{"gene":"ZNF143","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":1995,"finding":"Staf (ZNF143 Xenopus ortholog) was cloned and shown to bind a 15 bp activator element in the selenocysteine tRNA gene promoter and activate RNA polymerase III transcription in vivo; the protein contains seven zinc fingers and a separate acidic activation domain.","method":"Cloning, in vitro binding assays, expression assay in Xenopus oocytes by microinjection","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding assays plus in vivo functional validation in oocytes, foundational study replicated by subsequent work","pmids":["7641696"],"is_preprint":false},{"year":1997,"finding":"Staf (ZNF143 ortholog) is required for enhanced transcription of the majority of vertebrate snRNA and snRNA-type genes transcribed by both RNA polymerase II and III; a 19 bp consensus Staf-binding site was derived and shown necessary for activation in vivo.","method":"DNA binding assays, microinjection of mutant genes into Xenopus oocytes, recombinant Staf functional assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo oocyte microinjection combined with in vitro binding assays using recombinant protein, multiple gene targets tested","pmids":["9009278"],"is_preprint":false},{"year":1998,"finding":"Staf contains two physically and functionally distinct activation domains outside the DNA-binding domain: a 93-amino-acid domain with four repeated units selective for mRNA promoters, and an 18-amino-acid domain (with critical Leu-213) selective for Pol II and Pol III snRNA promoters.","method":"In vivo transcription assays with Staf deletion/point mutants in Xenopus oocytes and Drosophila cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vivo functional assays in two heterologous systems, single lab but multiple orthogonal approaches","pmids":["9566884"],"is_preprint":false},{"year":1998,"finding":"Human ZNF143 is 84% identical to Xenopus Staf and constitutes its human ortholog; ZNF143 (and ZNF76) bind the Staf DNA motif with similar affinity, activate transcription from mRNA and snRNA promoters in Drosophila cells and Xenopus oocytes through the Staf binding site, and chimeric proteins carrying a heterologous DNA-binding domain activate Pol II and Pol III promoters.","method":"Gel shift assays, transfection in Drosophila cells, microinjection in Xenopus oocytes using chimeric proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal assays (gel shift, transfection, oocyte injection) with chimeric proteins, established human ortholog identity","pmids":["9705341"],"is_preprint":false},{"year":1999,"finding":"Staf zinc fingers 3–6 constitute the minimal region for high-affinity DNA binding; zinc finger 7 makes no base-specific contacts; zinc finger 1 is required for binding to the Xenopus tRNA(Sec) site but dispensable for the human U6 site, demonstrating flexible utilization of zinc fingers for different target sequences.","method":"Binding site selection, EMSA with truncated Staf zinc finger polypeptides, interference (missing nucleoside) experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biochemical methods (EMSA, binding site selection, nucleoside interference) with systematic truncation mutants, single lab","pmids":["10446199"],"is_preprint":false},{"year":1999,"finding":"Optimal transcriptional activation of the human U6 gene requires zinc fingers 2–7 of Staf plus Oct-1 co-binding, whereas the Xenopus tRNA(Sec) gene needs all seven zinc fingers but not Oct-1; insertion of a zinc finger 1 binding site into the U6 promoter increased Staf binding but interfered with simultaneous Oct-1 binding and reduced transcription.","method":"Xenopus oocyte microinjection, EMSA, missing nucleoside interference with wild-type and mutant promoters","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — combinatorial mutagenesis, in vivo oocyte transcription assays, and biochemical binding assays in a single study","pmids":["10455183"],"is_preprint":false},{"year":2000,"finding":"Staf zinc fingers 1–6 make extensive DNA major groove contacts, predominantly with the non-template strand; zinc fingers 3–6 form the high-affinity core; a structural model of Staf–DNA complexes was proposed based on biochemical mapping and analogy to solved zinc finger–DNA structures.","method":"Binding assays with incremental zinc finger truncations, interference experiments, binding site selection","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical footprinting and interference methods, single lab; no crystal structure","pmids":["10773080"],"is_preprint":false},{"year":2003,"finding":"ZNF143 drives basal and tissue-specific expression of the human transaldolase gene by binding the core promoter (nt −29 to −16); dominant-negative ZNF143 DNA-binding domain abolished promoter activity; overexpression of ZNF143 increased transaldolase enzyme activity; ChIP confirmed in vivo occupancy.","method":"DNase I footprinting, EMSA, reporter assays with mutant promoters, overexpression/dominant-negative transfection, ChIP, enzyme activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (footprinting, EMSA, mutagenesis, dominant-negative, ChIP, enzymatic assay) in a single rigorous study","pmids":["14702349"],"is_preprint":false},{"year":2004,"finding":"STAF/ZNF143 (murine ortholog) binds the aldehyde reductase promoter 5′ element and drives constitutive expression; CHOP competes with STAF for the same binding site and mediates stress-induced induction in the human but not mouse promoter.","method":"Gel-shift assays, ChIP, deletion/mutation reporter analysis, transfection","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal EMSA and ChIP with mutational analysis, single lab, two orthogonal approaches","pmids":["14667815"],"is_preprint":false},{"year":2006,"finding":"A genome-scale in silico and biochemical analysis identified ~1175 conserved ZNF143 binding sites in ~938 mammalian promoters; ChIP confirmed 90% are bona fide ZNF143 targets; the presence of a single ZNF143 binding site is sufficient to direct luciferase reporter expression, suggesting ZNF143 can independently recruit transcription machinery.","method":"Bioinformatics binding-site identification, ChIP across 295 promoters, luciferase reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale ChIP combined with functional reporter assays, single lab, two orthogonal methods","pmids":["17092945"],"is_preprint":false},{"year":2007,"finding":"ZNF143 interacts with tumor suppressor p73 (but not p53); p73 stimulates ZNF143 binding to its recognition site and to cisplatin-modified DNA; ZNF143 directly activates Rad51 and FEN1 transcription; ZNF143 knockdown sensitizes prostate cancer cells to cisplatin.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, drug sensitivity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP combined with functional knockdown, single lab, two orthogonal methods","pmids":["17297437"],"is_preprint":false},{"year":2007,"finding":"ZNF143 (hStaf) is required for transcription of the human BUB1B (BubR1) gene; two conserved ZNF143 binding sites in the BUB1B promoter are indispensable for promoter activity; ZNF143 occupancy on the BUB1B promoter was confirmed by ChIP.","method":"EMSA, mutant reporter transfection assays, ChIP","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, mutagenesis, and ChIP in combination, single lab","pmids":["17478512"],"is_preprint":false},{"year":2007,"finding":"ZNF143 (hStaf) is required for expression of the human TFAM gene; two conserved ZNF143 binding sites were identified by promoter binding assays; mutant reporter assays and ChIP confirmed functional occupancy.","method":"Promoter binding assays, mutant TFAM reporter transfection, ChIP","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assays, mutagenesis, and ChIP, single lab","pmids":["17707600"],"is_preprint":false},{"year":2007,"finding":"ZNF143 activates U6 snRNA transcription from a preassembled chromatin template in vitro and associates with chromatin-modifying proteins including CHD8; CHD8 binds histone H3 dimethylated and trimethylated on K4, resides on the U6 promoter in vivo, and contributes to efficient Pol III transcription.","method":"In vitro chromatin transcription assay, mass spectrometry interactome of Staf/ZNF143, ChIP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro chromatin transcription assay plus MS interactome and ChIP, single lab with multiple orthogonal methods","pmids":["17938208"],"is_preprint":false},{"year":2010,"finding":"ZNF143 controls expression of divergent (bidirectional) gene pairs; ZNF143 binding sites are overrepresented in bidirectional versus unidirectional promoters; ChIP confirmed 93% occupancy; dual reporter assays showed dependence on ZNF143 binding site integrity; ZNF143 per se exhibits inherent bidirectional transcription activity.","method":"In silico binding-site analysis, ChIP, dual luciferase bidirectional reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional reporter assays, single lab, two orthogonal methods","pmids":["21177654"],"is_preprint":false},{"year":2011,"finding":"STAF/ZNF143 binds two conserved sites in the Skp2 promoter (identified by EMSA and ChIP) and is necessary and sufficient for Skp2 promoter activity and adhesion-dependent Skp2 expression; siRNA knockdown of STAF reduces Skp2 mRNA and protein and inhibits proliferation; ectopic Skp2 fully rescues STAF-silencing growth inhibition.","method":"EMSA, ChIP, promoter-reporter transfection, siRNA knockdown, rescue with ectopic Skp2","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, siRNA + rescue), single lab","pmids":["21352097"],"is_preprint":false},{"year":2012,"finding":"ZNF143 transcriptional activator is essential for normal development in zebrafish; morpholino knockdown causes pleiotropic defects (heart, blood, ear, midbrain-hindbrain boundary); rescue requires the amino-terminal activation domains; the pax2a promoter contains two ZNF143 binding sites and is directly activated by ZNF143.","method":"Morpholino knockdown in zebrafish, mRNA rescue with wild-type vs. activation-domain-deleted ZNF143, reporter assays with pax2a promoter","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with domain-specific rescue plus direct promoter assays, published replicated findings in zebrafish development","pmids":["22268977"],"is_preprint":false},{"year":2012,"finding":"ZNF143 promotes GPX1 activity and protects mitochondrial respiratory-deficient cells from oxidative stress; ZNF143 and GPX1 double knockdown showed that ZNF143 upregulates GPX1 activity in the context of mitochondrial dysfunction; ZNF143 also activates the selenocysteine synthesis pathway (SepSecS gene expression) under these conditions.","method":"ZNF143 and GPX1 siRNA knockdown, GPX enzyme activity assays, GSH measurement, gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with enzymatic readout and double-knockdown epistasis, single lab","pmids":["23152058"],"is_preprint":false},{"year":2013,"finding":"ZNF143 co-localizes with HCFC1 at ~5400 active CpG-island promoters in HeLa cells; the DNA sequences underlying HCFC1 binding sites contain ZNF143 (and THAP11) recognition motifs; ~90% of HCFC1-bound promoters are co-occupied by ZNF143.","method":"ChIP-seq for HCFC1 and ZNF143, motif analysis, genomic co-occupancy analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq co-occupancy, single lab, no direct binding/interaction assay","pmids":["23539139"],"is_preprint":false},{"year":2014,"finding":"THAP11 and ZNF143 form a mutually dependent complex with HCFC1 on chromatin; HCF-1 recruitment to E2F-bound promoters is mediated by THAP11 and ZNF143, not E2F directly; disruption of the THAP11/ZNF143/HCF-1 complex reduces expression of cell-cycle control genes, cell proliferation, cell-cycle progression, and cell viability.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, cell proliferation and cell-cycle assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ChIP, and functional knockdown with multiple cellular readouts, single lab with multiple orthogonal methods","pmids":["25437553"],"is_preprint":false},{"year":2015,"finding":"ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements; silencing ZNF143 disrupts chromatin interactions at gene promoters; SNP-mediated alteration of ZNF143 DNA-binding affinity reduces chromatin interactions in a sequence-dependent manner; chromatin interactions alone do not regulate gene expression.","method":"Integration of ChIP-seq with Hi-C/chromatin interaction maps (ENCODE), ZNF143 silencing, SNP analysis as surrogate mutagenesis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus chromatin interaction mapping plus functional silencing, single lab","pmids":["25645053"],"is_preprint":false},{"year":2015,"finding":"The ACTACA submotif, shared by THAP11 and ZNF143, directs recruitment of THAP11 and HCFC1 to ZNF143-occupied loci; position, spacing, and orientation of this submotif relative to the ZNF143 core motif are critical; CRISPR-Cas9 alteration of ACTACA at endogenous promoters altered gene transcription and histone modifications.","method":"Chromosomally integrated synthetic constructs, CRISPR-Cas9 endogenous promoter editing, ChIP, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — CRISPR-Cas9 endogenous mutagenesis combined with ChIP and gene expression, single lab but rigorous endogenous validation","pmids":["26416877"],"is_preprint":false},{"year":2016,"finding":"Mutations in ZNF143 (p.L284* and p.T340I) cause an inborn error of cobalamin metabolism; ZNF143 interacts with HCFC1 (confirmed by proximity biotinylation); ZNF143 regulates expression of the cobalamin trafficking gene MMACHC, as shown by reduced MMACHC expression in patient fibroblasts and in control fibroblasts treated with ZNF143 siRNA.","method":"Whole-exome sequencing, proximity biotinylation (BioID) for ZNF143–HCFC1 interaction, qRT-PCR of MMACHC in patient and siRNA-treated cells","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID interaction plus siRNA functional validation in patient cells, single lab","pmids":["27349184"],"is_preprint":false},{"year":2017,"finding":"ZNF143 binds a conserved CCCAGCAG octameric sequence ~100 bp upstream of the CEBPA transcription start site and activates C/EBPα expression in myeloid cells; mutational analysis showed this 8-bp sequence is crucial for C/EBPα expression; the mechanism in myeloid cells is distinct from that in liver and adipocytes.","method":"Mutational analysis of CEBPA promoter, reporter assays, ChIP, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis, ChIP, and knockdown, single lab, multiple orthogonal approaches","pmids":["28900037"],"is_preprint":false},{"year":2018,"finding":"ZNF143 co-binds with CTCF-Cohesin at chromatin loop anchors and acts as a cofactor of the CTCF-Cohesin complex; siRNA knockdown of ZNF143 in HEK293T cells followed by in situ Hi-C showed that the majority of chromatin loops are lost or weakened after ZNF143 silencing.","method":"siRNA knockdown, in situ Hi-C, computational motif analysis, aggregate peak analysis","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Hi-C after knockdown with computational loop analysis, single lab","pmids":["30120652"],"is_preprint":false},{"year":2020,"finding":"ZNF143 directly activates transcription of MDIG histone demethylase, which reduces H3K9me3 at the CDC6 promoter, thereby activating CDC6 expression and promoting hepatocellular carcinoma cell-cycle progression; ZNF143 knockdown reduces CDC6 and MDIG expression and tumor growth.","method":"ChIP, reporter assays, siRNA/shRNA knockdown, xenograft assays, co-expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with functional knockdown, single lab, multiple orthogonal approaches","pmids":["32312832"],"is_preprint":false},{"year":2020,"finding":"LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with ZNF143 (shown by ChIP-seq and co-immunoprecipitation) and activates downstream targets including adrenergic core regulatory circuitry transcription factors, GSK3B, and L1CAM; this is a let-7-independent transcriptional function.","method":"ChIP-seq, co-immunoprecipitation, overexpression of wild-type vs. let-7-binding-deficient LIN28B mutant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP-seq, single lab, two orthogonal methods","pmids":["32601179"],"is_preprint":false},{"year":2021,"finding":"ZNF143 is a key regulator of CTCF-bound promoter-enhancer loops in the murine genome; ZNF143 and CTCF binding motifs are distributed ~37 bp apart in convergent orientation at many genomic sites; genetic deletion of ZNF143 causes loss of CTCF binding at promoters and enhancers and disrupts promoter-enhancer loops essential for hematopoietic stem and progenitor cell function.","method":"ChIP-seq, Hi-C/chromatin interaction mapping, ZNF143 genetic deletion in mouse, hematopoietic cell functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion with Hi-C and ChIP-seq, multiple orthogonal methods, functional HSC phenotype","pmids":["33397967"],"is_preprint":false},{"year":2024,"finding":"Acute degradation of ZNF143/ZFP143 using an auxin-inducible degron in mouse and human cells shows no general chromatin looping function; a commonly used ZNF143 antibody cross-reacts with CTCF, explaining prior reports linking ZNF143 to loops; ZNF143 specifically activates nuclear-encoded mitochondrial genes and its loss causes severe mitochondrial dysfunction; ZNF143 binds promoters with an extremely stable chromatin dwell time (>20 min) and functions largely independently of CTCF.","method":"Auxin-inducible degron protein degradation, Hi-C/chromatin interaction mapping, GRO-seq/RNA-seq, FRAP/live imaging for dwell time, antibody cross-reactivity validation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — acute degron system with multiple orthogonal readouts (Hi-C, transcriptomics, live imaging), antibody validation; replicated independently in companion paper (PMID 39708803)","pmids":["39708805"],"is_preprint":false},{"year":2024,"finding":"Contrary to prior reports, ZNF143/ZFP143 possesses no general chromatin looping function; it is an essential transcription factor that binds promoters proximally with extremely stable dwell time (>20 min), regulates a subset of mitochondrial and ribosomal genes, and functions largely independently of CTCF.","method":"Dual degron/imaging tags on CTCF and ZNF143, combinatorial acute degradation, Hi-C, live-cell imaging, RNA-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — combinatorial degron system with imaging and genome-wide chromatin/transcriptomic readouts; independently consistent with companion paper (PMID 39708805)","pmids":["39708803"],"is_preprint":false},{"year":2024,"finding":"ZNF143 deletion alters CTCF/cohesin geometry at numerous CTCF sites; ZNF143 is located between CTCF and cohesin and its removal narrows the space between them; ZNF143 and CTCF collaborate in higher-order TAD organization; CTCF depletion enlarges direct ZNF143-mediated chromatin looping at promoter-enhancer sites.","method":"ChIP-seq, Hi-C, genetic deletion of ZNF143, acute CTCF degradation (combinatorial), cohesin ChIP","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and Hi-C with genetic deletion and acute degradation, single lab; some findings contradict higher-confidence 2024 Molecular Cell papers regarding looping","pmids":["38206813"],"is_preprint":false},{"year":2025,"finding":"ZNF143 facilitates RNA polymerase II initiation at target genes; ZNF143 binds promoters of nearly all activated target genes; ZNF143 also directly represses a subset of genes by competing with more efficient activators for promoter access, physically occluding transcription initiation sites and promoter-proximal elements, and acting as a molecular roadblock to RNA polymerases during early elongation.","method":"Rapid ZNF143 degradation (degron), nascent RNA sequencing (GRO-seq/PRO-seq), ChIP-seq, mechanistic analysis of promoter occupancy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — acute degradation combined with nascent transcription assays and ChIP-seq defining molecular mechanism; single lab but multiple rigorous orthogonal methods","pmids":["39676670"],"is_preprint":false}],"current_model":"ZNF143 (human ortholog of Xenopus Staf) is a C2H2 zinc-finger transcription factor that uses zinc fingers 3–6 as its DNA-binding core and two distinct activation domains to directly activate transcription of both protein-coding (Pol II) and small RNA (Pol II/III) genes at thousands of mammalian promoters; it facilitates RNA Pol II initiation as its primary mechanism and can also repress genes by physically occluding promoter elements; it forms a complex with THAP11 and HCFC1 at CpG-island promoters, interacts with the chromatin remodeler CHD8 to activate Pol III transcription from chromatin templates, and interacts with p73 and LIN28B to regulate DNA-repair and oncogenic gene programs; although ZNF143 co-occupies CTCF/cohesin sites and earlier studies implicated it in chromatin looping, rigorous acute-degradation experiments in 2024 established that ZNF143 has no general looping function and instead acts as an essential, promoter-proximal transcriptional regulator with unusually stable chromatin binding, primarily safeguarding expression of nuclear-encoded mitochondrial genes."},"narrative":{"mechanistic_narrative":"ZNF143 (the human ortholog of Xenopus Staf) is a sequence-specific C2H2 zinc-finger transcription factor that directly activates both protein-coding (Pol II) and small nuclear/tRNA-type (Pol II and Pol III) genes across thousands of mammalian promoters [PMID:7641696, PMID:9009278, PMID:9705341, PMID:17092945]. It recognizes its target motif through a zinc-finger array in which fingers 3–6 form the high-affinity DNA-binding core, with peripheral fingers selectively deployed for different sites, and it drives transcription through two physically and functionally distinct activation domains — one selective for mRNA promoters and an Oct-1-dependent activity at snRNA promoters [PMID:9566884, PMID:10446199, PMID:10455183]. Mechanistically, ZNF143 facilitates RNA polymerase II initiation at nearly all activated target genes, and at a subset of loci it represses transcription by competing with stronger activators and physically occluding promoter-proximal elements [PMID:39676670]; it can activate Pol III transcription from chromatin templates, associating with the chromatin remodeler CHD8 at the U6 promoter [PMID:17938208]. ZNF143 forms a mutually dependent complex with THAP11 and HCFC1 at active CpG-island promoters, where it recruits HCF-1 to control cell-cycle gene expression and proliferation [PMID:23539139, PMID:25437553, PMID:26416877], and it cooperates with partners including p73 to activate DNA-repair genes and LIN28B to drive oncogenic transcriptional programs [PMID:17297437, PMID:32601179]. Its target genes encompass metabolic, cell-cycle, and developmental regulators — including transaldolase, BUB1B, TFAM, Skp2, CEBPA, and the developmental gene pax2a — and ZNF143 is essential for normal vertebrate development [PMID:14702349, PMID:17478512, PMID:17707600, PMID:21352097, PMID:22268977, PMID:28900037]. Although ZNF143 co-occupies CTCF/cohesin sites and was implicated in chromatin looping [PMID:25645053, PMID:30120652, PMID:33397967], acute-degradation experiments established that it has no general looping function — prior associations were confounded by antibody cross-reactivity with CTCF — and showed instead that ZNF143 is an essential promoter-proximal transcriptional regulator with unusually stable chromatin binding (dwell time >20 min) that safeguards expression of nuclear-encoded mitochondrial genes [PMID:39708805, PMID:39708803]. Mutations in ZNF143 cause an inborn error of cobalamin metabolism through loss of MMACHC regulation [PMID:27349184].","teleology":[{"year":1995,"claim":"Established the founding activity by showing the protein is a DNA-binding activator of an RNA Pol III gene, defining ZNF143/Staf as a transcription factor rather than a generic zinc-finger protein.","evidence":"Cloning and in vitro binding plus Xenopus oocyte microinjection of the selenocysteine tRNA promoter","pmids":["7641696"],"confidence":"High","gaps":["Restricted to a single tRNA target","No mammalian validation yet","Activation domain architecture undefined"]},{"year":1997,"claim":"Generalized the activator role across the snRNA gene class transcribed by both Pol II and Pol III, defining a consensus binding site and showing it is necessary for activation.","evidence":"DNA-binding assays and oocyte microinjection of mutant snRNA-type genes","pmids":["9009278"],"confidence":"High","gaps":["Did not address protein-coding promoters","Human ortholog not yet established"]},{"year":1998,"claim":"Resolved how a single factor activates distinct promoter classes by mapping two separable activation domains, and confirmed human ZNF143 is the functional Staf ortholog.","evidence":"Deletion/point mutagenesis with in vivo transcription in oocytes and Drosophila cells; gel shift and chimeric-protein assays","pmids":["9566884","9705341"],"confidence":"High","gaps":["Coactivators bridging activation domains to the machinery unknown","Promoter selectivity mechanism of each domain unresolved"]},{"year":2000,"claim":"Defined the DNA-recognition logic by mapping the zinc-finger array, showing fingers 3–6 form the high-affinity core and peripheral fingers are deployed flexibly per target.","evidence":"Incremental zinc-finger truncations, EMSA, missing-nucleoside interference, and a model based on solved analogous structures","pmids":["10446199","10455183","10773080"],"confidence":"High","gaps":["No crystal structure of the ZNF143–DNA complex","Structural basis of Oct-1 cooperativity inferred, not solved"]},{"year":2007,"claim":"Expanded the target repertoire to specific protein-coding genes and revealed partner-dependent functions in DNA repair and cell-cycle control.","evidence":"ChIP, EMSA, reporter mutagenesis on transaldolase, BUB1B, TFAM; co-IP with p73 and knockdown/drug-sensitivity assays; in vitro chromatin transcription and CHD8 interactome","pmids":["14702349","17478512","17707600","17297437","17938208"],"confidence":"High","gaps":["Whether p73 stimulation is direct or via cofactors not fully resolved","CHD8 recruitment mechanism to ZNF143 sites unclear"]},{"year":2013,"claim":"Placed ZNF143 in a defined nuclear protein complex by showing co-occupancy with HCFC1 at thousands of CpG-island promoters and motif-driven recruitment of THAP11/HCF-1.","evidence":"ChIP-seq co-occupancy with HCFC1 and motif analysis; reciprocal co-IP, ChIP, and proliferation/cell-cycle knockdown assays; CRISPR editing of the ACTACA submotif","pmids":["23539139","25437553","26416877"],"confidence":"High","gaps":["Stoichiometry and assembly order of the THAP11/ZNF143/HCFC1 complex","How the complex modifies the transcription machinery"]},{"year":2015,"claim":"Linked ZNF143 occupancy to three-dimensional genome organization, reporting preferential binding at chromatin-interaction anchors and CTCF/cohesin co-binding.","evidence":"Integration of ChIP-seq with Hi-C, ZNF143 silencing, SNP and motif analyses across human and mouse genomes","pmids":["25645053","30120652","33397967"],"confidence":"High","gaps":["Knockdown/deletion approaches could not separate looping cause from transcriptional consequence","Antibody specificity not yet questioned"]},{"year":2016,"claim":"Connected ZNF143 to human disease by identifying causative mutations in an inborn error of cobalamin metabolism acting through loss of MMACHC regulation.","evidence":"Whole-exome sequencing, BioID confirmation of HCFC1 interaction, and qRT-PCR of MMACHC in patient and siRNA-treated fibroblasts","pmids":["27349184"],"confidence":"Medium","gaps":["Whether the two mutations act via the same molecular defect not dissected","Broader phenotypic spectrum of ZNF143 deficiency unknown"]},{"year":2020,"claim":"Extended ZNF143 into oncogenic transcriptional programs, showing it activates MDIG/CDC6 in hepatocellular carcinoma and serves as a chromatin-docking partner for LIN28B in neuroblastoma.","evidence":"ChIP, reporter and knockdown assays with xenografts; ChIP-seq and co-IP with let-7-binding-deficient LIN28B mutant","pmids":["32312832","32601179"],"confidence":"Medium","gaps":["Direct versus indirect contribution of ZNF143 to LIN28B target activation","Generality of these programs beyond the studied cancers"]},{"year":2024,"claim":"Overturned the looping model using acute degradation and antibody validation, establishing ZNF143 as a stably bound promoter-proximal transcription factor that safeguards nuclear-encoded mitochondrial genes rather than mediating loops.","evidence":"Auxin-inducible degron in mouse and human cells, Hi-C, GRO-seq/RNA-seq, FRAP dwell-time imaging, and demonstration of antibody cross-reactivity with CTCF; combinatorial dual-degron of CTCF and ZNF143","pmids":["39708805","39708803","38206813"],"confidence":"High","gaps":["How extremely stable promoter dwell time is achieved mechanistically","Residual ZNF143 contribution to CTCF/cohesin geometry remains debated across 2024 reports"]},{"year":2025,"claim":"Defined the molecular mode of action by showing ZNF143 facilitates Pol II initiation at activated genes and represses others by occluding promoter-proximal elements as a polymerase roadblock.","evidence":"Rapid degron depletion with nascent RNA sequencing (GRO-seq/PRO-seq) and ChIP-seq analysis of promoter occupancy","pmids":["39676670"],"confidence":"High","gaps":["Identity of the general initiation factors ZNF143 recruits not pinned down","Determinants distinguishing activated from repressed targets unclear"]},{"year":null,"claim":"It remains unknown how ZNF143's two activation domains and its THAP11/HCFC1 complex mechanistically engage the Pol II/III initiation machinery to produce its activating versus repressive outcomes.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of ZNF143 bound to promoter DNA or to the THAP11/HCFC1 complex","Direct biochemical link between ZNF143 and basal initiation factors undefined","Mechanism of its unusually stable chromatin dwell time unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,9,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,5,6,7]},{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,18,28]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[13,21]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3,9,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,15,19,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,27]}],"complexes":["THAP11/ZNF143/HCFC1 complex"],"partners":["THAP11","HCFC1","CHD8","P73","LIN28B","CTCF","OCT-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52747","full_name":"Zinc finger protein 143","aliases":["SPH-binding factor","Selenocysteine tRNA gene transcription-activating factor","hStaf"],"length_aa":638,"mass_kda":68.9,"function":"Transcription factor that activates expression of genes transcribed by both RNA polymerases II and III, and which is required to safeguard mitochondrial activity (PubMed:10893243, PubMed:14702349, PubMed:17938208, PubMed:26416877, PubMed:39708803, PubMed:9705341, PubMed:9776743). Specifically recognizes and binds the Staf-binding site (SBS), a consensus DNA-binding motif present in thousands of promoters (PubMed:17092945, PubMed:21177654, PubMed:23408857, PubMed:9705341). Activates the gene for selenocysteine tRNA (tRNAsec) (PubMed:23152058). Activates expression of small nuclear RNA (snRNA) transcribed by RNA polymerases II and III (PubMed:17938208, PubMed:9776743). Also activates expression of mRNAs and acts as a key regulator of cell proliferation and differentiation by specifically activating expression of a subset of nuclear-encoded mitochondrial genes, thereby controlling mitochondrial function (By similarity). Involved in the maintenance of embryonic stem cells by promoting association of POU5F1/OCT4 to promoters, leading to NANOG expresion (By similarity)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/P52747/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF143","classification":"Not Classified","n_dependent_lines":235,"n_total_lines":1208,"dependency_fraction":0.1945364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF143","total_profiled":1310},"omim":[{"mim_id":"606148","title":"FATTY ACID DESATURASE 1; FADS1","url":"https://www.omim.org/entry/606148"},{"mim_id":"603433","title":"ZINC FINGER PROTEIN 143; ZNF143","url":"https://www.omim.org/entry/603433"},{"mim_id":"194549","title":"ZINC FINGER PROTEIN 76; ZNF76","url":"https://www.omim.org/entry/194549"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF143"},"hgnc":{"alias_symbol":["SBF","pHZ-1","STAF"],"prev_symbol":[]},"alphafold":{"accession":"P52747","domains":[{"cath_id":"3.30.160.60","chopping":"238-279","consensus_level":"high","plddt":81.3748,"start":238,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52747","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52747-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52747-F1-predicted_aligned_error_v6.png","plddt_mean":49.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF143","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF143"},"sequence":{"accession":"P52747","fasta_url":"https://rest.uniprot.org/uniprotkb/P52747.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52747/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52747"}},"corpus_meta":[{"pmid":"11206552","id":"PMC_11206552","title":"Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11206552","citation_count":816,"is_preprint":false},{"pmid":"15210110","id":"PMC_15210110","title":"Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15210110","citation_count":318,"is_preprint":false},{"pmid":"9065400","id":"PMC_9065400","title":"SBF cell cycle regulator as a target of the yeast PKC-MAP kinase pathway.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9065400","citation_count":220,"is_preprint":false},{"pmid":"25645053","id":"PMC_25645053","title":"ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25645053","citation_count":148,"is_preprint":false},{"pmid":"19682934","id":"PMC_19682934","title":"Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19682934","citation_count":146,"is_preprint":false},{"pmid":"11378012","id":"PMC_11378012","title":"Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. 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Part 1: Syntheses, thermochemical and vibrational characterizations, and molecular structures as [Sb(2)F(11)](-) and [SbF(6)](-) salts. 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C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/27772726","citation_count":20,"is_preprint":false},{"pmid":"9535833","id":"PMC_9535833","title":"Molecular cloning and characterization of the murine staf cDNA encoding a transcription activating factor for the selenocysteine tRNA gene in mouse mammary gland.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9535833","citation_count":19,"is_preprint":false},{"pmid":"22525724","id":"PMC_22525724","title":"SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3.","date":"2012","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22525724","citation_count":19,"is_preprint":false},{"pmid":"26721204","id":"PMC_26721204","title":"Blockade of the interaction between Bcr-Abl and PTB1B by small molecule SBF-1 to overcome imatinib-resistance of chronic myeloid leukemia cells.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26721204","citation_count":19,"is_preprint":false},{"pmid":"23980633","id":"PMC_23980633","title":"Biomineralization of hydroxyapatite on DNA molecules in SBF: morphological features and computer simulation.","date":"2013","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/23980633","citation_count":19,"is_preprint":false},{"pmid":"22664458","id":"PMC_22664458","title":"Calcium phosphate-mediated gene delivery using simulated body fluid (SBF).","date":"2012","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/22664458","citation_count":19,"is_preprint":false},{"pmid":"2419423","id":"PMC_2419423","title":"Suppression of a pokeweed mitogen-stimulated plaque-forming cell response by a human B lymphocyte-derived aggregated IgG-stimulated suppressor factor: suppressive B cell factor (SBF).","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2419423","citation_count":19,"is_preprint":false},{"pmid":"21352097","id":"PMC_21352097","title":"Adhesion-dependent Skp2 transcription requires selenocysteine tRNA gene transcription-activating factor (STAF).","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21352097","citation_count":18,"is_preprint":false},{"pmid":"17707600","id":"PMC_17707600","title":"Transcription factor hStaf/ZNF143 is required for expression of the human TFAM gene.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17707600","citation_count":18,"is_preprint":false},{"pmid":"16809780","id":"PMC_16809780","title":"Cell cycle-dependent regulation of Saccharomyces cerevisiae donor preference during mating-type switching by SBF (Swi4/Swi6) and Fkh1.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16809780","citation_count":18,"is_preprint":false},{"pmid":"32076462","id":"PMC_32076462","title":"ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis.","date":"2020","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/32076462","citation_count":17,"is_preprint":false},{"pmid":"24213117","id":"PMC_24213117","title":"Forced Expression of ZNF143 Restrains Cancer Cell Growth.","date":"2011","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/24213117","citation_count":17,"is_preprint":false},{"pmid":"28900037","id":"PMC_28900037","title":"ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPα.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28900037","citation_count":17,"is_preprint":false},{"pmid":"6350167","id":"PMC_6350167","title":"Suppressive B-cell factor (SBF) produced by FcR-bearing B cells; suppression of B, but not non-B-cell proliferation.","date":"1983","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6350167","citation_count":17,"is_preprint":false},{"pmid":"6263976","id":"PMC_6263976","title":"Biologic and molecular characterization of the IgG serum blocking factor (SBF-IgG) isolated from sera of patients with EBV-induced infectious mononucleosis.","date":"1981","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6263976","citation_count":17,"is_preprint":false},{"pmid":"38206813","id":"PMC_38206813","title":"ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38206813","citation_count":16,"is_preprint":false},{"pmid":"33649401","id":"PMC_33649401","title":"3D reconstruction of structures of hatched larva and young juvenile of the larvacean Oikopleura dioica using SBF-SEM.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33649401","citation_count":16,"is_preprint":false},{"pmid":"39708805","id":"PMC_39708805","title":"ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39708805","citation_count":15,"is_preprint":false},{"pmid":"30935019","id":"PMC_30935019","title":"The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1⁻p53⁻Beclin1 Axis Under Metabolic Stress.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30935019","citation_count":15,"is_preprint":false},{"pmid":"33255086","id":"PMC_33255086","title":"Solution combustion synthesis (SCS) of theranostic ions doped biphasic calcium phosphates; kinetic of ions release in simulated body fluid (SBF) and reactive oxygen species (ROS) generation.","date":"2020","source":"Materials science & engineering. C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/33255086","citation_count":15,"is_preprint":false},{"pmid":"10773080","id":"PMC_10773080","title":"Structural organization of Staf-DNA complexes.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10773080","citation_count":14,"is_preprint":false},{"pmid":"27414788","id":"PMC_27414788","title":"[ZNF143 is involved in CTCF-mediated chromatin interactions by cooperation with cohesin and other partners].","date":"2016","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/27414788","citation_count":14,"is_preprint":false},{"pmid":"29853074","id":"PMC_29853074","title":"Fabrication and biological properties of calcium phosphate/chitosan composite coating on titanium in modified SBF.","date":"2018","source":"Materials science & engineering. C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/29853074","citation_count":14,"is_preprint":false},{"pmid":"37566742","id":"PMC_37566742","title":"ZNF143 inhibits hepatocyte mitophagy and promotes non-alcoholic fatty liver disease by targeting increased lncRNA NEAT1 expression to activate ROCK2 pathway.","date":"2023","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37566742","citation_count":13,"is_preprint":false},{"pmid":"30885238","id":"PMC_30885238","title":"Expression of zinc finger transcription factors (ZNF143 and ZNF281) in serous borderline ovarian tumors and low-grade ovarian cancers.","date":"2019","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/30885238","citation_count":13,"is_preprint":false},{"pmid":"35780101","id":"PMC_35780101","title":"The role of ZNF143 overexpression in rat liver cell proliferation.","date":"2022","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35780101","citation_count":12,"is_preprint":false},{"pmid":"35847937","id":"PMC_35847937","title":"FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35847937","citation_count":12,"is_preprint":false},{"pmid":"18231587","id":"PMC_18231587","title":"A novel genetic screen implicates Elm1 in the inactivation of the yeast transcription factor SBF.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18231587","citation_count":12,"is_preprint":false},{"pmid":"21479638","id":"PMC_21479638","title":"Hydrolysis of monetite/chitosan composites in α-MEM and SBF solutions.","date":"2011","source":"Journal of materials science. Materials in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21479638","citation_count":12,"is_preprint":false},{"pmid":"31969120","id":"PMC_31969120","title":"Two paralogous znf143 genes in zebrafish encode transcriptional activator proteins with similar functions but expressed at different levels during early development.","date":"2020","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31969120","citation_count":11,"is_preprint":false},{"pmid":"33254959","id":"PMC_33254959","title":"Bioactivity in SBF versus trace element effects: The isolated role of Mg2+ and Zn2+ in osteoblast behavior.","date":"2020","source":"Materials science & engineering. C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/33254959","citation_count":11,"is_preprint":false},{"pmid":"37423952","id":"PMC_37423952","title":"ZNF143 facilitates the growth and migration of glioma cells by regulating KPNA2-mediated Hippo signalling.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37423952","citation_count":10,"is_preprint":false},{"pmid":"33031894","id":"PMC_33031894","title":"The ubiquitous transcriptional protein ZNF143 activates a diversity of genes while assisting to organize chromatin structure.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/33031894","citation_count":10,"is_preprint":false},{"pmid":"35400998","id":"PMC_35400998","title":"ZNF143 Expression is Associated with COPD and Tumor Microenvironment in Non-Small Cell Lung Cancer.","date":"2022","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/35400998","citation_count":9,"is_preprint":false},{"pmid":"22393365","id":"PMC_22393365","title":"Yeast IME2 functions early in meiosis upstream of cell cycle-regulated SBF and MBF targets.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22393365","citation_count":9,"is_preprint":false},{"pmid":"39676670","id":"PMC_39676670","title":"ZNF143 binds DNA and stimulates transcription initiation to activate and repress direct target genes.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39676670","citation_count":8,"is_preprint":false},{"pmid":"30415825","id":"PMC_30415825","title":"SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells.","date":"2018","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30415825","citation_count":8,"is_preprint":false},{"pmid":"33411211","id":"PMC_33411211","title":"Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells.","date":"2021","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/33411211","citation_count":8,"is_preprint":false},{"pmid":"6360850","id":"PMC_6360850","title":"Monoclonal SBF produced by a hybridoma: in-vitro and in-vivo suppression of B tumour-cell proliferation.","date":"1983","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6360850","citation_count":8,"is_preprint":false},{"pmid":"3485142","id":"PMC_3485142","title":"Decreased suppressive B cell factor (SBF) in rheumatoid arthritis: evidence for a defect in B cell autoregulation.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3485142","citation_count":8,"is_preprint":false},{"pmid":"19943282","id":"PMC_19943282","title":"The protonation of HSO(3)F: preparation and characterization of fluorodihydroxyoxosulfonium hexafluoroantimonate [H(2)SO(3)F](+)[SbF(6)](-).","date":"2010","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/19943282","citation_count":8,"is_preprint":false},{"pmid":"38642782","id":"PMC_38642782","title":"CXXC5 drove inflammation and ovarian cancer proliferation via transcriptional activation of ZNF143 and EGR1.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38642782","citation_count":7,"is_preprint":false},{"pmid":"37158648","id":"PMC_37158648","title":"ATF1 promotes the malignancy of lung adenocarcinoma cells by transcriptionally regulating ZNF143 expression.","date":"2023","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37158648","citation_count":7,"is_preprint":false},{"pmid":"11670618","id":"PMC_11670618","title":"On the Reaction of Phosphorous Acid with Superacids and the Crystal Structure of H(5)O(2)(+)SbF(6)(-) and Me(4)N(+)HPF(5)(-).","date":"1998","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670618","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49791,"output_tokens":7598,"usd":0.131671,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17078,"output_tokens":4197,"usd":0.095158,"stage2_stop_reason":"end_turn"},"total_usd":0.226829,"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\": 1995,\n      \"finding\": \"Staf (ZNF143 Xenopus ortholog) was cloned and shown to bind a 15 bp activator element in the selenocysteine tRNA gene promoter and activate RNA polymerase III transcription in vivo; the protein contains seven zinc fingers and a separate acidic activation domain.\",\n      \"method\": \"Cloning, in vitro binding assays, expression assay in Xenopus oocytes by microinjection\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding assays plus in vivo functional validation in oocytes, foundational study replicated by subsequent work\",\n      \"pmids\": [\"7641696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Staf (ZNF143 ortholog) is required for enhanced transcription of the majority of vertebrate snRNA and snRNA-type genes transcribed by both RNA polymerase II and III; a 19 bp consensus Staf-binding site was derived and shown necessary for activation in vivo.\",\n      \"method\": \"DNA binding assays, microinjection of mutant genes into Xenopus oocytes, recombinant Staf functional assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo oocyte microinjection combined with in vitro binding assays using recombinant protein, multiple gene targets tested\",\n      \"pmids\": [\"9009278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Staf contains two physically and functionally distinct activation domains outside the DNA-binding domain: a 93-amino-acid domain with four repeated units selective for mRNA promoters, and an 18-amino-acid domain (with critical Leu-213) selective for Pol II and Pol III snRNA promoters.\",\n      \"method\": \"In vivo transcription assays with Staf deletion/point mutants in Xenopus oocytes and Drosophila cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vivo functional assays in two heterologous systems, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"9566884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human ZNF143 is 84% identical to Xenopus Staf and constitutes its human ortholog; ZNF143 (and ZNF76) bind the Staf DNA motif with similar affinity, activate transcription from mRNA and snRNA promoters in Drosophila cells and Xenopus oocytes through the Staf binding site, and chimeric proteins carrying a heterologous DNA-binding domain activate Pol II and Pol III promoters.\",\n      \"method\": \"Gel shift assays, transfection in Drosophila cells, microinjection in Xenopus oocytes using chimeric proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal assays (gel shift, transfection, oocyte injection) with chimeric proteins, established human ortholog identity\",\n      \"pmids\": [\"9705341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Staf zinc fingers 3–6 constitute the minimal region for high-affinity DNA binding; zinc finger 7 makes no base-specific contacts; zinc finger 1 is required for binding to the Xenopus tRNA(Sec) site but dispensable for the human U6 site, demonstrating flexible utilization of zinc fingers for different target sequences.\",\n      \"method\": \"Binding site selection, EMSA with truncated Staf zinc finger polypeptides, interference (missing nucleoside) experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biochemical methods (EMSA, binding site selection, nucleoside interference) with systematic truncation mutants, single lab\",\n      \"pmids\": [\"10446199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Optimal transcriptional activation of the human U6 gene requires zinc fingers 2–7 of Staf plus Oct-1 co-binding, whereas the Xenopus tRNA(Sec) gene needs all seven zinc fingers but not Oct-1; insertion of a zinc finger 1 binding site into the U6 promoter increased Staf binding but interfered with simultaneous Oct-1 binding and reduced transcription.\",\n      \"method\": \"Xenopus oocyte microinjection, EMSA, missing nucleoside interference with wild-type and mutant promoters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — combinatorial mutagenesis, in vivo oocyte transcription assays, and biochemical binding assays in a single study\",\n      \"pmids\": [\"10455183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Staf zinc fingers 1–6 make extensive DNA major groove contacts, predominantly with the non-template strand; zinc fingers 3–6 form the high-affinity core; a structural model of Staf–DNA complexes was proposed based on biochemical mapping and analogy to solved zinc finger–DNA structures.\",\n      \"method\": \"Binding assays with incremental zinc finger truncations, interference experiments, binding site selection\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical footprinting and interference methods, single lab; no crystal structure\",\n      \"pmids\": [\"10773080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ZNF143 drives basal and tissue-specific expression of the human transaldolase gene by binding the core promoter (nt −29 to −16); dominant-negative ZNF143 DNA-binding domain abolished promoter activity; overexpression of ZNF143 increased transaldolase enzyme activity; ChIP confirmed in vivo occupancy.\",\n      \"method\": \"DNase I footprinting, EMSA, reporter assays with mutant promoters, overexpression/dominant-negative transfection, ChIP, enzyme activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (footprinting, EMSA, mutagenesis, dominant-negative, ChIP, enzymatic assay) in a single rigorous study\",\n      \"pmids\": [\"14702349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"STAF/ZNF143 (murine ortholog) binds the aldehyde reductase promoter 5′ element and drives constitutive expression; CHOP competes with STAF for the same binding site and mediates stress-induced induction in the human but not mouse promoter.\",\n      \"method\": \"Gel-shift assays, ChIP, deletion/mutation reporter analysis, transfection\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal EMSA and ChIP with mutational analysis, single lab, two orthogonal approaches\",\n      \"pmids\": [\"14667815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A genome-scale in silico and biochemical analysis identified ~1175 conserved ZNF143 binding sites in ~938 mammalian promoters; ChIP confirmed 90% are bona fide ZNF143 targets; the presence of a single ZNF143 binding site is sufficient to direct luciferase reporter expression, suggesting ZNF143 can independently recruit transcription machinery.\",\n      \"method\": \"Bioinformatics binding-site identification, ChIP across 295 promoters, luciferase reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale ChIP combined with functional reporter assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"17092945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZNF143 interacts with tumor suppressor p73 (but not p53); p73 stimulates ZNF143 binding to its recognition site and to cisplatin-modified DNA; ZNF143 directly activates Rad51 and FEN1 transcription; ZNF143 knockdown sensitizes prostate cancer cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, drug sensitivity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP combined with functional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"17297437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZNF143 (hStaf) is required for transcription of the human BUB1B (BubR1) gene; two conserved ZNF143 binding sites in the BUB1B promoter are indispensable for promoter activity; ZNF143 occupancy on the BUB1B promoter was confirmed by ChIP.\",\n      \"method\": \"EMSA, mutant reporter transfection assays, ChIP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, mutagenesis, and ChIP in combination, single lab\",\n      \"pmids\": [\"17478512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZNF143 (hStaf) is required for expression of the human TFAM gene; two conserved ZNF143 binding sites were identified by promoter binding assays; mutant reporter assays and ChIP confirmed functional occupancy.\",\n      \"method\": \"Promoter binding assays, mutant TFAM reporter transfection, ChIP\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assays, mutagenesis, and ChIP, single lab\",\n      \"pmids\": [\"17707600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZNF143 activates U6 snRNA transcription from a preassembled chromatin template in vitro and associates with chromatin-modifying proteins including CHD8; CHD8 binds histone H3 dimethylated and trimethylated on K4, resides on the U6 promoter in vivo, and contributes to efficient Pol III transcription.\",\n      \"method\": \"In vitro chromatin transcription assay, mass spectrometry interactome of Staf/ZNF143, ChIP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro chromatin transcription assay plus MS interactome and ChIP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17938208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZNF143 controls expression of divergent (bidirectional) gene pairs; ZNF143 binding sites are overrepresented in bidirectional versus unidirectional promoters; ChIP confirmed 93% occupancy; dual reporter assays showed dependence on ZNF143 binding site integrity; ZNF143 per se exhibits inherent bidirectional transcription activity.\",\n      \"method\": \"In silico binding-site analysis, ChIP, dual luciferase bidirectional reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional reporter assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"21177654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STAF/ZNF143 binds two conserved sites in the Skp2 promoter (identified by EMSA and ChIP) and is necessary and sufficient for Skp2 promoter activity and adhesion-dependent Skp2 expression; siRNA knockdown of STAF reduces Skp2 mRNA and protein and inhibits proliferation; ectopic Skp2 fully rescues STAF-silencing growth inhibition.\",\n      \"method\": \"EMSA, ChIP, promoter-reporter transfection, siRNA knockdown, rescue with ectopic Skp2\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, siRNA + rescue), single lab\",\n      \"pmids\": [\"21352097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZNF143 transcriptional activator is essential for normal development in zebrafish; morpholino knockdown causes pleiotropic defects (heart, blood, ear, midbrain-hindbrain boundary); rescue requires the amino-terminal activation domains; the pax2a promoter contains two ZNF143 binding sites and is directly activated by ZNF143.\",\n      \"method\": \"Morpholino knockdown in zebrafish, mRNA rescue with wild-type vs. activation-domain-deleted ZNF143, reporter assays with pax2a promoter\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with domain-specific rescue plus direct promoter assays, published replicated findings in zebrafish development\",\n      \"pmids\": [\"22268977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZNF143 promotes GPX1 activity and protects mitochondrial respiratory-deficient cells from oxidative stress; ZNF143 and GPX1 double knockdown showed that ZNF143 upregulates GPX1 activity in the context of mitochondrial dysfunction; ZNF143 also activates the selenocysteine synthesis pathway (SepSecS gene expression) under these conditions.\",\n      \"method\": \"ZNF143 and GPX1 siRNA knockdown, GPX enzyme activity assays, GSH measurement, gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with enzymatic readout and double-knockdown epistasis, single lab\",\n      \"pmids\": [\"23152058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZNF143 co-localizes with HCFC1 at ~5400 active CpG-island promoters in HeLa cells; the DNA sequences underlying HCFC1 binding sites contain ZNF143 (and THAP11) recognition motifs; ~90% of HCFC1-bound promoters are co-occupied by ZNF143.\",\n      \"method\": \"ChIP-seq for HCFC1 and ZNF143, motif analysis, genomic co-occupancy analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq co-occupancy, single lab, no direct binding/interaction assay\",\n      \"pmids\": [\"23539139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"THAP11 and ZNF143 form a mutually dependent complex with HCFC1 on chromatin; HCF-1 recruitment to E2F-bound promoters is mediated by THAP11 and ZNF143, not E2F directly; disruption of the THAP11/ZNF143/HCF-1 complex reduces expression of cell-cycle control genes, cell proliferation, cell-cycle progression, and cell viability.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, cell proliferation and cell-cycle assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ChIP, and functional knockdown with multiple cellular readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25437553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements; silencing ZNF143 disrupts chromatin interactions at gene promoters; SNP-mediated alteration of ZNF143 DNA-binding affinity reduces chromatin interactions in a sequence-dependent manner; chromatin interactions alone do not regulate gene expression.\",\n      \"method\": \"Integration of ChIP-seq with Hi-C/chromatin interaction maps (ENCODE), ZNF143 silencing, SNP analysis as surrogate mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus chromatin interaction mapping plus functional silencing, single lab\",\n      \"pmids\": [\"25645053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ACTACA submotif, shared by THAP11 and ZNF143, directs recruitment of THAP11 and HCFC1 to ZNF143-occupied loci; position, spacing, and orientation of this submotif relative to the ZNF143 core motif are critical; CRISPR-Cas9 alteration of ACTACA at endogenous promoters altered gene transcription and histone modifications.\",\n      \"method\": \"Chromosomally integrated synthetic constructs, CRISPR-Cas9 endogenous promoter editing, ChIP, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — CRISPR-Cas9 endogenous mutagenesis combined with ChIP and gene expression, single lab but rigorous endogenous validation\",\n      \"pmids\": [\"26416877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in ZNF143 (p.L284* and p.T340I) cause an inborn error of cobalamin metabolism; ZNF143 interacts with HCFC1 (confirmed by proximity biotinylation); ZNF143 regulates expression of the cobalamin trafficking gene MMACHC, as shown by reduced MMACHC expression in patient fibroblasts and in control fibroblasts treated with ZNF143 siRNA.\",\n      \"method\": \"Whole-exome sequencing, proximity biotinylation (BioID) for ZNF143–HCFC1 interaction, qRT-PCR of MMACHC in patient and siRNA-treated cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID interaction plus siRNA functional validation in patient cells, single lab\",\n      \"pmids\": [\"27349184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZNF143 binds a conserved CCCAGCAG octameric sequence ~100 bp upstream of the CEBPA transcription start site and activates C/EBPα expression in myeloid cells; mutational analysis showed this 8-bp sequence is crucial for C/EBPα expression; the mechanism in myeloid cells is distinct from that in liver and adipocytes.\",\n      \"method\": \"Mutational analysis of CEBPA promoter, reporter assays, ChIP, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis, ChIP, and knockdown, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"28900037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZNF143 co-binds with CTCF-Cohesin at chromatin loop anchors and acts as a cofactor of the CTCF-Cohesin complex; siRNA knockdown of ZNF143 in HEK293T cells followed by in situ Hi-C showed that the majority of chromatin loops are lost or weakened after ZNF143 silencing.\",\n      \"method\": \"siRNA knockdown, in situ Hi-C, computational motif analysis, aggregate peak analysis\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Hi-C after knockdown with computational loop analysis, single lab\",\n      \"pmids\": [\"30120652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZNF143 directly activates transcription of MDIG histone demethylase, which reduces H3K9me3 at the CDC6 promoter, thereby activating CDC6 expression and promoting hepatocellular carcinoma cell-cycle progression; ZNF143 knockdown reduces CDC6 and MDIG expression and tumor growth.\",\n      \"method\": \"ChIP, reporter assays, siRNA/shRNA knockdown, xenograft assays, co-expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with functional knockdown, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"32312832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with ZNF143 (shown by ChIP-seq and co-immunoprecipitation) and activates downstream targets including adrenergic core regulatory circuitry transcription factors, GSK3B, and L1CAM; this is a let-7-independent transcriptional function.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, overexpression of wild-type vs. let-7-binding-deficient LIN28B mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP-seq, single lab, two orthogonal methods\",\n      \"pmids\": [\"32601179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF143 is a key regulator of CTCF-bound promoter-enhancer loops in the murine genome; ZNF143 and CTCF binding motifs are distributed ~37 bp apart in convergent orientation at many genomic sites; genetic deletion of ZNF143 causes loss of CTCF binding at promoters and enhancers and disrupts promoter-enhancer loops essential for hematopoietic stem and progenitor cell function.\",\n      \"method\": \"ChIP-seq, Hi-C/chromatin interaction mapping, ZNF143 genetic deletion in mouse, hematopoietic cell functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion with Hi-C and ChIP-seq, multiple orthogonal methods, functional HSC phenotype\",\n      \"pmids\": [\"33397967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Acute degradation of ZNF143/ZFP143 using an auxin-inducible degron in mouse and human cells shows no general chromatin looping function; a commonly used ZNF143 antibody cross-reacts with CTCF, explaining prior reports linking ZNF143 to loops; ZNF143 specifically activates nuclear-encoded mitochondrial genes and its loss causes severe mitochondrial dysfunction; ZNF143 binds promoters with an extremely stable chromatin dwell time (>20 min) and functions largely independently of CTCF.\",\n      \"method\": \"Auxin-inducible degron protein degradation, Hi-C/chromatin interaction mapping, GRO-seq/RNA-seq, FRAP/live imaging for dwell time, antibody cross-reactivity validation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — acute degron system with multiple orthogonal readouts (Hi-C, transcriptomics, live imaging), antibody validation; replicated independently in companion paper (PMID 39708803)\",\n      \"pmids\": [\"39708805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Contrary to prior reports, ZNF143/ZFP143 possesses no general chromatin looping function; it is an essential transcription factor that binds promoters proximally with extremely stable dwell time (>20 min), regulates a subset of mitochondrial and ribosomal genes, and functions largely independently of CTCF.\",\n      \"method\": \"Dual degron/imaging tags on CTCF and ZNF143, combinatorial acute degradation, Hi-C, live-cell imaging, RNA-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — combinatorial degron system with imaging and genome-wide chromatin/transcriptomic readouts; independently consistent with companion paper (PMID 39708805)\",\n      \"pmids\": [\"39708803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF143 deletion alters CTCF/cohesin geometry at numerous CTCF sites; ZNF143 is located between CTCF and cohesin and its removal narrows the space between them; ZNF143 and CTCF collaborate in higher-order TAD organization; CTCF depletion enlarges direct ZNF143-mediated chromatin looping at promoter-enhancer sites.\",\n      \"method\": \"ChIP-seq, Hi-C, genetic deletion of ZNF143, acute CTCF degradation (combinatorial), cohesin ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and Hi-C with genetic deletion and acute degradation, single lab; some findings contradict higher-confidence 2024 Molecular Cell papers regarding looping\",\n      \"pmids\": [\"38206813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF143 facilitates RNA polymerase II initiation at target genes; ZNF143 binds promoters of nearly all activated target genes; ZNF143 also directly represses a subset of genes by competing with more efficient activators for promoter access, physically occluding transcription initiation sites and promoter-proximal elements, and acting as a molecular roadblock to RNA polymerases during early elongation.\",\n      \"method\": \"Rapid ZNF143 degradation (degron), nascent RNA sequencing (GRO-seq/PRO-seq), ChIP-seq, mechanistic analysis of promoter occupancy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — acute degradation combined with nascent transcription assays and ChIP-seq defining molecular mechanism; single lab but multiple rigorous orthogonal methods\",\n      \"pmids\": [\"39676670\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF143 (human ortholog of Xenopus Staf) is a C2H2 zinc-finger transcription factor that uses zinc fingers 3–6 as its DNA-binding core and two distinct activation domains to directly activate transcription of both protein-coding (Pol II) and small RNA (Pol II/III) genes at thousands of mammalian promoters; it facilitates RNA Pol II initiation as its primary mechanism and can also repress genes by physically occluding promoter elements; it forms a complex with THAP11 and HCFC1 at CpG-island promoters, interacts with the chromatin remodeler CHD8 to activate Pol III transcription from chromatin templates, and interacts with p73 and LIN28B to regulate DNA-repair and oncogenic gene programs; although ZNF143 co-occupies CTCF/cohesin sites and earlier studies implicated it in chromatin looping, rigorous acute-degradation experiments in 2024 established that ZNF143 has no general looping function and instead acts as an essential, promoter-proximal transcriptional regulator with unusually stable chromatin binding, primarily safeguarding expression of nuclear-encoded mitochondrial genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF143 (the human ortholog of Xenopus Staf) is a sequence-specific C2H2 zinc-finger transcription factor that directly activates both protein-coding (Pol II) and small nuclear/tRNA-type (Pol II and Pol III) genes across thousands of mammalian promoters [#0, #1, #3, #9]. It recognizes its target motif through a zinc-finger array in which fingers 3\\u20136 form the high-affinity DNA-binding core, with peripheral fingers selectively deployed for different sites, and it drives transcription through two physically and functionally distinct activation domains \\u2014 one selective for mRNA promoters and an Oct-1-dependent activity at snRNA promoters [#2, #4, #5]. Mechanistically, ZNF143 facilitates RNA polymerase II initiation at nearly all activated target genes, and at a subset of loci it represses transcription by competing with stronger activators and physically occluding promoter-proximal elements [#31]; it can activate Pol III transcription from chromatin templates, associating with the chromatin remodeler CHD8 at the U6 promoter [#13]. ZNF143 forms a mutually dependent complex with THAP11 and HCFC1 at active CpG-island promoters, where it recruits HCF-1 to control cell-cycle gene expression and proliferation [#18, #19, #21], and it cooperates with partners including p73 to activate DNA-repair genes and LIN28B to drive oncogenic transcriptional programs [#10, #26]. Its target genes encompass metabolic, cell-cycle, and developmental regulators \\u2014 including transaldolase, BUB1B, TFAM, Skp2, CEBPA, and the developmental gene pax2a \\u2014 and ZNF143 is essential for normal vertebrate development [#7, #11, #12, #15, #16, #23]. Although ZNF143 co-occupies CTCF/cohesin sites and was implicated in chromatin looping [#20, #24, #27], acute-degradation experiments established that it has no general looping function \\u2014 prior associations were confounded by antibody cross-reactivity with CTCF \\u2014 and showed instead that ZNF143 is an essential promoter-proximal transcriptional regulator with unusually stable chromatin binding (dwell time >20 min) that safeguards expression of nuclear-encoded mitochondrial genes [#28, #29]. Mutations in ZNF143 cause an inborn error of cobalamin metabolism through loss of MMACHC regulation [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding activity by showing the protein is a DNA-binding activator of an RNA Pol III gene, defining ZNF143/Staf as a transcription factor rather than a generic zinc-finger protein.\",\n      \"evidence\": \"Cloning and in vitro binding plus Xenopus oocyte microinjection of the selenocysteine tRNA promoter\",\n      \"pmids\": [\"7641696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Restricted to a single tRNA target\", \"No mammalian validation yet\", \"Activation domain architecture undefined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Generalized the activator role across the snRNA gene class transcribed by both Pol II and Pol III, defining a consensus binding site and showing it is necessary for activation.\",\n      \"evidence\": \"DNA-binding assays and oocyte microinjection of mutant snRNA-type genes\",\n      \"pmids\": [\"9009278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address protein-coding promoters\", \"Human ortholog not yet established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved how a single factor activates distinct promoter classes by mapping two separable activation domains, and confirmed human ZNF143 is the functional Staf ortholog.\",\n      \"evidence\": \"Deletion/point mutagenesis with in vivo transcription in oocytes and Drosophila cells; gel shift and chimeric-protein assays\",\n      \"pmids\": [\"9566884\", \"9705341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators bridging activation domains to the machinery unknown\", \"Promoter selectivity mechanism of each domain unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the DNA-recognition logic by mapping the zinc-finger array, showing fingers 3\\u20136 form the high-affinity core and peripheral fingers are deployed flexibly per target.\",\n      \"evidence\": \"Incremental zinc-finger truncations, EMSA, missing-nucleoside interference, and a model based on solved analogous structures\",\n      \"pmids\": [\"10446199\", \"10455183\", \"10773080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the ZNF143\\u2013DNA complex\", \"Structural basis of Oct-1 cooperativity inferred, not solved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded the target repertoire to specific protein-coding genes and revealed partner-dependent functions in DNA repair and cell-cycle control.\",\n      \"evidence\": \"ChIP, EMSA, reporter mutagenesis on transaldolase, BUB1B, TFAM; co-IP with p73 and knockdown/drug-sensitivity assays; in vitro chromatin transcription and CHD8 interactome\",\n      \"pmids\": [\"14702349\", \"17478512\", \"17707600\", \"17297437\", \"17938208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p73 stimulation is direct or via cofactors not fully resolved\", \"CHD8 recruitment mechanism to ZNF143 sites unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed ZNF143 in a defined nuclear protein complex by showing co-occupancy with HCFC1 at thousands of CpG-island promoters and motif-driven recruitment of THAP11/HCF-1.\",\n      \"evidence\": \"ChIP-seq co-occupancy with HCFC1 and motif analysis; reciprocal co-IP, ChIP, and proliferation/cell-cycle knockdown assays; CRISPR editing of the ACTACA submotif\",\n      \"pmids\": [\"23539139\", \"25437553\", \"26416877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the THAP11/ZNF143/HCFC1 complex\", \"How the complex modifies the transcription machinery\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked ZNF143 occupancy to three-dimensional genome organization, reporting preferential binding at chromatin-interaction anchors and CTCF/cohesin co-binding.\",\n      \"evidence\": \"Integration of ChIP-seq with Hi-C, ZNF143 silencing, SNP and motif analyses across human and mouse genomes\",\n      \"pmids\": [\"25645053\", \"30120652\", \"33397967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Knockdown/deletion approaches could not separate looping cause from transcriptional consequence\", \"Antibody specificity not yet questioned\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ZNF143 to human disease by identifying causative mutations in an inborn error of cobalamin metabolism acting through loss of MMACHC regulation.\",\n      \"evidence\": \"Whole-exome sequencing, BioID confirmation of HCFC1 interaction, and qRT-PCR of MMACHC in patient and siRNA-treated fibroblasts\",\n      \"pmids\": [\"27349184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the two mutations act via the same molecular defect not dissected\", \"Broader phenotypic spectrum of ZNF143 deficiency unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ZNF143 into oncogenic transcriptional programs, showing it activates MDIG/CDC6 in hepatocellular carcinoma and serves as a chromatin-docking partner for LIN28B in neuroblastoma.\",\n      \"evidence\": \"ChIP, reporter and knockdown assays with xenografts; ChIP-seq and co-IP with let-7-binding-deficient LIN28B mutant\",\n      \"pmids\": [\"32312832\", \"32601179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect contribution of ZNF143 to LIN28B target activation\", \"Generality of these programs beyond the studied cancers\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Overturned the looping model using acute degradation and antibody validation, establishing ZNF143 as a stably bound promoter-proximal transcription factor that safeguards nuclear-encoded mitochondrial genes rather than mediating loops.\",\n      \"evidence\": \"Auxin-inducible degron in mouse and human cells, Hi-C, GRO-seq/RNA-seq, FRAP dwell-time imaging, and demonstration of antibody cross-reactivity with CTCF; combinatorial dual-degron of CTCF and ZNF143\",\n      \"pmids\": [\"39708805\", \"39708803\", \"38206813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extremely stable promoter dwell time is achieved mechanistically\", \"Residual ZNF143 contribution to CTCF/cohesin geometry remains debated across 2024 reports\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the molecular mode of action by showing ZNF143 facilitates Pol II initiation at activated genes and represses others by occluding promoter-proximal elements as a polymerase roadblock.\",\n      \"evidence\": \"Rapid degron depletion with nascent RNA sequencing (GRO-seq/PRO-seq) and ChIP-seq analysis of promoter occupancy\",\n      \"pmids\": [\"39676670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the general initiation factors ZNF143 recruits not pinned down\", \"Determinants distinguishing activated from repressed targets unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ZNF143's two activation domains and its THAP11/HCFC1 complex mechanistically engage the Pol II/III initiation machinery to produce its activating versus repressive outcomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of ZNF143 bound to promoter DNA or to the THAP11/HCFC1 complex\", \"Direct biochemical link between ZNF143 and basal initiation factors undefined\", \"Mechanism of its unusually stable chromatin dwell time unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 9, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 5, 6, 7]},\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 18, 28]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [13, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3, 9, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 15, 19, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 27]}\n    ],\n    \"complexes\": [\"THAP11/ZNF143/HCFC1 complex\"],\n    \"partners\": [\"THAP11\", \"HCFC1\", \"CHD8\", \"p73\", \"LIN28B\", \"CTCF\", \"Oct-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}