Affinage

ZNF263

Zinc finger protein 263 · UniProt O14978

Length
683 aa
Mass
77.3 kDa
Annotated
2026-04-28
16 papers in source corpus 12 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF263 is a C2H2 zinc finger transcription factor that functions as both a transcriptional repressor and activator depending on promoter context and cofactor recruitment, operating at the intersection of epigenetic silencing, metabolic regulation, and lineage commitment. As a repressor, ZNF263 binds target promoters and recruits the KAP1/HATS/DNMT corepressor complex to silence genes such as SIX3, EGFR, and heparan sulfate biosynthesis enzymes (HS3ST1, HS3ST3A1) through H3K27me3 deposition and DNA methylation (PMID:32051553, PMID:32277030, PMID:38335093); as an activator, it directly drives transcription of CPT1B, RNF126, and GPSM2, promoting fatty acid oxidation and cell cycle progression (PMID:39500874, PMID:38515383, PMID:41772960). ZNF263 chromatin occupancy is regulated by OGT-mediated O-GlcNAcylation at Ser662, while its protein stability is controlled by ERK-dependent inhibition of ubiquitination downstream of EGFR-MAPK signaling (PMID:37353617, PMID:32051553). In human embryonic stem cells, ZNF263 initiates early differentiation gene expression and dampens the core pluripotency network, and its loss impairs pluripotency dissolution and multi-lineage differentiation (PMID:41193435).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2012 Medium

    Defining ZNF263's DNA-binding specificity resolved its 24-nt consensus motif, establishing that its in vivo binding preference diverges from zinc finger code predictions and enabling downstream target identification.

    Evidence ChIP-seq with de novo motif discovery (ChIPMotifs/MEME/Weeder) and bootstrap resampling

    PMID:22130890

    Open questions at the time
    • Motif computationally derived without systematic biochemical validation of individual zinc finger–base contacts
    • No functional consequence of motif binding assessed
  2. 2019 Medium

    Demonstrating that ZNF263 can function as a transcriptional activator (on the bovine TORC2 promoter) established that ZNF263 is not exclusively a repressor, foreshadowing its context-dependent dual role.

    Evidence EMSA, luciferase reporter assays with serial deletions and site-directed mutagenesis, siRNA knockdown in bovine cells

    PMID:31487963

    Open questions at the time
    • Bovine ortholog context; generalizability to human ZNF263 not directly tested
    • Co-activator partners not identified
  3. 2020 High

    Two studies simultaneously established ZNF263 as a transcriptional repressor that recruits the KAP1/HATS/DNMT corepressor complex to silence target genes (SIX3 and heparan sulfate biosynthesis enzymes), and revealed that ERK-mediated inhibition of ZNF263 ubiquitination stabilizes the protein, linking EGFR-MAPK signaling to ZNF263 activity.

    Evidence Co-IP, ChIP, promoter assays, mutagenesis, siRNA/CRISPR KO, functional anticoagulant assays in glioblastoma and mammalian cell lines

    PMID:32051553 PMID:32277030

    Open questions at the time
    • E3 ubiquitin ligase responsible for ZNF263 turnover not identified
    • Structural basis for KAP1/DNMT recruitment unknown
    • Whether ERK directly phosphorylates ZNF263 or acts indirectly not resolved
  4. 2023 High

    Identification of OGT-mediated O-GlcNAcylation at Ser662 as a requirement for ZNF263 chromatin association revealed a metabolic-sensing mechanism controlling its transcription factor activity.

    Evidence Mass spectrometry PTM site identification, Ser662 mutagenesis, ChIP-seq, Co-IP, in vitro and in vivo functional assays in hepatocellular carcinoma

    PMID:37353617

    Open questions at the time
    • Whether O-GlcNAcylation and ERK-dependent stabilization act on the same or distinct ZNF263 pools is unknown
    • Genome-wide targets specifically dependent on Ser662 modification not fully delineated
  5. 2024 High

    Multiple studies expanded ZNF263's direct target repertoire to include EGFR (repressed via DNMT1-mediated methylation), CPT1B (activated to drive fatty acid oxidation), and RNF126 (co-activated with ZNF31), demonstrating its dual repressor/activator function across diverse cancer contexts.

    Evidence ChIP, Co-IP, luciferase reporters, promoter methylation assays, xenograft models, FAO rate measurements in lung adenocarcinoma and pancreatic cancer cells

    PMID:38335093 PMID:38515383 PMID:39500874

    Open questions at the time
    • Determinants that switch ZNF263 between activator and repressor modes at different promoters remain unclear
    • ZNF31 interaction interface not mapped
    • Whether CPT1B activation requires the same cofactors as repression targets is untested
  6. 2025 High

    Establishing ZNF263 as a regulator of pluripotency exit in human embryonic stem cells showed it directly activates early differentiation genes and dampens the core pluripotency circuitry, placing it in normal developmental biology beyond cancer.

    Evidence Genetic knockout, scRNA-seq, ChIP, chromatin accessibility assays, multi-lineage differentiation assays in hESCs

    PMID:41193435

    Open questions at the time
    • Upstream signals triggering ZNF263 activity during differentiation not identified
    • Whether OGT-dependent O-GlcNAcylation regulates ZNF263 in stem cell context is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular logic governing ZNF263's switch between activator and repressor modes — including which cofactors, post-translational modifications, or chromatin features determine the outcome at a given locus — remains the central unresolved question.
  • No structural information on ZNF263 or its cofactor complexes
  • The E3 ligase mediating ZNF263 ubiquitination is unidentified
  • Genome-wide classification of activator vs. repressor targets with matched cofactor occupancy has not been performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 10 GO:0140110 transcription regulator activity 9
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 1
Partners
DNMT1EGFRERKKAP1OGTZNF31
Complex memberships
KAP1/HATS/DNMT corepressor complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and DNA methylation. ERK, when activated by EGFR-MAPK signaling, binds ZNF263 and abrogates its ubiquitination, leading to ZNF263 stabilization. Co-immunoprecipitation, ChIP, promoter assays, mutagenesis, siRNA knockdown, gain-of-function experiments in glioblastoma cells Oncogene High 32051553
2020 ZNF263 acts as a transcriptional repressor of heparan sulfate biosynthesis genes, including HS3ST1 and HS3ST3A1. CRISPR knockout or siRNA knockdown of ZNF263 dramatically increases expression of these enzymes, enhancing 3-O-sulfation, antithrombin binding, Factor Xa inhibition, and neuropilin-1 binding. CRISPR-mediated knockout, siRNA knockdown, transcriptomics, ChIP-seq (motif analysis), functional heparin anticoagulant assays Proceedings of the National Academy of Sciences of the United States of America High 32277030
2024 ZNF263 binds the EGFR gene promoter and recruits DNMT1 to suppress EGFR transcription via DNA hypermethylation. ZNF263 also interacts with nuclear EGFR protein, impairing the EGFR-STAT5 interaction to enhance AURKA expression, thereby sensitizing lung adenocarcinoma cells to EGFR-targeted therapy. ChIP, Co-IP, promoter methylation assays, luciferase reporter assays, overexpression/knockdown, xenograft animal models Cell reports High 38335093
2023 OGT O-GlcNAcylates ZNF263 at Ser662, which is responsible for ZNF263's chromatin association at candidate gene promoters. This OGT-ZNF263 cooperation activates downstream transcription and drives HCC malignant progression. ChIP-seq, Co-IP, mass spectrometry for PTM site identification, mutagenesis of Ser662, in vitro and in vivo functional assays Oncogene High 37353617
2024 ZNF263 binds the promoter of CPT1B to activate its transcription, thereby enhancing fatty acid β-oxidation and promoting cisplatin resistance in lung adenocarcinoma cells. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, western blot, IC50 assays, FAO rate measurement The pharmacogenomics journal Medium 39500874
2024 ZNF263 acts as a transcriptional activator of RNF126 by binding its promoter. ZNF263 interacts with ZNF31 to co-regulate RNF126 transcription, which promotes ubiquitination-mediated degradation of PTEN, activating AKT/Cyclin D1 and AKT/GSK-3β/β-catenin signaling to drive EMT and drug resistance in pancreatic cancer. ChIP, Co-IP, luciferase reporter assay, siRNA knockdown, overexpression, in vivo xenograft and metastasis models Journal of cellular physiology Medium 38515383
2025 ZNF263 directly initiates expression of early differentiation genes and dampens the core pluripotency circuitry in human embryonic stem cells, promoting pluripotency priming and lineage commitment. ZNF263 deficiency impairs pluripotency dissolution and multi-lineage differentiation, particularly toward ectoderm. Genetic knockout, functional differentiation assays, single-cell transcriptomics (scRNA-seq), ChIP, chromatin accessibility assays Nature communications High 41193435
2021 ZNF263 transcriptionally induces circFOXP1 expression in renal cell carcinoma cells, contributing to the ZNF263/circFOXP1/miR-423-5p/U2AF2 regulatory axis that promotes tumor progression. siRNA knockdown, overexpression, luciferase reporter assay, qRT-PCR Journal of immunology research Low 34514002
2021 ZNF263 binding at a CpG site (cg11797365) in an intron of COL4A3 is associated with regulation of COL4A3 expression in bronchial epithelium; ZNF263 silencing by siRNA affects COL4A3 expression levels. ChIP-seq with qPCR, siRNA knockdown, DNA methylation bead arrays, RNA-seq in bronchial biopsies ERJ open research Medium 34109240
2012 ZNF263 binds to a 24-nucleotide DNA motif that differs from the motif predicted by the zinc finger code in several positions, as determined by de novo ChIP-based motif discovery. ChIP-seq, de novo motif discovery (ChIPMotifs/MEME/Weeder), bootstrap re-sampling Methods in molecular biology Medium 22130890
2019 ZNF263 functions as a transcriptional activator of the bovine TORC2 gene promoter, binding within the core promoter region (-314 to -69 bp upstream of TSS), as confirmed by EMSA with nuclear extracts and luciferase reporter assays with mutated binding sites. Luciferase reporter assay with serial deletions and site-directed mutagenesis, EMSA, siRNA knockdown International journal of molecular sciences Medium 31487963
2024 ZNF263 regulates the expression of LINC00599 via a super-enhancer mechanism in pulmonary arterial smooth muscle cells, contributing to pulmonary hypertension progression. Super-enhancer analysis, transcription factor binding assays (details in preprint) bioRxivpreprint Low
2026 ZNF263 acts as a transcriptional activator of GPSM2 by binding its promoter, activating the cell cycle pathway in a GPSM2-dependent manner to drive invasion, migration, and proliferation in colorectal cancer cells. ChIP, luciferase reporter assay, siRNA knockdown, overexpression, cell invasion/migration assays Acta biochimica et biophysica Sinica Medium 41772960

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263. International journal of molecular sciences 42 31487963
2020 The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. Oncogene 33 32051553
2020 ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 32 32277030
2020 A zinc finger family protein, ZNF263, promotes hepatocellular carcinoma resistance to apoptosis via activation of ER stress-dependent autophagy. Translational oncology 31 32898766
2015 High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases. Clinical epigenetics 31 26339299
2024 Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma. Cell reports 22 38335093
2021 Circular RNA FOXP1 Induced by ZNF263 Upregulates U2AF2 Expression to Accelerate Renal Cell Carcinoma Tumorigenesis and Warburg Effect through Sponging miR-423-5p. Journal of immunology research 20 34514002
2023 Chromatin-associated OGT promotes the malignant progression of hepatocellular carcinoma by activating ZNF263. Oncogene 11 37353617
2024 ZNF263 cooperates with ZNF31 to promote the drug resistance and EMT of pancreatic cancer through transactivating RNF126. Journal of cellular physiology 9 38515383
2021 COL4A3 expression in asthmatic epithelium depends on intronic methylation and ZNF263 binding. ERJ open research 8 34109240
2024 The ZNF263/CPT1B axis regulates fatty acid β-oxidation to affect cisplatin resistance in lung adenocarcinoma. The pharmacogenomics journal 4 39500874
2012 Using ChIPMotifs for de novo motif discovery of OCT4 and ZNF263 based on ChIP-based high-throughput experiments. Methods in molecular biology (Clifton, N.J.) 4 22130890
2023 Bufei Yishen Formula Inhibits the Cell Senescence in COPD by Up-Regulating the ZNF263 and Klotho Expression. International journal of chronic obstructive pulmonary disease 2 37065635
2026 Transcriptional regulation of GPSM2 by ZNF263 in colorectal cancer: implications for tumor aggressiveness. Acta biochimica et biophysica Sinica 0 41772960
2025 Transcription factor ZNF263 primes human embryonic stem cells for pluripotency dissolution and lineage commitment. Nature communications 0 41193435
2023 The underlying mechanism of transcription factor IRF1, PRDM1, and ZNF263 involved in the regulation of NPPB rs3753581 on pulse pressure hypertension. Gene 0 37339722