{"gene":"ZNF423","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2002,"finding":"ZNF423 (EBFAZ) physically binds to Early B-cell Factor (EBF/OLF1) and negatively regulates its activity, and also binds to SMAD1 and SMAD4 in response to BMP2 signaling to activate the homeobox regulator Xvent-2. The EBF-binding requires the terminal zinc fingers (ZF29-30).","method":"Protein binding assays and functional transactivation assays; nuclear localization confirmed by cellular fractionation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assays and functional transactivation data from single lab, multiple interactions demonstrated","pmids":["12393497"],"is_preprint":false},{"year":2005,"finding":"The terminal six zinc fingers (C-terminal domain) of ZNF423/Evi3 are required for modulation of EBF transcriptional activity, as shown by domain deletion analysis in transactivation assays; Evi3 overexpression in tumors upregulates EBF target genes CD19 and CD38.","method":"Transactivation reporter assay with deletion constructs; reconstitution in primary leukemia cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mapping with reporter assays and primary cell reconstitution, single lab","pmids":["15580294"],"is_preprint":false},{"year":2009,"finding":"ZNF423 is essential for retinoic acid (RA)-induced differentiation in neuroblastoma cells; it physically associates with the RARα/RXRα nuclear receptor complex and is required for transactivation in response to retinoids. RNAi knockdown confers RA resistance and growth advantage; overexpression leads to growth inhibition and enhanced differentiation.","method":"Large-scale RNAi screen; co-immunoprecipitation (ZNF423 with RARα/RXRα); gain- and loss-of-function in neuroblastoma cell lines","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex, plus bidirectional loss/gain-of-function with defined phenotype, replicated across cell lines","pmids":["19345331"],"is_preprint":false},{"year":2009,"finding":"Aberrant expression of Zfp423/ZNF423, cooperating with p210BCR/ABL, promotes blast crisis of CML; ZNF423 increases colony-forming ability in BCR/ABL-expressing bone marrow cells and transplantation causes acute leukemia in mice, demonstrating a functional oncogenic role.","method":"Retroviral insertional mutagenesis screen; bone marrow transduction/transplantation; RNAi knockdown in BCR/ABL-positive cells; colony-forming assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo and in vitro functional assays including transplantation model, knockdown, and colony assay, single lab with orthogonal methods","pmids":["19234145"],"is_preprint":false},{"year":2012,"finding":"ZNF423 functions within the DNA damage response (DDR) pathway; upon induced DNA damage, ZNF423 colocalizes to nuclear foci positive for TIP60 (known to activate ATM at DNA damage sites) together with CEP164 and NPHP10. Knockdown of ZNF423 causes increased sensitivity to DNA damaging agents.","method":"Immunofluorescence colocalization to nuclear foci after DNA damage; siRNA knockdown followed by DNA damage sensitivity assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence (DDR sensitivity upon KD), multiple partners identified, published in high-impact journal with orthogonal methods","pmids":["22863007"],"is_preprint":false},{"year":2013,"finding":"ZNF423 acts as an estrogen-inducible transcription factor for BRCA1; ZNF423 transactivates the BRCA1 promoter in an estrogen-dependent manner, and SNPs in ZNF423 intronic sites near estrogen response elements alter this induction.","method":"Functional genomics; luciferase reporter assays; estrogen induction experiments in breast cancer cell lines; SNP-dependent variation in transcriptional induction","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and SNP-dependent functional assays, single lab, multiple orthogonal approaches","pmids":["23764426"],"is_preprint":false},{"year":2013,"finding":"A UBR5-ZNF423 fusion protein (containing exon 1 of UBR5 fused to exons 7–9 of ZNF423, including the C-terminal EBF-binding domain ZF29-30) drives NPC cell proliferation; its knockdown inhibits growth and colony formation, and its ectopic expression in NIH3T3 cells induces anchorage-independent growth and tumor formation in nude mice.","method":"Paired-end whole-transcriptome sequencing; fusion-specific siRNA knockdown; NIH3T3 transformation assay; nude mouse tumor formation","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with defined cellular and in vivo phenotypes, multiple orthogonal methods, single lab","pmids":["23878065"],"is_preprint":false},{"year":2013,"finding":"Aberrant ZNF423 (including a novel ZNF423β isoform encoding a NuRD complex-interacting domain) inhibits EBF-1 target gene transactivation and causes B cell maturation arrest in vivo; hypomethylation of ZNF423 regulatory sequences and BMP2 signaling drive ZNF423 expression in B-precursor ALL.","method":"Epigenetic analysis (bisulfite sequencing); in vivo B-cell differentiation assays; functional transactivation assays; BMP2 stimulation experiments","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo B-cell maturation arrest demonstrated, epigenetic regulation validated, EBF1 antagonism functionally demonstrated, multiple orthogonal methods","pmids":["24081948"],"is_preprint":false},{"year":2017,"finding":"ZNF423 regulates cell cycle progression and mitotic spindle orientation in cerebellar Purkinje cell progenitors; deletion of distinct ZNF423 zinc-finger domains in vivo causes premature cell cycle exit and loss of the progenitor pool (one domain) or impairs PC differentiation (another domain); DDR markers are upregulated in cerebellar progenitors of both mutants.","method":"Allelic series of in-frame zinc finger domain deletions in mice; neuroanatomical analysis; cell cycle marker immunostaining; DDR marker analysis in cerebellar ventricular zone","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple alleles with domain-specific phenotypes, in vivo functional dissection, orthogonal cellular readouts","pmids":["28893945"],"is_preprint":false},{"year":2017,"finding":"Epigenetic regulation (promoter DNA methylation and nucleosome occupancy) controls Zfp423/ZNF423 expression and thereby determines adipocyte precursor commitment; BMP4 can initiate these epigenetic changes; demethylation with 5-azacytidine increases ZNF423 expression and induces adipocyte differentiation in otherwise non-adipogenic cells.","method":"Bisulfite sequencing; micrococcal nuclease protection assay; 5-azacytidine treatment; Oil Red O differentiation assay; comparison of committed (3T3-L1) vs uncommitted (NIH-3T3) cells","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic measurements with functional rescue experiments, single lab, multiple orthogonal methods","pmids":["29067487"],"is_preprint":false},{"year":2019,"finding":"ZNF423 regulates mitosis-related genes VRK1 and PBK (histone H3 kinases); ZNF423 knockdown decreases VRK1 and PBK expression and activity and enhances docetaxel-induced G2/M arrest and cytotoxicity. The ZNF423 rs9940645 SNP modulates these effects in an estrogen- and tamoxifen-dependent fashion.","method":"Chromatin immunoprecipitation; luciferase reporter assays; CRISPR/Cas9-engineered isogenic cell lines; cell cycle analysis; cell viability assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates direct regulation, CRISPR isogenic lines for SNP-dependent effects, single lab","pmids":["30937657"],"is_preprint":false},{"year":2020,"finding":"ZNF423 acts as an RNA-binding protein that binds AU-rich elements in the 3'-UTR of BCAT1 mRNA to promote autophagy via the IRE1-XBP1-RIDD axis in pulmonary artery smooth muscle cells under hypoxia.","method":"RNA-binding assays; co-immunoprecipitation (ZNF423 with BCAT1 mRNA); functional autophagy assays; pathway inhibition experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-binding and Co-IP data with functional readout, single lab, mechanism partially characterized","pmids":["32938905"],"is_preprint":false},{"year":2021,"finding":"ZNF423 occupies canonical EBF1-binding sites genome-wide (including in the absence of EBF1), is associated with depletion of activating histone marks at bound loci, specifically disrupts EBF1-dependent transactivation (but not EBF1 repressive/pioneering activities), and represses the TGFB1 promoter by outcompeting EBF1 while also interacting with SMADs. CRISPR-mediated ablation of ZNF423 in a pro-B ALL model decreased cell viability and prolonged mouse survival upon xenotransplantation.","method":"ChIP-seq (genome-wide ZNF423 binding); ATAC-seq/histone mark profiling; CRISPR-Cas9 ablation; xenotransplantation; transcriptome analysis; motif analysis","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with chromatin landscape profiling, CRISPR functional validation in vivo, multiple orthogonal methods, single lab","pmids":["33646306"],"is_preprint":false},{"year":2021,"finding":"ZNF423 rs9940645 SNP modulates AMPK signaling and metformin response in breast cancer cells in an estrogen- and SERM-dependent fashion; CRISPR-engineered isogenic cell lines with different SNP genotypes showed striking differences in response to metformin alone or combined with tamoxifen, both in vitro and in xenograft models.","method":"RNA sequencing; label-free quantitative proteomics; CRISPR/Cas9-engineered isogenic cell lines; xenograft mouse model; pathway enrichment analysis","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR isogenic cells and in vivo xenograft, multi-omics pathway identification, single lab","pmids":["34001842"],"is_preprint":false},{"year":2024,"finding":"ZNF423 patient-derived variants and in-frame zinc finger domain deletions modeled in mice reveal allele-dependent ranges of midline brain abnormalities; several variants previously asserted pathogenic appeared benign, while one was effectively null; heterozygous premature termination codons showed mild haploinsufficiency consistent with loss-of-function intolerance.","method":"Mouse in vivo modeling of ~50 patient-derived variants; neuroanatomical quantitative analysis of 791 littermate pairs; allelic series","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic in vivo functional validation of multiple variants with quantitative neuroanatomical phenotyping, large sample size, rigorous controls","pmids":["32925911"],"is_preprint":false}],"current_model":"ZNF423 is a multifunctional 30-zinc-finger transcription factor that operates through several mechanistically distinct modes: it physically associates with RARα/RXRα to mediate retinoic acid-induced differentiation; antagonizes EBF1 transcriptional activity by occupying EBF1-binding sites genome-wide and depleting activating histone marks; binds SMAD1/SMAD4 to transduce BMP signaling; acts as a transcriptional activator of BRCA1 downstream of estrogen receptor signaling; participates in the DNA damage response by colocalizing with TIP60 at nuclear damage foci (loss of ZNF423 sensitizes cells to DNA damaging agents); regulates mitotic spindle orientation and cell cycle progression in neural progenitors through domain-specific zinc-finger activities; promotes adipocyte commitment via epigenetic derepression of its own promoter; and post-transcriptionally stabilizes BCAT1 mRNA via AU-rich element binding to activate autophagy, with its activity modulated by specific SNPs that alter estrogen receptor binding and downstream pathway responses."},"narrative":{"mechanistic_narrative":"ZNF423 is a multi-zinc-finger transcription factor that integrates several developmental signaling inputs at chromatin, acting as a context-dependent node in differentiation programs and in disease [PMID:12393497, PMID:19345331, PMID:33646306]. Through distinct zinc-finger surfaces it physically engages multiple partners: its terminal fingers (ZF29-30) bind Early B-cell Factor (EBF1/OLF1) to antagonize EBF1 transactivation, while internal regions bind SMAD1 and SMAD4 to transduce BMP signaling toward targets such as Xvent-2 [PMID:12393497, PMID:23764426]. Genome-wide, ZNF423 occupies canonical EBF1-binding sites even in the absence of EBF1, depletes activating histone marks at those loci, and selectively blocks EBF1-dependent transactivation, including repression of the TGFB1 promoter [PMID:33646306]. In neuroblastoma it associates with the RARα/RXRα nuclear receptor complex and is required for retinoic acid-induced differentiation [PMID:19345331]. ZNF423 also participates in the DNA damage response, colocalizing with TIP60 at nuclear damage foci alongside CEP164 and NPHP10, with its loss sensitizing cells to DNA-damaging agents [PMID:22863007]. In breast cancer it is an estrogen-inducible activator of the BRCA1 promoter and of the mitotic kinases VRK1 and PBK, with intronic SNPs near estrogen response elements modulating these responses and downstream drug sensitivity [PMID:23764426, PMID:30937657]. Beyond DNA-directed roles, ZNF423 acts as an RNA-binding protein that binds AU-rich elements in the BCAT1 3'-UTR to promote autophagy via the IRE1-XBP1-RIDD axis [PMID:32938905]. Its own expression is controlled epigenetically: promoter DNA methylation and nucleosome occupancy gate adipocyte precursor commitment, and hypomethylation drives aberrant ZNF423 expression in B-precursor ALL where it enforces B-cell maturation arrest [PMID:24081948, PMID:29067487]. ZNF423 has both oncogenic activity—cooperating with BCR/ABL in CML blast crisis and acting through a UBR5-ZNF423 fusion in nasopharyngeal carcinoma—and developmental functions, with patient-derived and engineered zinc-finger variants producing allele-dependent midline brain abnormalities in mice [PMID:19234145, PMID:23878065, PMID:28893945, PMID:32925911].","teleology":[{"year":2002,"claim":"Established ZNF423 as a dual-function transcriptional regulator that bridges EBF antagonism and BMP/SMAD signaling, defining its first molecular partnerships and the domain (ZF29-30) responsible for EBF binding.","evidence":"Protein binding and transactivation assays with cellular fractionation","pmids":["12393497"],"confidence":"Medium","gaps":["No genome-wide binding map","Structural basis of SMAD versus EBF engagement undefined"]},{"year":2005,"claim":"Mapped the C-terminal six zinc fingers as the module required to modulate EBF activity and linked ZNF423 overexpression to upregulation of EBF target genes in tumors, connecting the molecular activity to an oncogenic readout.","evidence":"Domain-deletion transactivation reporter assays and reconstitution in primary leukemia cells","pmids":["15580294"],"confidence":"Medium","gaps":["Mechanism of EBF target derepression at chromatin not addressed","Single-lab functional data"]},{"year":2009,"claim":"Demonstrated that ZNF423 is required for retinoic acid-induced differentiation by physically associating with the RARα/RXRα complex, explaining a clinically relevant determinant of neuroblastoma retinoid response.","evidence":"Large-scale RNAi screen, reciprocal Co-IP, and bidirectional gain/loss-of-function in neuroblastoma lines","pmids":["19345331"],"confidence":"High","gaps":["Direct target genes of the ZNF423-RAR/RXR complex not defined","Domain mediating nuclear receptor contact unmapped"]},{"year":2009,"claim":"Showed ZNF423 has a functional oncogenic role, cooperating with p210BCR/ABL to drive CML blast crisis, moving it from a transcriptional regulator to a validated cancer driver.","evidence":"Retroviral insertional mutagenesis, bone marrow transduction/transplantation, knockdown and colony assays in mice","pmids":["19234145"],"confidence":"High","gaps":["Molecular target program underlying cooperation with BCR/ABL unresolved"]},{"year":2012,"claim":"Placed ZNF423 in the DNA damage response by showing it colocalizes with TIP60, CEP164 and NPHP10 at damage foci and that its loss sensitizes cells to genotoxins, revealing a function distinct from its transcriptional roles.","evidence":"Immunofluorescence colocalization after DNA damage and siRNA knockdown with damage-sensitivity assays","pmids":["22863007"],"confidence":"High","gaps":["Whether ZNF423 acts catalytically or as scaffold at foci unknown","Direct binding partners at foci not biochemically defined"]},{"year":2013,"claim":"Identified ZNF423 as an estrogen-inducible transcriptional activator of BRCA1 and showed intronic SNPs near estrogen response elements alter this induction, linking ZNF423 genetics to hormone-responsive transcription.","evidence":"Functional genomics, luciferase reporters and estrogen induction in breast cancer cells","pmids":["23764426"],"confidence":"Medium","gaps":["Mechanism by which SNPs alter ER occupancy not fully resolved","Direct versus indirect promoter engagement unclear"]},{"year":2013,"claim":"Demonstrated oncogenic gain-of-function through a UBR5-ZNF423 fusion retaining the EBF-binding ZF29-30 domain, showing the C-terminal module is sufficient to drive transformation and tumor formation.","evidence":"Whole-transcriptome sequencing, fusion-specific knockdown, NIH3T3 transformation, and nude mouse tumorigenesis","pmids":["23878065"],"confidence":"High","gaps":["Transcriptional targets of the fusion not enumerated","Contribution of UBR5 portion to oncogenicity unclear"]},{"year":2013,"claim":"Connected epigenetic derepression and BMP2 signaling to aberrant ZNF423 expression that drives B-cell maturation arrest, and identified a NuRD-interacting ZNF423β isoform, mechanistically tying ZNF423 to B-precursor ALL.","evidence":"Bisulfite sequencing, in vivo B-cell differentiation assays, transactivation and BMP2 stimulation experiments","pmids":["24081948"],"confidence":"High","gaps":["Role of the NuRD-interacting domain in repression not isolated","Relative contributions of hypomethylation versus BMP2 not separated"]},{"year":2017,"claim":"Dissected domain-specific in vivo functions in cerebellar Purkinje progenitors, showing distinct zinc fingers govern cell-cycle exit, spindle orientation and differentiation, and that DDR markers rise when these are lost.","evidence":"Allelic series of in-frame zinc-finger deletions in mice with cell-cycle and DDR marker analysis","pmids":["28893945"],"confidence":"High","gaps":["Molecular partners of each zinc-finger domain in progenitors undefined","Link between transcriptional and DDR roles unresolved"]},{"year":2017,"claim":"Showed that promoter DNA methylation and nucleosome occupancy gate ZNF423 expression to determine adipocyte commitment, with BMP4 initiating these changes, establishing an epigenetic switch upstream of ZNF423.","evidence":"Bisulfite sequencing, MNase protection, 5-azacytidine treatment and Oil Red O differentiation assays","pmids":["29067487"],"confidence":"Medium","gaps":["Downstream adipogenic targets of ZNF423 not mapped here","Single-lab cell-line system"]},{"year":2019,"claim":"Defined direct ZNF423 transcriptional targets VRK1 and PBK that influence mitotic progression and chemotherapy sensitivity, with a SNP modulating effects in an estrogen/tamoxifen-dependent manner.","evidence":"ChIP, luciferase reporters, CRISPR isogenic lines, cell-cycle and viability assays","pmids":["30937657"],"confidence":"Medium","gaps":["Mechanism of SNP-dependent ER coupling not fully resolved","Single-lab data"]},{"year":2020,"claim":"Revealed an unanticipated post-transcriptional role: ZNF423 acts as an RNA-binding protein recognizing AU-rich elements in BCAT1 mRNA to promote autophagy via the IRE1-XBP1-RIDD axis.","evidence":"RNA-binding assays, ZNF423-BCAT1 mRNA Co-IP, and functional autophagy/pathway-inhibition assays","pmids":["32938905"],"confidence":"Medium","gaps":["Domain mediating RNA binding not mapped","Relationship to its DNA-binding functions unknown","Single-lab finding"]},{"year":2021,"claim":"Provided genome-wide evidence that ZNF423 occupies EBF1 sites independently of EBF1, depletes activating histone marks, selectively disrupts EBF1 transactivation, and is required for pro-B ALL viability in vivo, defining its chromatin mechanism of EBF1 antagonism.","evidence":"ChIP-seq, histone-mark/ATAC profiling, CRISPR ablation and xenotransplantation","pmids":["33646306"],"confidence":"High","gaps":["Cofactors recruited to deplete activating marks not identified","Basis of selective interference with transactivation versus pioneering activity unclear"]},{"year":2021,"claim":"Showed the rs9940645 SNP genotype reprograms AMPK signaling and metformin response in an estrogen/SERM-dependent manner, linking ZNF423 genetic variation to therapeutic outcome.","evidence":"RNA-seq, quantitative proteomics, CRISPR isogenic lines and xenograft models","pmids":["34001842"],"confidence":"Medium","gaps":["Direct molecular link between SNP and AMPK pathway not established","Single-lab data"]},{"year":2024,"claim":"Systematically resolved which ZNF423 patient variants are functionally consequential, showing allele-dependent midline brain abnormalities and reclassifying several asserted-pathogenic variants as benign, refining genotype-phenotype interpretation.","evidence":"In vivo mouse modeling of ~50 variants with quantitative neuroanatomy across 791 littermate pairs","pmids":["32925911"],"confidence":"High","gaps":["Molecular consequences of each variant on partner binding not assayed","Human disease mechanism inferred from mouse phenotypes"]},{"year":null,"claim":"How ZNF423 partitions among its transcriptional (EBF1/SMAD/RAR-RXR/ER), DNA-damage-response, and RNA-binding roles within a single cell, and what governs which function dominates in a given context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model coupling its chromatin, DDR, and RNA functions","Domain-to-function map incomplete","Structural basis of multi-partner selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8,9,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,7]}],"complexes":[],"partners":["EBF1","SMAD1","SMAD4","RARA","RXRA","TIP60","CEP164","NPHP10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2M1K9","full_name":"Zinc finger protein 423","aliases":["Olf1/EBF-associated zinc finger protein","hOAZ","Smad- and Olf-interacting zinc finger protein"],"length_aa":1284,"mass_kda":144.6,"function":"Transcription factor that can both act as an activator or a repressor depending on the context. Plays a central role in BMP signaling and olfactory neurogenesis. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved in terminal olfactory receptor neurons differentiation; this interaction preventing EBF1 to bind DNA and activate olfactory-specific genes. Involved in olfactory neurogenesis by participating in a developmental switch that regulates the transition from differentiation to maturation in olfactory receptor neurons. Controls proliferation and differentiation of neural precursors in cerebellar vermis formation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q2M1K9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF423","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNF423","total_profiled":1310},"omim":[{"mim_id":"614848","title":"CENTROSOMAL PROTEIN, 164-KD; CEP164","url":"https://www.omim.org/entry/614848"},{"mim_id":"614845","title":"NEPHRONOPHTHISIS 15; NPHP15","url":"https://www.omim.org/entry/614845"},{"mim_id":"614844","title":"NEPHRONOPHTHISIS 14; NPHP14","url":"https://www.omim.org/entry/614844"},{"mim_id":"613524","title":"SHH SIGNALING AND CILIOGENESIS REGULATOR SDCCAG8; SDCCAG8","url":"https://www.omim.org/entry/613524"},{"mim_id":"610974","title":"ZINC FINGER PROTEIN 521; ZNF521","url":"https://www.omim.org/entry/610974"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":25.8}],"url":"https://www.proteinatlas.org/search/ZNF423"},"hgnc":{"alias_symbol":["KIAA0760","OAZ","hOAZ","Ebfaz","Zfp104","NPHP14","JBTS19"],"prev_symbol":[]},"alphafold":{"accession":"Q2M1K9","domains":[{"cath_id":"3.30.160.60","chopping":"139-248","consensus_level":"medium","plddt":79.7344,"start":139,"end":248},{"cath_id":"-","chopping":"663-804","consensus_level":"medium","plddt":67.9391,"start":663,"end":804},{"cath_id":"-","chopping":"1199-1283","consensus_level":"medium","plddt":82.9928,"start":1199,"end":1283},{"cath_id":"3.30.160","chopping":"1166-1196","consensus_level":"medium","plddt":71.8271,"start":1166,"end":1196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2M1K9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2M1K9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2M1K9-F1-predicted_aligned_error_v6.png","plddt_mean":60.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF423","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF423"},"sequence":{"accession":"Q2M1K9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2M1K9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2M1K9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2M1K9"}},"corpus_meta":[{"pmid":"22863007","id":"PMC_22863007","title":"Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22863007","citation_count":316,"is_preprint":false},{"pmid":"19345331","id":"PMC_19345331","title":"ZNF423 is critically required for retinoic acid-induced differentiation and is a marker of neuroblastoma outcome.","date":"2009","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/19345331","citation_count":120,"is_preprint":false},{"pmid":"23764426","id":"PMC_23764426","title":"Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression: individualized breast cancer prevention.","date":"2013","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/23764426","citation_count":63,"is_preprint":false},{"pmid":"12393497","id":"PMC_12393497","title":"Evi3, a common retroviral integration site in murine B-cell lymphoma, encodes an EBFAZ-related Krüppel-like zinc finger protein.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12393497","citation_count":56,"is_preprint":false},{"pmid":"29067487","id":"PMC_29067487","title":"Epigenetic modifications of the Zfp/ZNF423 gene control murine adipogenic commitment and are dysregulated in human hypertrophic obesity.","date":"2017","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/29067487","citation_count":47,"is_preprint":false},{"pmid":"23878065","id":"PMC_23878065","title":"Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23878065","citation_count":47,"is_preprint":false},{"pmid":"24081948","id":"PMC_24081948","title":"Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia.","date":"2013","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24081948","citation_count":32,"is_preprint":false},{"pmid":"28893945","id":"PMC_28893945","title":"Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28893945","citation_count":32,"is_preprint":false},{"pmid":"15580294","id":"PMC_15580294","title":"Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15580294","citation_count":28,"is_preprint":false},{"pmid":"26788497","id":"PMC_26788497","title":"ZNF423 and ZNF521: EBF1 Antagonists of Potential Relevance in B-Lymphoid Malignancies.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/26788497","citation_count":25,"is_preprint":false},{"pmid":"32938905","id":"PMC_32938905","title":"BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32938905","citation_count":22,"is_preprint":false},{"pmid":"19234145","id":"PMC_19234145","title":"Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19234145","citation_count":22,"is_preprint":false},{"pmid":"24976683","id":"PMC_24976683","title":"Expression profiling and functional implications of a set of zinc finger proteins, ZNF423, ZNF470, ZNF521, and ZNF780B, in primary osteoarthritic articular chondrocytes.","date":"2014","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/24976683","citation_count":21,"is_preprint":false},{"pmid":"29867779","id":"PMC_29867779","title":"ZNF423: A New Player in Estrogen Receptor-Positive Breast Cancer.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29867779","citation_count":20,"is_preprint":false},{"pmid":"27308357","id":"PMC_27308357","title":"ZNF423: Transcriptional modulation in development and cancer.","date":"2014","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27308357","citation_count":18,"is_preprint":false},{"pmid":"28856246","id":"PMC_28856246","title":"Breast cancer chemoprevention pharmacogenomics: Deep sequencing and functional genomics of the ZNF423 and CTSO genes.","date":"2017","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28856246","citation_count":13,"is_preprint":false},{"pmid":"32925911","id":"PMC_32925911","title":"ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32925911","citation_count":12,"is_preprint":false},{"pmid":"30937657","id":"PMC_30937657","title":"4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.","date":"2019","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/30937657","citation_count":9,"is_preprint":false},{"pmid":"27400912","id":"PMC_27400912","title":"Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/27400912","citation_count":7,"is_preprint":false},{"pmid":"38128789","id":"PMC_38128789","title":"Transcriptional regulatory mechanism of NR2F2 and ZNF423 in avian preadipocyte differentiation.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38128789","citation_count":3,"is_preprint":false},{"pmid":"33646306","id":"PMC_33646306","title":"Genome-wide interference of ZNF423 with B-lineage transcriptional circuitries in acute lymphoblastic leukemia.","date":"2021","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33646306","citation_count":3,"is_preprint":false},{"pmid":"33531950","id":"PMC_33531950","title":"An Atypical Presentation of Joubert Syndrome Due to a Novel Mutation in ZNF423 Gene.","date":"2020","source":"Journal of pediatric neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/33531950","citation_count":3,"is_preprint":false},{"pmid":"34001842","id":"PMC_34001842","title":"ZNF423 modulates the AMP-activated protein kinase pathway and metformin response in a single nucleotide polymorphisms, estrogen and selective estrogen receptor modulator dependent fashion.","date":"2021","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34001842","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.25.650726","title":"<i>Tulp3</i>  quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress  <i>Zfp423</i>  mutations in mice","date":"2025-04-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.25.650726","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14692,"output_tokens":3844,"usd":0.050868,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11723,"output_tokens":5279,"usd":0.095295,"stage2_stop_reason":"end_turn"},"total_usd":0.146163,"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\": 2002,\n      \"finding\": \"ZNF423 (EBFAZ) physically binds to Early B-cell Factor (EBF/OLF1) and negatively regulates its activity, and also binds to SMAD1 and SMAD4 in response to BMP2 signaling to activate the homeobox regulator Xvent-2. The EBF-binding requires the terminal zinc fingers (ZF29-30).\",\n      \"method\": \"Protein binding assays and functional transactivation assays; nuclear localization confirmed by cellular fractionation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assays and functional transactivation data from single lab, multiple interactions demonstrated\",\n      \"pmids\": [\"12393497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The terminal six zinc fingers (C-terminal domain) of ZNF423/Evi3 are required for modulation of EBF transcriptional activity, as shown by domain deletion analysis in transactivation assays; Evi3 overexpression in tumors upregulates EBF target genes CD19 and CD38.\",\n      \"method\": \"Transactivation reporter assay with deletion constructs; reconstitution in primary leukemia cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mapping with reporter assays and primary cell reconstitution, single lab\",\n      \"pmids\": [\"15580294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ZNF423 is essential for retinoic acid (RA)-induced differentiation in neuroblastoma cells; it physically associates with the RARα/RXRα nuclear receptor complex and is required for transactivation in response to retinoids. RNAi knockdown confers RA resistance and growth advantage; overexpression leads to growth inhibition and enhanced differentiation.\",\n      \"method\": \"Large-scale RNAi screen; co-immunoprecipitation (ZNF423 with RARα/RXRα); gain- and loss-of-function in neuroblastoma cell lines\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex, plus bidirectional loss/gain-of-function with defined phenotype, replicated across cell lines\",\n      \"pmids\": [\"19345331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Aberrant expression of Zfp423/ZNF423, cooperating with p210BCR/ABL, promotes blast crisis of CML; ZNF423 increases colony-forming ability in BCR/ABL-expressing bone marrow cells and transplantation causes acute leukemia in mice, demonstrating a functional oncogenic role.\",\n      \"method\": \"Retroviral insertional mutagenesis screen; bone marrow transduction/transplantation; RNAi knockdown in BCR/ABL-positive cells; colony-forming assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo and in vitro functional assays including transplantation model, knockdown, and colony assay, single lab with orthogonal methods\",\n      \"pmids\": [\"19234145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZNF423 functions within the DNA damage response (DDR) pathway; upon induced DNA damage, ZNF423 colocalizes to nuclear foci positive for TIP60 (known to activate ATM at DNA damage sites) together with CEP164 and NPHP10. Knockdown of ZNF423 causes increased sensitivity to DNA damaging agents.\",\n      \"method\": \"Immunofluorescence colocalization to nuclear foci after DNA damage; siRNA knockdown followed by DNA damage sensitivity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence (DDR sensitivity upon KD), multiple partners identified, published in high-impact journal with orthogonal methods\",\n      \"pmids\": [\"22863007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZNF423 acts as an estrogen-inducible transcription factor for BRCA1; ZNF423 transactivates the BRCA1 promoter in an estrogen-dependent manner, and SNPs in ZNF423 intronic sites near estrogen response elements alter this induction.\",\n      \"method\": \"Functional genomics; luciferase reporter assays; estrogen induction experiments in breast cancer cell lines; SNP-dependent variation in transcriptional induction\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and SNP-dependent functional assays, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"23764426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A UBR5-ZNF423 fusion protein (containing exon 1 of UBR5 fused to exons 7–9 of ZNF423, including the C-terminal EBF-binding domain ZF29-30) drives NPC cell proliferation; its knockdown inhibits growth and colony formation, and its ectopic expression in NIH3T3 cells induces anchorage-independent growth and tumor formation in nude mice.\",\n      \"method\": \"Paired-end whole-transcriptome sequencing; fusion-specific siRNA knockdown; NIH3T3 transformation assay; nude mouse tumor formation\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with defined cellular and in vivo phenotypes, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23878065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aberrant ZNF423 (including a novel ZNF423β isoform encoding a NuRD complex-interacting domain) inhibits EBF-1 target gene transactivation and causes B cell maturation arrest in vivo; hypomethylation of ZNF423 regulatory sequences and BMP2 signaling drive ZNF423 expression in B-precursor ALL.\",\n      \"method\": \"Epigenetic analysis (bisulfite sequencing); in vivo B-cell differentiation assays; functional transactivation assays; BMP2 stimulation experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo B-cell maturation arrest demonstrated, epigenetic regulation validated, EBF1 antagonism functionally demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"24081948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZNF423 regulates cell cycle progression and mitotic spindle orientation in cerebellar Purkinje cell progenitors; deletion of distinct ZNF423 zinc-finger domains in vivo causes premature cell cycle exit and loss of the progenitor pool (one domain) or impairs PC differentiation (another domain); DDR markers are upregulated in cerebellar progenitors of both mutants.\",\n      \"method\": \"Allelic series of in-frame zinc finger domain deletions in mice; neuroanatomical analysis; cell cycle marker immunostaining; DDR marker analysis in cerebellar ventricular zone\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple alleles with domain-specific phenotypes, in vivo functional dissection, orthogonal cellular readouts\",\n      \"pmids\": [\"28893945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Epigenetic regulation (promoter DNA methylation and nucleosome occupancy) controls Zfp423/ZNF423 expression and thereby determines adipocyte precursor commitment; BMP4 can initiate these epigenetic changes; demethylation with 5-azacytidine increases ZNF423 expression and induces adipocyte differentiation in otherwise non-adipogenic cells.\",\n      \"method\": \"Bisulfite sequencing; micrococcal nuclease protection assay; 5-azacytidine treatment; Oil Red O differentiation assay; comparison of committed (3T3-L1) vs uncommitted (NIH-3T3) cells\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic measurements with functional rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29067487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZNF423 regulates mitosis-related genes VRK1 and PBK (histone H3 kinases); ZNF423 knockdown decreases VRK1 and PBK expression and activity and enhances docetaxel-induced G2/M arrest and cytotoxicity. The ZNF423 rs9940645 SNP modulates these effects in an estrogen- and tamoxifen-dependent fashion.\",\n      \"method\": \"Chromatin immunoprecipitation; luciferase reporter assays; CRISPR/Cas9-engineered isogenic cell lines; cell cycle analysis; cell viability assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates direct regulation, CRISPR isogenic lines for SNP-dependent effects, single lab\",\n      \"pmids\": [\"30937657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZNF423 acts as an RNA-binding protein that binds AU-rich elements in the 3'-UTR of BCAT1 mRNA to promote autophagy via the IRE1-XBP1-RIDD axis in pulmonary artery smooth muscle cells under hypoxia.\",\n      \"method\": \"RNA-binding assays; co-immunoprecipitation (ZNF423 with BCAT1 mRNA); functional autophagy assays; pathway inhibition experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-binding and Co-IP data with functional readout, single lab, mechanism partially characterized\",\n      \"pmids\": [\"32938905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF423 occupies canonical EBF1-binding sites genome-wide (including in the absence of EBF1), is associated with depletion of activating histone marks at bound loci, specifically disrupts EBF1-dependent transactivation (but not EBF1 repressive/pioneering activities), and represses the TGFB1 promoter by outcompeting EBF1 while also interacting with SMADs. CRISPR-mediated ablation of ZNF423 in a pro-B ALL model decreased cell viability and prolonged mouse survival upon xenotransplantation.\",\n      \"method\": \"ChIP-seq (genome-wide ZNF423 binding); ATAC-seq/histone mark profiling; CRISPR-Cas9 ablation; xenotransplantation; transcriptome analysis; motif analysis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with chromatin landscape profiling, CRISPR functional validation in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33646306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF423 rs9940645 SNP modulates AMPK signaling and metformin response in breast cancer cells in an estrogen- and SERM-dependent fashion; CRISPR-engineered isogenic cell lines with different SNP genotypes showed striking differences in response to metformin alone or combined with tamoxifen, both in vitro and in xenograft models.\",\n      \"method\": \"RNA sequencing; label-free quantitative proteomics; CRISPR/Cas9-engineered isogenic cell lines; xenograft mouse model; pathway enrichment analysis\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR isogenic cells and in vivo xenograft, multi-omics pathway identification, single lab\",\n      \"pmids\": [\"34001842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF423 patient-derived variants and in-frame zinc finger domain deletions modeled in mice reveal allele-dependent ranges of midline brain abnormalities; several variants previously asserted pathogenic appeared benign, while one was effectively null; heterozygous premature termination codons showed mild haploinsufficiency consistent with loss-of-function intolerance.\",\n      \"method\": \"Mouse in vivo modeling of ~50 patient-derived variants; neuroanatomical quantitative analysis of 791 littermate pairs; allelic series\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic in vivo functional validation of multiple variants with quantitative neuroanatomical phenotyping, large sample size, rigorous controls\",\n      \"pmids\": [\"32925911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF423 is a multifunctional 30-zinc-finger transcription factor that operates through several mechanistically distinct modes: it physically associates with RARα/RXRα to mediate retinoic acid-induced differentiation; antagonizes EBF1 transcriptional activity by occupying EBF1-binding sites genome-wide and depleting activating histone marks; binds SMAD1/SMAD4 to transduce BMP signaling; acts as a transcriptional activator of BRCA1 downstream of estrogen receptor signaling; participates in the DNA damage response by colocalizing with TIP60 at nuclear damage foci (loss of ZNF423 sensitizes cells to DNA damaging agents); regulates mitotic spindle orientation and cell cycle progression in neural progenitors through domain-specific zinc-finger activities; promotes adipocyte commitment via epigenetic derepression of its own promoter; and post-transcriptionally stabilizes BCAT1 mRNA via AU-rich element binding to activate autophagy, with its activity modulated by specific SNPs that alter estrogen receptor binding and downstream pathway responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF423 is a multi-zinc-finger transcription factor that integrates several developmental signaling inputs at chromatin, acting as a context-dependent node in differentiation programs and in disease [#0, #2, #12]. Through distinct zinc-finger surfaces it physically engages multiple partners: its terminal fingers (ZF29-30) bind Early B-cell Factor (EBF1/OLF1) to antagonize EBF1 transactivation, while internal regions bind SMAD1 and SMAD4 to transduce BMP signaling toward targets such as Xvent-2 [#0, #5]. Genome-wide, ZNF423 occupies canonical EBF1-binding sites even in the absence of EBF1, depletes activating histone marks at those loci, and selectively blocks EBF1-dependent transactivation, including repression of the TGFB1 promoter [#12]. In neuroblastoma it associates with the RARα/RXRα nuclear receptor complex and is required for retinoic acid-induced differentiation [#2]. ZNF423 also participates in the DNA damage response, colocalizing with TIP60 at nuclear damage foci alongside CEP164 and NPHP10, with its loss sensitizing cells to DNA-damaging agents [#4]. In breast cancer it is an estrogen-inducible activator of the BRCA1 promoter and of the mitotic kinases VRK1 and PBK, with intronic SNPs near estrogen response elements modulating these responses and downstream drug sensitivity [#5, #10]. Beyond DNA-directed roles, ZNF423 acts as an RNA-binding protein that binds AU-rich elements in the BCAT1 3'-UTR to promote autophagy via the IRE1-XBP1-RIDD axis [#11]. Its own expression is controlled epigenetically: promoter DNA methylation and nucleosome occupancy gate adipocyte precursor commitment, and hypomethylation drives aberrant ZNF423 expression in B-precursor ALL where it enforces B-cell maturation arrest [#7, #9]. ZNF423 has both oncogenic activity—cooperating with BCR/ABL in CML blast crisis and acting through a UBR5-ZNF423 fusion in nasopharyngeal carcinoma—and developmental functions, with patient-derived and engineered zinc-finger variants producing allele-dependent midline brain abnormalities in mice [#3, #6, #8, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established ZNF423 as a dual-function transcriptional regulator that bridges EBF antagonism and BMP/SMAD signaling, defining its first molecular partnerships and the domain (ZF29-30) responsible for EBF binding.\",\n      \"evidence\": \"Protein binding and transactivation assays with cellular fractionation\",\n      \"pmids\": [\"12393497\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No genome-wide binding map\", \"Structural basis of SMAD versus EBF engagement undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the C-terminal six zinc fingers as the module required to modulate EBF activity and linked ZNF423 overexpression to upregulation of EBF target genes in tumors, connecting the molecular activity to an oncogenic readout.\",\n      \"evidence\": \"Domain-deletion transactivation reporter assays and reconstitution in primary leukemia cells\",\n      \"pmids\": [\"15580294\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of EBF target derepression at chromatin not addressed\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that ZNF423 is required for retinoic acid-induced differentiation by physically associating with the RARα/RXRα complex, explaining a clinically relevant determinant of neuroblastoma retinoid response.\",\n      \"evidence\": \"Large-scale RNAi screen, reciprocal Co-IP, and bidirectional gain/loss-of-function in neuroblastoma lines\",\n      \"pmids\": [\"19345331\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct target genes of the ZNF423-RAR/RXR complex not defined\", \"Domain mediating nuclear receptor contact unmapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed ZNF423 has a functional oncogenic role, cooperating with p210BCR/ABL to drive CML blast crisis, moving it from a transcriptional regulator to a validated cancer driver.\",\n      \"evidence\": \"Retroviral insertional mutagenesis, bone marrow transduction/transplantation, knockdown and colony assays in mice\",\n      \"pmids\": [\"19234145\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular target program underlying cooperation with BCR/ABL unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed ZNF423 in the DNA damage response by showing it colocalizes with TIP60, CEP164 and NPHP10 at damage foci and that its loss sensitizes cells to genotoxins, revealing a function distinct from its transcriptional roles.\",\n      \"evidence\": \"Immunofluorescence colocalization after DNA damage and siRNA knockdown with damage-sensitivity assays\",\n      \"pmids\": [\"22863007\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether ZNF423 acts catalytically or as scaffold at foci unknown\", \"Direct binding partners at foci not biochemically defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified ZNF423 as an estrogen-inducible transcriptional activator of BRCA1 and showed intronic SNPs near estrogen response elements alter this induction, linking ZNF423 genetics to hormone-responsive transcription.\",\n      \"evidence\": \"Functional genomics, luciferase reporters and estrogen induction in breast cancer cells\",\n      \"pmids\": [\"23764426\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which SNPs alter ER occupancy not fully resolved\", \"Direct versus indirect promoter engagement unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated oncogenic gain-of-function through a UBR5-ZNF423 fusion retaining the EBF-binding ZF29-30 domain, showing the C-terminal module is sufficient to drive transformation and tumor formation.\",\n      \"evidence\": \"Whole-transcriptome sequencing, fusion-specific knockdown, NIH3T3 transformation, and nude mouse tumorigenesis\",\n      \"pmids\": [\"23878065\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Transcriptional targets of the fusion not enumerated\", \"Contribution of UBR5 portion to oncogenicity unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected epigenetic derepression and BMP2 signaling to aberrant ZNF423 expression that drives B-cell maturation arrest, and identified a NuRD-interacting ZNF423β isoform, mechanistically tying ZNF423 to B-precursor ALL.\",\n      \"evidence\": \"Bisulfite sequencing, in vivo B-cell differentiation assays, transactivation and BMP2 stimulation experiments\",\n      \"pmids\": [\"24081948\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Role of the NuRD-interacting domain in repression not isolated\", \"Relative contributions of hypomethylation versus BMP2 not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected domain-specific in vivo functions in cerebellar Purkinje progenitors, showing distinct zinc fingers govern cell-cycle exit, spindle orientation and differentiation, and that DDR markers rise when these are lost.\",\n      \"evidence\": \"Allelic series of in-frame zinc-finger deletions in mice with cell-cycle and DDR marker analysis\",\n      \"pmids\": [\"28893945\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular partners of each zinc-finger domain in progenitors undefined\", \"Link between transcriptional and DDR roles unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that promoter DNA methylation and nucleosome occupancy gate ZNF423 expression to determine adipocyte commitment, with BMP4 initiating these changes, establishing an epigenetic switch upstream of ZNF423.\",\n      \"evidence\": \"Bisulfite sequencing, MNase protection, 5-azacytidine treatment and Oil Red O differentiation assays\",\n      \"pmids\": [\"29067487\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream adipogenic targets of ZNF423 not mapped here\", \"Single-lab cell-line system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined direct ZNF423 transcriptional targets VRK1 and PBK that influence mitotic progression and chemotherapy sensitivity, with a SNP modulating effects in an estrogen/tamoxifen-dependent manner.\",\n      \"evidence\": \"ChIP, luciferase reporters, CRISPR isogenic lines, cell-cycle and viability assays\",\n      \"pmids\": [\"30937657\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of SNP-dependent ER coupling not fully resolved\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an unanticipated post-transcriptional role: ZNF423 acts as an RNA-binding protein recognizing AU-rich elements in BCAT1 mRNA to promote autophagy via the IRE1-XBP1-RIDD axis.\",\n      \"evidence\": \"RNA-binding assays, ZNF423-BCAT1 mRNA Co-IP, and functional autophagy/pathway-inhibition assays\",\n      \"pmids\": [\"32938905\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Domain mediating RNA binding not mapped\", \"Relationship to its DNA-binding functions unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided genome-wide evidence that ZNF423 occupies EBF1 sites independently of EBF1, depletes activating histone marks, selectively disrupts EBF1 transactivation, and is required for pro-B ALL viability in vivo, defining its chromatin mechanism of EBF1 antagonism.\",\n      \"evidence\": \"ChIP-seq, histone-mark/ATAC profiling, CRISPR ablation and xenotransplantation\",\n      \"pmids\": [\"33646306\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cofactors recruited to deplete activating marks not identified\", \"Basis of selective interference with transactivation versus pioneering activity unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the rs9940645 SNP genotype reprograms AMPK signaling and metformin response in an estrogen/SERM-dependent manner, linking ZNF423 genetic variation to therapeutic outcome.\",\n      \"evidence\": \"RNA-seq, quantitative proteomics, CRISPR isogenic lines and xenograft models\",\n      \"pmids\": [\"34001842\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between SNP and AMPK pathway not established\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Systematically resolved which ZNF423 patient variants are functionally consequential, showing allele-dependent midline brain abnormalities and reclassifying several asserted-pathogenic variants as benign, refining genotype-phenotype interpretation.\",\n      \"evidence\": \"In vivo mouse modeling of ~50 variants with quantitative neuroanatomy across 791 littermate pairs\",\n      \"pmids\": [\"32925911\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular consequences of each variant on partner binding not assayed\", \"Human disease mechanism inferred from mouse phenotypes\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZNF423 partitions among its transcriptional (EBF1/SMAD/RAR-RXR/ER), DNA-damage-response, and RNA-binding roles within a single cell, and what governs which function dominates in a given context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No integrated model coupling its chromatin, DDR, and RNA functions\", \"Domain-to-function map incomplete\", \"Structural basis of multi-partner selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8, 9, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EBF1\", \"SMAD1\", \"SMAD4\", \"RARA\", \"RXRA\", \"TIP60\", \"CEP164\", \"NPHP10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}