of USP9X as ZBTB38 interactor, siRNA knockdown of USP9X and ZBTB38, ROS measurement assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — deubiquitination assay plus reciprocal Co-IP and MS identification of interactor, functional validation with concordant knockdowns","pmids":["29490077"],"is_preprint":false},{"year":2018,"finding":"ZBTB38 binds methylated promoters of IL1r2 (interleukin-1 receptor 2) in B cells and represses IL1r2 transcription, forming a molecular bridge between an arthritis-associated DNA hypomethylation epimutation at the Zbtb38 locus and silencing of an anti-inflammatory gene.","method":"ChIP, gene expression studies, correlation of Zbtb38 promoter methylation with IL1r2 expression in a murine RA model","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP supporting direct binding, but single lab with limited mechanistic follow-up","pmids":["30343694"],"is_preprint":false},{"year":2018,"finding":"ZBTB38 regulates the cellular response to DNA methyltransferase inhibitors (DNMTi; 5-azacytidine, decitabine, zebularine): DNMTi treatment causes ZBTB38 protein downregulation. ZBTB38 depletion enhances DNMTi toxicity, and this effect is mediated at least in part through upregulation of CDKN1C mRNA.","method":"siRNA knockdown of ZBTB38, western blotting, cell viability assays, RT-PCR for CDKN1C in multiple cancer cell lines","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis between ZBTB38 and CDKN1C confirmed by knockdown in multiple cell lines, single lab","pmids":["30310057"],"is_preprint":false},{"year":2021,"finding":"ZBTB38 binds the DKK1 (Dickkopf WNT signaling pathway inhibitor 1) locus and promotes DKK1 expression in prostate cancer cells. Reduction of DKK1 rescues ZBTB38-mediated suppression of migration and proliferation. PRKDC (DNA-PKcs) was identified as a ZBTB38-interacting protein that represses ZBTB38 function.","method":"ChIP demonstrating ZBTB38 binding to DKK1 promoter, DKK1 knockdown rescue experiments, Co-IP identifying PRKDC as interactor, cell migration and proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct target binding plus epistasis via DKK1 rescue and Co-IP identification of interactor, single lab","pmids":["34697293"],"is_preprint":false},{"year":2022,"finding":"ZBTB38 binds methylated CpG-containing sequences in vivo at two classes of consensus sites (corresponding to its N-terminal and C-terminal ZF domains). Approximately 10% of ZBTB38 binding sites overlap with CTCF binding, while 90% reside in closed chromatin not occupied by other mapped factors; ~one-third of ZBTB38 sites are found upstream of long active CpG islands.","method":"ChIP-seq in human cell line, intersection with ENCODE datasets for chromatin state and other TF binding","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with in vivo validation of in vitro-defined consensus sequences; single lab","pmids":["36000449"],"is_preprint":false},{"year":2022,"finding":"Heterozygous loss of Zbtb38 in mice leads to early embryonic lethality shortly after implantation due to reduced epiblast proliferation and increased apoptosis. This is associated with reduced expression of Nanog and Sox2. Zbtb38 is dispensable for ESC establishment and identity in vitro.","method":"Conditional knockout via Cre-loxP, immunofluorescence for proliferation and apoptosis markers, qRT-PCR and western blotting for Nanog/Sox2, ESC derivation from knockout embryos","journal":"Cell proliferation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout in vivo with defined embryonic phenotype and molecular mechanism (Nanog/Sox2 reduction), multiple readouts","pmids":["35297517"],"is_preprint":false},{"year":2024,"finding":"ZBTB38 regulates autophagy initiation: ZBTB38 knockdown blocks autophagy (decreased LC3B II/I ratio, increased p62). RB1CC1/FIP200, a key component of the autophagy initiation complex, is transcriptionally regulated by ZBTB38 and decreases ~4.2-fold upon ZBTB38 knockdown. Overexpression of RB1CC1 in ZBTB38-knockdown cells rescues the autophagy block and restores cell proliferation.","method":"ZBTB38 siRNA knockdown, LC3B/p62 western blotting, transcriptome sequencing, RB1CC1 rescue overexpression, lentiviral ZBTB38 overexpression in SCI mouse model","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics identifying target plus epistasis rescue experiment, single lab","pmids":["30075197"],"is_preprint":false},{"year":2026,"finding":"Zbtb38 transcriptionally activates XIAP by binding E-box motifs within the upstream regulatory regions of the XIAP gene. XIAP overexpression rescues apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated anti-apoptotic function is at least partially XIAP-dependent. This operates independently of p53 status.","method":"Loss- and gain-of-function experiments (siRNA knockdown and overexpression), ChIP for ZBTB38 binding to XIAP regulatory regions, XIAP rescue overexpression, apoptosis assays in ESC differentiation and cancer cell lines","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding combined with epistasis rescue experiment; single lab, single study","pmids":["41842907"],"is_preprint":false},{"year":2026,"finding":"The N-terminal zinc finger (ZF) domain of ZBTB38 defines a distinct mCpG-containing consensus DNA sequence for binding. Unlike the other two ZBTB MBP family members (ZBTB33/Kaiso and ZBTB4), the shared core ZF domain of ZBTB38 discriminates against TpG-containing DNA (i.e., requires the methyl group), and at least one additional N-terminal ZF is required to stabilize DNA engagement. Each ZF domain preferentially recognizes its own cognate methylated consensus motif.","method":"Fluorescence polarization DNA binding assays, systematic mutagenesis of ZF domains, in vitro binding with mCpG vs. TpG-containing oligonucleotides","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro binding assays with domain mutagenesis but preprint, single lab, not yet peer-reviewed","pmids":["42146383"],"is_preprint":true}],"current_model":"ZBTB38 is a methyl-CpG-binding transcriptional repressor that uses two independent sets of zinc finger domains to recognize distinct methylated CpG consensus sequences; it recruits the CtBP/HDAC complex via a PLDLR motif to repress target genes, directly regulates key developmental transcription factors (Myog, T/Brachyury, Mesp1, Nanog, Sox2, XIAP, DKK1) by binding their methylated promoters, and is itself controlled post-translationally by RBBP6-mediated ubiquitination/degradation and USP9X-mediated deubiquitination/stabilization, placing it at the intersection of DNA methylation readout, DNA replication fidelity (via MCM10 regulation), oxidative stress response, and apoptosis control (via caspase-3 cleavage and XIAP transcriptional activation)."},"narrative":{"mechanistic_narrative":"ZBTB38 (CIBZ) is a methyl-CpG-binding transcriptional regulator that reads DNA methylation through two independent sets of zinc fingers and controls developmental gene expression, cell proliferation, and apoptosis [PMID:21625269, PMID:30355731, PMID:35297517]. Its N-terminal and C-terminal zinc-finger arrays each recognize a distinct methylated CpG consensus, with the C-terminal fingers (ZF6–9) binding methylated DNA at high affinity via base-specific contacts from ZF7 and ZF8 while ZF6 and ZF9 provide structural stabilization, a methyl-CpG recognition mode distinct from other zinc-finger methyl readers [PMID:29287967, PMID:30355731]. Genome-wide, ZBTB38 occupies methylated sites in largely closed chromatin and upstream of active CpG islands [PMID:36000449]. It functions principally as a methylation-dependent repressor, associating with the CtBP corepressor through a PLDLR motif and acting through both HDAC-dependent and HDAC-independent repression domains [PMID:16115196], and represses methylated promoters of myogenic and mesendodermal regulators including Myogenin, Brachyury (T), and Mesp1 to restrain differentiation [PMID:21625269, PMID:27659197]. ZBTB38 supports proliferation and pluripotency by sustaining Nanog and Sox2, and its heterozygous loss in mice causes peri-implantation lethality from reduced epiblast proliferation and increased apoptosis [PMID:22315219, PMID:35297517]. The protein is a node controlling apoptosis and stress responses: it is a direct caspase-3 substrate whose depletion triggers mitochondrial p53-independent apoptosis [PMID:18375381], it transcriptionally activates the anti-apoptotic factor XIAP via E-box binding [PMID:41842907], and its abundance is governed post-translationally by RBBP6-mediated ubiquitination/destabilization and USP9X-mediated deubiquitination/stabilization, the latter linking it to oxidative-stress control [PMID:24726359, PMID:29490077]. Through these axes ZBTB38 also influences DNA replication by limiting MCM10 [PMID:24726359], autophagy initiation via RB1CC1/FIP200 [PMID:30075197], and responses to DNA methyltransferase inhibitors [PMID:30310057].","teleology":[{"year":2005,"claim":"Established how ZBTB38 represses transcription by defining its corepressor partner and the motif required for that interaction, framing it as a recruiter of CtBP-based repression machinery.","evidence":"Co-IP, PLDLR motif mutagenesis, heterologous DNA-targeting repression assay and immunofluorescence","pmids":["16115196"],"confidence":"High","gaps":["Did not link CtBP recruitment to specific endogenous target genes","HDAC-independent BTB repression mechanism not resolved at the molecular level"]},{"year":2008,"claim":"Showed ZBTB38 is a direct caspase-3 substrate and that its loss triggers mitochondrial apoptosis, placing it as a pro-survival factor cleaved during cell death.","evidence":"In vitro caspase-3 cleavage with cleavage-site mutagenesis, siRNA knockdown, apoptosis and caspase assays in p53-/- cells","pmids":["18375381"],"confidence":"High","gaps":["Transcriptional targets mediating the anti-apoptotic effect not identified at this stage","Functional consequence of caspase cleavage products unknown"]},{"year":2011,"claim":"Demonstrated methylation-dependent target repression in a developmental context, showing ZBTB38 binds the methylated Myog promoter to restrain myogenic differentiation without demethylation.","evidence":"ChIP, luciferase reporter, loss/gain-of-function and differentiation assays in C2C12 cells","pmids":["21625269"],"confidence":"High","gaps":["Did not define the consensus motif recognized at the Myog promoter","Corepressor requirement at this locus not tested"]},{"year":2012,"claim":"Connected ZBTB38 to proliferation control in pluripotent cells via post-transcriptional maintenance of Nanog, advancing it from a repressor to a regulator of stem-cell cycle progression.","evidence":"siRNA knockdown, deletion, overexpression, cell-cycle analysis and Nanog rescue in ESCs","pmids":["22315219"],"confidence":"Medium","gaps":["Mechanism by which ZBTB38 maintains Nanog protein not defined","Only partial rescue, implying additional effectors"]},{"year":2014,"claim":"Identified post-translational control of ZBTB38 abundance and a downstream replication target, linking RBBP6-driven degradation to MCM10 levels and fork stability.","evidence":"Ubiquitination assays, RBBP6/ZBTB38 knockdown, ChIP, DNA fiber and common fragile site FISH","pmids":["24726359"],"confidence":"High","gaps":["Whether MCM10 regulation is direct or methylation-dependent not fully resolved","Cell-type generality of the RBBP6 axis untested"]},{"year":2016,"claim":"Extended ZBTB38's developmental repression to germ-layer specification, showing it directly silences Brachyury and Mesp1 to suppress mesoderm and cardiomyocyte differentiation.","evidence":"ChIP, luciferase, ESC knockout/overexpression and cardiomyocyte differentiation assays","pmids":["27659197"],"confidence":"High","gaps":["Methylation status of these promoters during differentiation not detailed","Corepressor dependence not addressed"]},{"year":2017,"claim":"Defined the biochemical basis of ZBTB38's C-terminal zinc-finger methyl-CpG selectivity and showed these fingers occupy cognate promoters in a methylation-dependent manner.","evidence":"Fluorescence polarization binding, SAXS modeling, ChIP and expression analysis","pmids":["29287967"],"confidence":"Medium","gaps":["Atomic basis of recognition not yet resolved","Relative in vivo contribution of N- vs C-terminal fingers unquantified"]},{"year":2017,"claim":"Placed ZBTB38 downstream of ER-stress signaling by showing ATF4 directly activates its transcription, with reduced binding after spinal cord injury exacerbating apoptosis.","evidence":"ChIP-qPCR and lentiviral ZBTB38 rescue in an SCI mouse model with apoptosis and motor readouts","pmids":["28514761"],"confidence":"Medium","gaps":["Direct ZBTB38 targets mediating the SCI phenotype not defined","Generality beyond the injury model untested"]},{"year":2018,"claim":"Provided atomic-resolution insight into methyl-CpG readout, defining how ZF7/ZF8 make base-specific contacts at the methylated CpG while ZF6/ZF9 stabilize binding.","evidence":"1.75 A crystal structure with bound methylated DNA, NMR and EMSA","pmids":["30355731"],"confidence":"High","gaps":["Structure of the N-terminal ZF array bound to its consensus not solved","Allosteric coordination between the two ZF arrays unknown"]},{"year":2018,"claim":"Revealed stabilizing post-translational control opposing RBBP6, with USP9X deubiquitinating ZBTB38 and the axis buffering oxidative stress.","evidence":"Co-IP, MS interactor identification, deubiquitination and ubiquitination assays, ROS measurements with knockdowns","pmids":["29490077"],"confidence":"High","gaps":["Transcriptional targets linking ZBTB38 to ROS control not identified","Crosstalk timing between RBBP6 and USP9X not resolved"]},{"year":2018,"claim":"Linked ZBTB38 to inflammation by showing it represses the methylated IL1r2 promoter, bridging an arthritis-associated epimutation to anti-inflammatory gene silencing.","evidence":"ChIP and expression/methylation correlation in a murine RA model","pmids":["30343694"],"confidence":"Medium","gaps":["Single-lab study with limited mechanistic follow-up","Causality between the epimutation and phenotype not established in vivo"]},{"year":2018,"claim":"Connected ZBTB38 to DNA methyltransferase inhibitor sensitivity, showing its depletion enhances DNMTi toxicity partly via CDKN1C upregulation.","evidence":"siRNA knockdown, viability assays and CDKN1C RT-PCR across multiple cancer lines","pmids":["30310057"],"confidence":"Medium","gaps":["Whether CDKN1C is a direct ZBTB38 target not established","Mechanism of DNMTi-induced ZBTB38 downregulation unknown"]},{"year":2021,"claim":"Showed ZBTB38 can act as a positive regulator, promoting DKK1 expression to suppress prostate cancer cell migration, and identified PRKDC as an interactor repressing its function.","evidence":"ChIP, DKK1 rescue, Co-IP for PRKDC, migration/proliferation assays","pmids":["34697293"],"confidence":"Medium","gaps":["Mechanism of activation versus repression at different loci unresolved","How PRKDC represses ZBTB38 function not defined"]},{"year":2022,"claim":"Mapped ZBTB38 genome-wide, validating both ZF consensus motifs in vivo and showing predominant binding in closed chromatin with partial CTCF overlap.","evidence":"ChIP-seq in a human cell line with ENCODE chromatin/TF intersection","pmids":["36000449"],"confidence":"Medium","gaps":["Functional consequence of binding in closed chromatin unclear","Single cell-line dataset"]},{"year":2022,"claim":"Established ZBTB38's essential developmental role in vivo, with heterozygous loss causing peri-implantation lethality through reduced epiblast proliferation and Nanog/Sox2 loss.","evidence":"Cre-loxP knockout, proliferation/apoptosis IF, Nanog/Sox2 qRT-PCR/WB, ESC derivation","pmids":["35297517"],"confidence":"High","gaps":["Direct versus indirect regulation of Nanog/Sox2 in embryo not resolved","Reason for haploinsufficiency not explained"]},{"year":2024,"claim":"Linked ZBTB38 to autophagy initiation by identifying RB1CC1/FIP200 as a transcriptional target whose restoration rescues the autophagy block and proliferation upon ZBTB38 loss.","evidence":"siRNA knockdown, LC3B/p62 WB, transcriptome sequencing and RB1CC1 rescue","pmids":["30075197"],"confidence":"Medium","gaps":["Directness of RB1CC1 promoter regulation not shown by ChIP","Whether autophagy effect is methylation-dependent unknown"]},{"year":2026,"claim":"Defined the anti-apoptotic transcriptional effector of ZBTB38, showing it activates XIAP via E-box binding to rescue apoptosis from its loss, independent of p53.","evidence":"Knockdown/overexpression, ChIP at XIAP regulatory regions, XIAP rescue and apoptosis assays in ESC and cancer cells","pmids":["41842907"],"confidence":"Medium","gaps":["Relationship between E-box (XIAP) activation and methyl-CpG repression modes unresolved","Single study"]},{"year":2026,"claim":"Characterized the N-terminal ZF domain's methyl-discriminating recognition, showing it requires the methyl group and an additional finger for stable engagement, distinguishing ZBTB38 from ZBTB33 and ZBTB4.","evidence":"Fluorescence polarization binding and systematic ZF mutagenesis with mCpG versus TpG oligonucleotides (preprint)","pmids":["42146383"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structure of N-terminal ZF-DNA complex not determined","In vivo significance of the two distinct consensus motifs not functionally separated"]},{"year":null,"claim":"How ZBTB38 switches between methylation-dependent repression and target activation (e.g. DKK1, XIAP), and how its two distinct ZF consensus motifs and post-translational regulators are coordinated across developmental, stress, and disease contexts, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling repressor and activator functions","Locus-specific corepressor versus coactivator recruitment not mapped","Integration of RBBP6/USP9X/PRKDC inputs into target selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,8,13,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,14]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15]}],"complexes":[],"partners":["CTBP","RBBP6","USP9X","PRKDC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NAP3","full_name":"Zinc finger and BTB domain-containing protein 38","aliases":[],"length_aa":1195,"mass_kda":134.3,"function":"Transcriptional regulator with bimodal DNA-binding specificity. Binds with a higher affinity to methylated CpG dinucleotides in the consensus sequence 5'-CGCG-3' but can also bind to E-box elements (5'-CACGTG-3'). Can also bind specifically to a single methyl-CpG pair. Represses transcription in a methyl-CpG-dependent manner (PubMed:16354688). Plays an important role in regulating DNA replication and common fragile sites (CFS) stability in a RBBP6- and MCM10-dependent manner; represses expression of MCM10 which plays an important role in DNA-replication (PubMed:24726359). Acts as a transcriptional activator. May be involved in the differentiation and/or survival of late postmitotic neurons (By similarity)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8NAP3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZBTB38","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZBTB38","total_profiled":1310},"omim":[{"mim_id":"615898","title":"NADH DEHYDROGENASE (UBIQUINONE) COMPLEX I, ASSEMBLY FACTOR 7; NDUFAF7","url":"https://www.omim.org/entry/615898"},{"mim_id":"612308","title":"ZINC FINGER AND BTB DOMAIN-CONTAINING 4; ZBTB4","url":"https://www.omim.org/entry/612308"},{"mim_id":"612221","title":"STATURE QUANTITATIVE TRAIT LOCUS 10; STQTL10","url":"https://www.omim.org/entry/612221"},{"mim_id":"612218","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 38; ZBTB38","url":"https://www.omim.org/entry/612218"},{"mim_id":"300329","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 33; ZBTB33","url":"https://www.omim.org/entry/300329"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZBTB38"},"hgnc":{"alias_symbol":["FLJ35036","CIBZ","ZNF921","PPP1R171"],"prev_symbol":[]},"alphafold":{"accession":"Q8NAP3","domains":[{"cath_id":"-","chopping":"14-122","consensus_level":"high","plddt":46.4306,"start":14,"end":122},{"cath_id":"-","chopping":"451-478","consensus_level":"medium","plddt":74.7218,"start":451,"end":478}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NAP3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NAP3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NAP3-F1-predicted_aligned_error_v6.png","plddt_mean":43.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZBTB38","jax_strain_url":"https://www.jax.org/strain/search?query=ZBTB38"},"sequence":{"accession":"Q8NAP3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NAP3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NAP3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NAP3"}},"corpus_meta":[{"pmid":"24726359","id":"PMC_24726359","title":"The RBBP6/ZBTB38/MCM10 axis regulates DNA replication and common fragile site stability.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24726359","citation_count":61,"is_preprint":false},{"pmid":"21625269","id":"PMC_21625269","title":"The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression.","date":"2011","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21625269","citation_count":43,"is_preprint":false},{"pmid":"16115196","id":"PMC_16115196","title":"Identification of a novel BTB-zinc finger transcriptional repressor, CIBZ, that interacts with CtBP corepressor.","date":"2005","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/16115196","citation_count":40,"is_preprint":false},{"pmid":"18375381","id":"PMC_18375381","title":"Down-regulation of CIBZ, a novel substrate of caspase-3, induces apoptosis.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18375381","citation_count":34,"is_preprint":false},{"pmid":"22315219","id":"PMC_22315219","title":"CtBP-interacting BTB zinc finger protein (CIBZ) promotes proliferation and G1/S transition in embryonic stem cells via Nanog.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22315219","citation_count":24,"is_preprint":false},{"pmid":"29490077","id":"PMC_29490077","title":"Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29490077","citation_count":23,"is_preprint":false},{"pmid":"29287967","id":"PMC_29287967","title":"The C-Terminal Zinc Fingers of ZBTB38 are Novel Selective Readers of DNA Methylation.","date":"2017","source":"Journal of molecular 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30355731","citation_count":18,"is_preprint":false},{"pmid":"20237851","id":"PMC_20237851","title":"Molecular characterization, polymorphism of bovine ZBTB38 gene and association with body measurement traits in native Chinese cattle breeds.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20237851","citation_count":17,"is_preprint":false},{"pmid":"27659197","id":"PMC_27659197","title":"CIBZ Regulates Mesodermal and Cardiac Differentiation of by Suppressing T and Mesp1 Expression in Mouse Embryonic Stem Cells.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27659197","citation_count":17,"is_preprint":false},{"pmid":"22427977","id":"PMC_22427977","title":"CIBZ, a novel BTB domain-containing protein, is involved in mouse spinal cord injury via mitochondrial pathway independent of p53 gene.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22427977","citation_count":16,"is_preprint":false},{"pmid":"29151236","id":"PMC_29151236","title":"Tauroursodeoxycholic acid alleviates secondary injury in the spinal cord via up-regulation of CIBZ gene.","date":"2017","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/29151236","citation_count":16,"is_preprint":false},{"pmid":"30343694","id":"PMC_30343694","title":"Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis.","date":"2018","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30343694","citation_count":15,"is_preprint":false},{"pmid":"30480223","id":"PMC_30480223","title":"DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38.","date":"2018","source":"Epigenetics insights","url":"https://pubmed.ncbi.nlm.nih.gov/30480223","citation_count":14,"is_preprint":false},{"pmid":"28514761","id":"PMC_28514761","title":"Zbtb38 is a novel target for spinal cord injury.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28514761","citation_count":13,"is_preprint":false},{"pmid":"30310057","id":"PMC_30310057","title":"Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation.","date":"2018","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30310057","citation_count":13,"is_preprint":false},{"pmid":"29216791","id":"PMC_29216791","title":"The associations of two SNPs in miRNA-146a and one SNP in ZBTB38-RASA2 with the disease susceptibility and the clinical features of the Chinese patients of sCJD and FFI.","date":"2018","source":"Prion","url":"https://pubmed.ncbi.nlm.nih.gov/29216791","citation_count":12,"is_preprint":false},{"pmid":"23302005","id":"PMC_23302005","title":"An SNP of the ZBTB38 gene is associated with idiopathic short stature in the Chinese Han population.","date":"2013","source":"Clinical endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23302005","citation_count":11,"is_preprint":false},{"pmid":"36000449","id":"PMC_36000449","title":"Context-dependent CpG methylation directs cell-specific binding of transcription factor ZBTB38.","date":"2022","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36000449","citation_count":10,"is_preprint":false},{"pmid":"35297517","id":"PMC_35297517","title":"Heterozygous loss of Zbtb38 leads to early embryonic lethality via the suppression of Nanog and Sox2 expression.","date":"2022","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/35297517","citation_count":9,"is_preprint":false},{"pmid":"30697495","id":"PMC_30697495","title":"Transcriptome profiling reveals the role of ZBTB38 knock-down in human neuroblastoma.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30697495","citation_count":8,"is_preprint":false},{"pmid":"30075197","id":"PMC_30075197","title":"ZBTB38, a novel regulator of autophagy initiation targeted by RB1CC1/FIP200 in spinal cord injury.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30075197","citation_count":6,"is_preprint":false},{"pmid":"32956421","id":"PMC_32956421","title":"ZBTB38 is dispensable for antibody responses.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32956421","citation_count":5,"is_preprint":false},{"pmid":"35178492","id":"PMC_35178492","title":"Role of ZBTB38 Genotype and Expression in Growth and Response to Recombinant Human Growth Hormone Treatment.","date":"2022","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/35178492","citation_count":5,"is_preprint":false},{"pmid":"37782752","id":"PMC_37782752","title":"Sex-specific DNA methylation and transcription of zbtb38 and effects of gene-environment interactions on its natural antisense transcript in zebrafish.","date":"2023","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37782752","citation_count":3,"is_preprint":false},{"pmid":"23137638","id":"PMC_23137638","title":"ZBTB38 gene polymorphism associated with body measurement traits in native Chinese cattle breeds.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23137638","citation_count":3,"is_preprint":false},{"pmid":"38800625","id":"PMC_38800625","title":"Association of ZBTB38 gene polymorphism (rs724016) with height and fetal hemoglobin in individuals with sickle cell anemia.","date":"2024","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/38800625","citation_count":1,"is_preprint":false},{"pmid":"40759373","id":"PMC_40759373","title":"Epigenetic regulation of sex: the role of DNA methylation and zbtb38 in zebrafish sex differentiation and heat-induced masculinization.","date":"2025","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40759373","citation_count":1,"is_preprint":false},{"pmid":"41916004","id":"PMC_41916004","title":"Circ-ZBTB38 as an oncogenic circular RNA: Mechanisms in disrupting RalGAP complexes and its clinical value in melanoma.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41916004","citation_count":0,"is_preprint":false},{"pmid":"41842907","id":"PMC_41842907","title":"Zbtb38 transcriptionally activates XIAP to regulate apoptosis in development and cancer.","date":"2026","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41842907","citation_count":0,"is_preprint":false},{"pmid":"42146383","id":"PMC_42146383","title":"ZBTB38 requires an extended N-terminal zinc finger network to read mCpG- and discriminate TpG-containing DNA sequences.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42146383","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17354,"output_tokens":4942,"usd":0.063096,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13138,"output_tokens":5361,"usd":0.099858,"stage2_stop_reason":"end_turn"},"total_usd":0.162954,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"ZBTB38 (CIBZ) physically associates with the transcriptional corepressor CtBP via a conserved PLDLR motif. CIBZ represses transcription through two independent repression domains: an N-terminal BTB domain (HDAC-independent) and a PLDLR-containing RD2 region (HDAC-dependent). CIBZ redistributes CtBP from diffuse nuclear localization to pericentromeric foci; mutation of the PLDLR motif abolishes CtBP interaction, RD2 repression activity, and pericentromeric targeting of CtBP, but not CIBZ's own localization to pericentromeric foci.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of PLDLR motif, heterologous DNA-targeting transcriptional repression assay, immunofluorescence localization\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal interaction confirmed by Co-IP, mutagenesis of binding motif with functional readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"16115196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZBTB38 (CIBZ) is a direct substrate of caspase-3: in vitro caspase cleavage assays with mutagenesis identified two caspase-3 recognition sites in CIBZ. Knockdown of CIBZ induces apoptosis through the mitochondrial pathway (activating caspases-3, -7, and -9 and PARP cleavage) in a p53-independent manner.\",\n      \"method\": \"In vitro caspase-3 cleavage assay, site-directed mutagenesis of caspase recognition sites, siRNA knockdown, annexin V/PI flow cytometry, caspase activation assays in p53-/- cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay plus mutagenesis of recognition sites, combined with functional knockdown phenotype using multiple orthogonal readouts\",\n      \"pmids\": [\"18375381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZBTB38 (CIBZ) binds to a methylated CpG-containing proximal region of the Myogenin (Myog) promoter and represses Myog transcription in a DNA methylation-dependent manner, thereby suppressing myogenic differentiation. Loss of CIBZ promotes myogenic differentiation; ectopic CIBZ expression impairs it. Importantly, CIBZ-mediated repression does not require demethylation of the Myog promoter CpGs.\",\n      \"method\": \"siRNA knockdown and ectopic overexpression in C2C12 cells, chromatin immunoprecipitation (ChIP), luciferase reporter assay, myogenic differentiation assays in vitro and in vivo\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, combined with loss- and gain-of-function experiments showing concordant phenotype\",\n      \"pmids\": [\"21625269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZBTB38 (CIBZ) promotes ESC proliferation and G1/S transition at least in part by post-transcriptionally maintaining Nanog protein levels. CIBZ deletion or siRNA knockdown inhibits ESC proliferation and delays G1/S transition; ectopic CIBZ expression accelerates it. Constitutive overexpression of Nanog partially rescues the proliferation defect caused by CIBZ knockdown.\",\n      \"method\": \"siRNA knockdown, CIBZ deletion, ectopic overexpression in ESCs, cell cycle analysis, Nanog rescue experiment, western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via Nanog rescue, loss- and gain-of-function, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"22315219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBBP6 (an E3 ubiquitin ligase) ubiquitinates ZBTB38, destabilizing it. ZBTB38 in turn negatively regulates transcription and chromatin-associated levels of the MCM10 replication factor. Cells lacking RBBP6 accumulate ZBTB38, which causes MCM10 downregulation, reduced replication fork progression, and increased DNA damage at common fragile sites.\",\n      \"method\": \"Ubiquitination assays, siRNA knockdown of RBBP6 and ZBTB38, ChIP, DNA fiber assay for replication fork speed, FISH for common fragile site stability\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ubiquitination assay establishing enzymatic relationship, combined with functional epistasis and multiple orthogonal cellular readouts\",\n      \"pmids\": [\"24726359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZBTB38 (CIBZ) binds directly to the promoters of Brachyury (T) and Mesp1 in undifferentiated ESCs, repressing their transcription and thereby suppressing mesodermal and cardiac differentiation. Loss of CIBZ induces mesoderm specification and cardiomyocyte differentiation; overexpression delays these processes.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, CIBZ knockout and overexpression in ESCs, differentiation assays toward cardiomyocytes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP, luciferase assay for transcriptional repression, concordant loss- and gain-of-function phenotypes\",\n      \"pmids\": [\"27659197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZBTB38's C-terminal zinc fingers (ZFs 6–9) exhibit high-affinity, methyl-CpG-selective DNA binding to a consensus sequence distinct from the N-terminal ZF consensus. These C-terminal ZFs can directly occupy promoters containing this motif in cells in a DNA methylation-dependent manner and modulate transcriptional responses at those loci.\",\n      \"method\": \"Fluorescence polarization DNA binding assays, small-angle X-ray scattering (SAXS) structural modeling, ChIP in cell lines, gene expression analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assays plus ChIP in cells, hybrid structural modeling; single lab\",\n      \"pmids\": [\"29287967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATF4 (an ER-stress-inducible transcription factor) directly activates ZBTB38 transcription by binding to the ZBTB38 promoter under normal conditions; this binding is significantly reduced following spinal cord injury, causing decreased ZBTB38 expression and increased ER stress-associated apoptosis.\",\n      \"method\": \"ChIP-qPCR, lentiviral overexpression of ZBTB38 in SCI mouse model, apoptosis assays, motor function assessment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly demonstrating ATF4 binding to ZBTB38 promoter, supported by in vivo rescue experiment\",\n      \"pmids\": [\"28514761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of ZBTB38 C-terminal zinc fingers 6–9 in complex with a methylated consensus DNA sequence (1.75 Å resolution) reveals that methyl-selective binding is mediated by base-specific interactions from residues in the α-helices of ZF7 and ZF8 at the 5' mCpG site, while ZF6 and ZF9 serve structural stabilization roles. This represents a mode of mCpG recognition distinct from other ZF methyl-CpG binding proteins.\",\n      \"method\": \"X-ray crystallography (1.75 Å), solution NMR spectroscopy, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with NMR and EMSA validating methylated DNA recognition mechanism\",\n      \"pmids\": [\"30355731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The deubiquitinase USP9X interacts with ZBTB38, deubiquitinates it, and stabilizes it. USP9X is itself stabilized by oxidative stress. The USP9X/ZBTB38 axis limits basal ROS production and is required for the cellular response to acute oxidative stress; loss of either protein increases ROS toxicity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mass spectrometry identification of USP9X as ZBTB38 interactor, siRNA knockdown of USP9X and ZBTB38, ROS measurement assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — deubiquitination assay plus reciprocal Co-IP and MS identification of interactor, functional validation with concordant knockdowns\",\n      \"pmids\": [\"29490077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZBTB38 binds methylated promoters of IL1r2 (interleukin-1 receptor 2) in B cells and represses IL1r2 transcription, forming a molecular bridge between an arthritis-associated DNA hypomethylation epimutation at the Zbtb38 locus and silencing of an anti-inflammatory gene.\",\n      \"method\": \"ChIP, gene expression studies, correlation of Zbtb38 promoter methylation with IL1r2 expression in a murine RA model\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP supporting direct binding, but single lab with limited mechanistic follow-up\",\n      \"pmids\": [\"30343694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZBTB38 regulates the cellular response to DNA methyltransferase inhibitors (DNMTi; 5-azacytidine, decitabine, zebularine): DNMTi treatment causes ZBTB38 protein downregulation. ZBTB38 depletion enhances DNMTi toxicity, and this effect is mediated at least in part through upregulation of CDKN1C mRNA.\",\n      \"method\": \"siRNA knockdown of ZBTB38, western blotting, cell viability assays, RT-PCR for CDKN1C in multiple cancer cell lines\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis between ZBTB38 and CDKN1C confirmed by knockdown in multiple cell lines, single lab\",\n      \"pmids\": [\"30310057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZBTB38 binds the DKK1 (Dickkopf WNT signaling pathway inhibitor 1) locus and promotes DKK1 expression in prostate cancer cells. Reduction of DKK1 rescues ZBTB38-mediated suppression of migration and proliferation. PRKDC (DNA-PKcs) was identified as a ZBTB38-interacting protein that represses ZBTB38 function.\",\n      \"method\": \"ChIP demonstrating ZBTB38 binding to DKK1 promoter, DKK1 knockdown rescue experiments, Co-IP identifying PRKDC as interactor, cell migration and proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct target binding plus epistasis via DKK1 rescue and Co-IP identification of interactor, single lab\",\n      \"pmids\": [\"34697293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZBTB38 binds methylated CpG-containing sequences in vivo at two classes of consensus sites (corresponding to its N-terminal and C-terminal ZF domains). Approximately 10% of ZBTB38 binding sites overlap with CTCF binding, while 90% reside in closed chromatin not occupied by other mapped factors; ~one-third of ZBTB38 sites are found upstream of long active CpG islands.\",\n      \"method\": \"ChIP-seq in human cell line, intersection with ENCODE datasets for chromatin state and other TF binding\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with in vivo validation of in vitro-defined consensus sequences; single lab\",\n      \"pmids\": [\"36000449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Heterozygous loss of Zbtb38 in mice leads to early embryonic lethality shortly after implantation due to reduced epiblast proliferation and increased apoptosis. This is associated with reduced expression of Nanog and Sox2. Zbtb38 is dispensable for ESC establishment and identity in vitro.\",\n      \"method\": \"Conditional knockout via Cre-loxP, immunofluorescence for proliferation and apoptosis markers, qRT-PCR and western blotting for Nanog/Sox2, ESC derivation from knockout embryos\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in vivo with defined embryonic phenotype and molecular mechanism (Nanog/Sox2 reduction), multiple readouts\",\n      \"pmids\": [\"35297517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB38 regulates autophagy initiation: ZBTB38 knockdown blocks autophagy (decreased LC3B II/I ratio, increased p62). RB1CC1/FIP200, a key component of the autophagy initiation complex, is transcriptionally regulated by ZBTB38 and decreases ~4.2-fold upon ZBTB38 knockdown. Overexpression of RB1CC1 in ZBTB38-knockdown cells rescues the autophagy block and restores cell proliferation.\",\n      \"method\": \"ZBTB38 siRNA knockdown, LC3B/p62 western blotting, transcriptome sequencing, RB1CC1 rescue overexpression, lentiviral ZBTB38 overexpression in SCI mouse model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics identifying target plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"30075197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Zbtb38 transcriptionally activates XIAP by binding E-box motifs within the upstream regulatory regions of the XIAP gene. XIAP overexpression rescues apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated anti-apoptotic function is at least partially XIAP-dependent. This operates independently of p53 status.\",\n      \"method\": \"Loss- and gain-of-function experiments (siRNA knockdown and overexpression), ChIP for ZBTB38 binding to XIAP regulatory regions, XIAP rescue overexpression, apoptosis assays in ESC differentiation and cancer cell lines\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding combined with epistasis rescue experiment; single lab, single study\",\n      \"pmids\": [\"41842907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The N-terminal zinc finger (ZF) domain of ZBTB38 defines a distinct mCpG-containing consensus DNA sequence for binding. Unlike the other two ZBTB MBP family members (ZBTB33/Kaiso and ZBTB4), the shared core ZF domain of ZBTB38 discriminates against TpG-containing DNA (i.e., requires the methyl group), and at least one additional N-terminal ZF is required to stabilize DNA engagement. Each ZF domain preferentially recognizes its own cognate methylated consensus motif.\",\n      \"method\": \"Fluorescence polarization DNA binding assays, systematic mutagenesis of ZF domains, in vitro binding with mCpG vs. TpG-containing oligonucleotides\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro binding assays with domain mutagenesis but preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"42146383\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZBTB38 is a methyl-CpG-binding transcriptional repressor that uses two independent sets of zinc finger domains to recognize distinct methylated CpG consensus sequences; it recruits the CtBP/HDAC complex via a PLDLR motif to repress target genes, directly regulates key developmental transcription factors (Myog, T/Brachyury, Mesp1, Nanog, Sox2, XIAP, DKK1) by binding their methylated promoters, and is itself controlled post-translationally by RBBP6-mediated ubiquitination/degradation and USP9X-mediated deubiquitination/stabilization, placing it at the intersection of DNA methylation readout, DNA replication fidelity (via MCM10 regulation), oxidative stress response, and apoptosis control (via caspase-3 cleavage and XIAP transcriptional activation).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZBTB38 (CIBZ) is a methyl-CpG-binding transcriptional regulator that reads DNA methylation through two independent sets of zinc fingers and controls developmental gene expression, cell proliferation, and apoptosis [#2, #8, #14]. Its N-terminal and C-terminal zinc-finger arrays each recognize a distinct methylated CpG consensus, with the C-terminal fingers (ZF6–9) binding methylated DNA at high affinity via base-specific contacts from ZF7 and ZF8 while ZF6 and ZF9 provide structural stabilization, a methyl-CpG recognition mode distinct from other zinc-finger methyl readers [#6, #8]. Genome-wide, ZBTB38 occupies methylated sites in largely closed chromatin and upstream of active CpG islands [#13]. It functions principally as a methylation-dependent repressor, associating with the CtBP corepressor through a PLDLR motif and acting through both HDAC-dependent and HDAC-independent repression domains [#0], and represses methylated promoters of myogenic and mesendodermal regulators including Myogenin, Brachyury (T), and Mesp1 to restrain differentiation [#2, #5]. ZBTB38 supports proliferation and pluripotency by sustaining Nanog and Sox2, and its heterozygous loss in mice causes peri-implantation lethality from reduced epiblast proliferation and increased apoptosis [#3, #14]. The protein is a node controlling apoptosis and stress responses: it is a direct caspase-3 substrate whose depletion triggers mitochondrial p53-independent apoptosis [#1], it transcriptionally activates the anti-apoptotic factor XIAP via E-box binding [#16], and its abundance is governed post-translationally by RBBP6-mediated ubiquitination/destabilization and USP9X-mediated deubiquitination/stabilization, the latter linking it to oxidative-stress control [#4, #9]. Through these axes ZBTB38 also influences DNA replication by limiting MCM10 [#4], autophagy initiation via RB1CC1/FIP200 [#15], and responses to DNA methyltransferase inhibitors [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established how ZBTB38 represses transcription by defining its corepressor partner and the motif required for that interaction, framing it as a recruiter of CtBP-based repression machinery.\",\n      \"evidence\": \"Co-IP, PLDLR motif mutagenesis, heterologous DNA-targeting repression assay and immunofluorescence\",\n      \"pmids\": [\"16115196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link CtBP recruitment to specific endogenous target genes\", \"HDAC-independent BTB repression mechanism not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed ZBTB38 is a direct caspase-3 substrate and that its loss triggers mitochondrial apoptosis, placing it as a pro-survival factor cleaved during cell death.\",\n      \"evidence\": \"In vitro caspase-3 cleavage with cleavage-site mutagenesis, siRNA knockdown, apoptosis and caspase assays in p53-/- cells\",\n      \"pmids\": [\"18375381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets mediating the anti-apoptotic effect not identified at this stage\", \"Functional consequence of caspase cleavage products unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated methylation-dependent target repression in a developmental context, showing ZBTB38 binds the methylated Myog promoter to restrain myogenic differentiation without demethylation.\",\n      \"evidence\": \"ChIP, luciferase reporter, loss/gain-of-function and differentiation assays in C2C12 cells\",\n      \"pmids\": [\"21625269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the consensus motif recognized at the Myog promoter\", \"Corepressor requirement at this locus not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ZBTB38 to proliferation control in pluripotent cells via post-transcriptional maintenance of Nanog, advancing it from a repressor to a regulator of stem-cell cycle progression.\",\n      \"evidence\": \"siRNA knockdown, deletion, overexpression, cell-cycle analysis and Nanog rescue in ESCs\",\n      \"pmids\": [\"22315219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ZBTB38 maintains Nanog protein not defined\", \"Only partial rescue, implying additional effectors\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified post-translational control of ZBTB38 abundance and a downstream replication target, linking RBBP6-driven degradation to MCM10 levels and fork stability.\",\n      \"evidence\": \"Ubiquitination assays, RBBP6/ZBTB38 knockdown, ChIP, DNA fiber and common fragile site FISH\",\n      \"pmids\": [\"24726359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MCM10 regulation is direct or methylation-dependent not fully resolved\", \"Cell-type generality of the RBBP6 axis untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended ZBTB38's developmental repression to germ-layer specification, showing it directly silences Brachyury and Mesp1 to suppress mesoderm and cardiomyocyte differentiation.\",\n      \"evidence\": \"ChIP, luciferase, ESC knockout/overexpression and cardiomyocyte differentiation assays\",\n      \"pmids\": [\"27659197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methylation status of these promoters during differentiation not detailed\", \"Corepressor dependence not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the biochemical basis of ZBTB38's C-terminal zinc-finger methyl-CpG selectivity and showed these fingers occupy cognate promoters in a methylation-dependent manner.\",\n      \"evidence\": \"Fluorescence polarization binding, SAXS modeling, ChIP and expression analysis\",\n      \"pmids\": [\"29287967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic basis of recognition not yet resolved\", \"Relative in vivo contribution of N- vs C-terminal fingers unquantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed ZBTB38 downstream of ER-stress signaling by showing ATF4 directly activates its transcription, with reduced binding after spinal cord injury exacerbating apoptosis.\",\n      \"evidence\": \"ChIP-qPCR and lentiviral ZBTB38 rescue in an SCI mouse model with apoptosis and motor readouts\",\n      \"pmids\": [\"28514761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZBTB38 targets mediating the SCI phenotype not defined\", \"Generality beyond the injury model untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided atomic-resolution insight into methyl-CpG readout, defining how ZF7/ZF8 make base-specific contacts at the methylated CpG while ZF6/ZF9 stabilize binding.\",\n      \"evidence\": \"1.75 A crystal structure with bound methylated DNA, NMR and EMSA\",\n      \"pmids\": [\"30355731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the N-terminal ZF array bound to its consensus not solved\", \"Allosteric coordination between the two ZF arrays unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed stabilizing post-translational control opposing RBBP6, with USP9X deubiquitinating ZBTB38 and the axis buffering oxidative stress.\",\n      \"evidence\": \"Co-IP, MS interactor identification, deubiquitination and ubiquitination assays, ROS measurements with knockdowns\",\n      \"pmids\": [\"29490077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets linking ZBTB38 to ROS control not identified\", \"Crosstalk timing between RBBP6 and USP9X not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked ZBTB38 to inflammation by showing it represses the methylated IL1r2 promoter, bridging an arthritis-associated epimutation to anti-inflammatory gene silencing.\",\n      \"evidence\": \"ChIP and expression/methylation correlation in a murine RA model\",\n      \"pmids\": [\"30343694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study with limited mechanistic follow-up\", \"Causality between the epimutation and phenotype not established in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected ZBTB38 to DNA methyltransferase inhibitor sensitivity, showing its depletion enhances DNMTi toxicity partly via CDKN1C upregulation.\",\n      \"evidence\": \"siRNA knockdown, viability assays and CDKN1C RT-PCR across multiple cancer lines\",\n      \"pmids\": [\"30310057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDKN1C is a direct ZBTB38 target not established\", \"Mechanism of DNMTi-induced ZBTB38 downregulation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ZBTB38 can act as a positive regulator, promoting DKK1 expression to suppress prostate cancer cell migration, and identified PRKDC as an interactor repressing its function.\",\n      \"evidence\": \"ChIP, DKK1 rescue, Co-IP for PRKDC, migration/proliferation assays\",\n      \"pmids\": [\"34697293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of activation versus repression at different loci unresolved\", \"How PRKDC represses ZBTB38 function not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped ZBTB38 genome-wide, validating both ZF consensus motifs in vivo and showing predominant binding in closed chromatin with partial CTCF overlap.\",\n      \"evidence\": \"ChIP-seq in a human cell line with ENCODE chromatin/TF intersection\",\n      \"pmids\": [\"36000449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of binding in closed chromatin unclear\", \"Single cell-line dataset\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ZBTB38's essential developmental role in vivo, with heterozygous loss causing peri-implantation lethality through reduced epiblast proliferation and Nanog/Sox2 loss.\",\n      \"evidence\": \"Cre-loxP knockout, proliferation/apoptosis IF, Nanog/Sox2 qRT-PCR/WB, ESC derivation\",\n      \"pmids\": [\"35297517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect regulation of Nanog/Sox2 in embryo not resolved\", \"Reason for haploinsufficiency not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ZBTB38 to autophagy initiation by identifying RB1CC1/FIP200 as a transcriptional target whose restoration rescues the autophagy block and proliferation upon ZBTB38 loss.\",\n      \"evidence\": \"siRNA knockdown, LC3B/p62 WB, transcriptome sequencing and RB1CC1 rescue\",\n      \"pmids\": [\"30075197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of RB1CC1 promoter regulation not shown by ChIP\", \"Whether autophagy effect is methylation-dependent unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the anti-apoptotic transcriptional effector of ZBTB38, showing it activates XIAP via E-box binding to rescue apoptosis from its loss, independent of p53.\",\n      \"evidence\": \"Knockdown/overexpression, ChIP at XIAP regulatory regions, XIAP rescue and apoptosis assays in ESC and cancer cells\",\n      \"pmids\": [\"41842907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between E-box (XIAP) activation and methyl-CpG repression modes unresolved\", \"Single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized the N-terminal ZF domain's methyl-discriminating recognition, showing it requires the methyl group and an additional finger for stable engagement, distinguishing ZBTB38 from ZBTB33 and ZBTB4.\",\n      \"evidence\": \"Fluorescence polarization binding and systematic ZF mutagenesis with mCpG versus TpG oligonucleotides (preprint)\",\n      \"pmids\": [\"42146383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structure of N-terminal ZF-DNA complex not determined\", \"In vivo significance of the two distinct consensus motifs not functionally separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZBTB38 switches between methylation-dependent repression and target activation (e.g. DKK1, XIAP), and how its two distinct ZF consensus motifs and post-translational regulators are coordinated across developmental, stress, and disease contexts, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling repressor and activator functions\", \"Locus-specific corepressor versus coactivator recruitment not mapped\", \"Integration of RBBP6/USP9X/PRKDC inputs into target selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 8, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 14]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTBP\", \"RBBP6\", \"USP9X\", \"PRKDC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}