Affinage

ZBTB24

Zinc finger and BTB domain-containing protein 24 · UniProt O43167

Length
697 aa
Mass
78.3 kDa
Annotated
2026-04-28
47 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZBTB24 is a BTB-zinc finger transcription factor that establishes and maintains DNA methylation at centromeric satellite repeats and gene regulatory regions, functioning as a master regulator of heterochromatin integrity, B cell development, and DNA repair. Its ZF5-8 domains bind a specific 12-bp DNA motif to directly activate target genes including CDCA7, forming the ZBTB24-CDCA7-HELLS axis that maintains CpG methylation at heterochromatin and suppresses totipotent 2C-like reprogramming by silencing the Dux cluster (PMID:30085123, PMID:31226215, PMID:40226918, PMID:39562305). ZBTB24 also recruits DNMT3B to centromeric satellite DNA and gene loci, associates with PARP1 to stimulate auto-PARylation and facilitate LIG4/XRCC4-dependent NHEJ at DNA breaks promoting immunoglobulin class-switch recombination, and controls Il5ra promoter methylation to regulate CD19 signaling and antibody production in B cells (PMID:32865561, PMID:37990035, PMID:39562305). Loss-of-function mutations in any functional domain of ZBTB24—including the BTB domain required for protein stability and the zinc-finger domains required for DNA binding and heterochromatin localization—cause ICF syndrome type 2, characterized by centromeric instability, DNA hypomethylation, and immunodeficiency (PMID:21596365, PMID:41359419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2011 High

    Identification of ZBTB24 as the ICF2 disease gene established that a previously uncharacterized BTB-zinc finger protein is required for juxtacentromeric DNA methylation and immune function.

    Evidence Homozygosity mapping and exome sequencing in multiple unrelated ICF2 families

    PMID:21596365

    Open questions at the time
    • Mechanism by which ZBTB24 controls DNA methylation unknown
    • Target genes and DNA binding specificity undefined
    • Contribution to immunodeficiency versus centromeric instability unresolved
  2. 2013 Medium

    Demonstration that ICF2 missense mutations displace ZBTB24 from pericentromeric heterochromatin established the zinc-finger domains as essential for subnuclear targeting, independent of pre-existing DNA methylation.

    Evidence Immunofluorescence of wild-type and ICF2 mutant Zbtb24 in mouse cells

    PMID:23739126

    Open questions at the time
    • Direct DNA binding of ZBTB24 not demonstrated
    • Mechanism of heterochromatin recognition not resolved
    • Only two mutations tested
  3. 2016 High

    Discovery that ZBTB24 directly activates CDCA7 transcription and that BTB domain loss causes embryonic lethality identified the first direct transcriptional target and demonstrated ZBTB24 is essential for development.

    Evidence Zbtb24 BTB-deletion mouse, transcriptomics, ChIP at CDCA7 promoter, ectopic expression rescue

    PMID:27466202

    Open questions at the time
    • DNA binding motif not yet defined
    • How ZBTB24 connects to the DNA methylation machinery unresolved
    • Role of CDCA7 in methylation maintenance not yet tested
  4. 2018 High

    Genome-wide binding analysis revealed ZBTB24 co-occupies loci with DNMT3B, defined a 12-bp binding motif, and identified multiple direct target genes, while comparative methylomics placed ZBTB24, CDCA7, and HELLS in a shared heterochromatin methylation pathway distinct from DNMT3B.

    Evidence ChIP-seq for ZBTB24 and DNMT3B, motif discovery, genome-wide methylation profiling across all four ICF genotypes

    PMID:29659838 PMID:30085123

    Open questions at the time
    • Structural basis of DNA recognition unknown
    • Whether ZBTB24 directly recruits DNMT3B not tested
    • How the ZBTB24-CDCA7-HELLS axis cooperates mechanistically unresolved
  5. 2019 High

    Crystal structure of ZF5-8 bound to cognate DNA defined the atomic basis of sequence-specific recognition, showed ICF2 mutations abolish binding, and domain dissection separated heterochromatin localization (AT-hook + ZF6) from transcriptional activation (ZF6-7) functions.

    Evidence X-ray crystallography, DNA binding assays with ICF2 mutants, domain deletion and promoter deletion analyses

    PMID:31226215 PMID:31561277

    Open questions at the time
    • Role of ZF1-4 undefined
    • No full-length structure available
    • In vivo validation of domain-specific functions limited
  6. 2020 High

    Discovery that ZBTB24 associates with PARP1, stimulates auto-PARylation, protects PAR chains from degradation, and facilitates LIG4/XRCC4-dependent NHEJ revealed a DNA methylation-independent function in DNA double-strand break repair and immunoglobulin class-switch recombination.

    Evidence Co-IP, PARylation assays, PAR binding assays, recruitment to DNA breaks, CSR assays in ICF2 patient cells and Zbtb24-deficient mice

    PMID:32865561

    Open questions at the time
    • Relative contribution of NHEJ defect versus methylation defect to ICF2 immunodeficiency unknown
    • Whether ZBTB24 PAR binding and DNA binding are mutually exclusive unresolved
    • Structural basis of PAR chain interaction not determined
  7. 2023 High

    Conditional hematopoietic knockout established that ZBTB24 controls Il5ra promoter methylation, linking its loss to IL-5Rα derepression, hyperactive CD19 signaling, and hypogammaglobulinemia—a mechanism confirmed by genetic epistasis with Cd19.

    Evidence Vav-Cre conditional KO mouse, methylation analysis at Il5ra, CD19 phosphorylation assay, Cd19 heterozygous rescue

    PMID:37990035

    Open questions at the time
    • Whether ZBTB24 directly binds the Il5ra promoter not shown
    • Applicability to human ICF2 B cells not confirmed
    • Role of other ZBTB24 targets in B cell dysfunction not dissected
  8. 2024 Medium

    B cell-specific deletion revealed that ZBTB24 is selectively required for B1 (not B2) plasma cell differentiation through maintenance of heme biosynthesis partially via mTORC1, uncovering a metabolic role.

    Evidence B cell-specific CRISPR KO mice, RNA-seq, hemin rescue of B1 differentiation defect

    PMID:39277732

    Open questions at the time
    • Direct transcriptional targets mediating heme pathway control not identified
    • mTORC1 connection is partial and mechanism incomplete
    • Single study; independent replication needed
  9. 2025 High

    Acute degradation and ICF-like mouse models demonstrated that ZBTB24 recruits DNMT3B to centromeric satellite DNA for both establishment and maintenance of methylation, and the ZBTB24-CDCA7-HELLS axis silences the Dux cluster to suppress 2C-like reprogramming, validated by site-specific re-methylation rescue.

    Evidence Auxin-inducible degron in mESCs, constitutive ICF-like mouse, ChIP at satellite DNA, Dux promoter re-methylation in ZBTB24/CDCA7/HELLS-disrupted mESCs

    PMID:39562305 PMID:40226918

    Open questions at the time
    • Whether ZBTB24 physically bridges DNMT3B to chromatin or acts indirectly through CDCA7/HELLS not resolved
    • Relevance of 2C-like derepression to ICF2 patient phenotype unknown
    • Contribution of individual satellite subfamilies to ICF2 centromeric instability not dissected
  10. 2026 Medium

    Identification of BTB domain missense variants causing protein instability and ICF2 established that the BTB domain is essential not only for protein-protein interactions but for overall ZBTB24 protein stability.

    Evidence Patient genotyping, protein stability assays, genome-wide methylation profiling matching verified ICF2 patterns

    PMID:41359419

    Open questions at the time
    • Degradation pathway for unstable ZBTB24 not identified
    • Whether BTB domain mutations affect specific interaction partners not tested
    • Single study with limited number of variants

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether ZBTB24 directly bridges DNMT3B to target chromatin or acts exclusively via CDCA7/HELLS, the structural basis of PAR chain recognition by the zinc-finger domain, and the relative contributions of NHEJ defects versus DNA methylation loss to ICF2 immunodeficiency.
  • No full-length ZBTB24 structure or ZBTB24-DNMT3B co-structure available
  • Relative pathogenic contribution of NHEJ versus methylation defect in ICF2 unknown
  • Whether ZBTB24 has additional transcription-independent roles beyond PARP1/NHEJ not explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 GO:0003677 DNA binding 2 R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 1
Partners
CDCA7DNMT3BHELLSLIG4PARP1XRCC4

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Mutations in ZBTB24 cause ICF syndrome type 2 (ICF2), characterized by hypomethylation of juxtacentromeric repeat sequences, immunodeficiency, and centromeric instability, identifying ZBTB24 as a gene involved in DNA methylation of juxtacentromeric DNA and B cell development. Homozygosity mapping, whole-exome sequencing, and Sanger sequencing in ICF2 patients American journal of human genetics High 21596365
2013 Mouse Zbtb24 proteins carrying ICF2 missense mutations (C383Y or R320X equivalents) are mislocalized from pericentromeric heterochromatin, demonstrating that zinc-finger domains are required for proper intranuclear localization of ZBTB24 to pericentromeric heterochromatin, and that this localization does not require DNA methylation. Immunofluorescence analysis of wild-type and mutant Zbtb24 in mouse cells Journal of human genetics Medium 23739126
2016 ZBTB24 directly controls transcription of CDCA7 by binding to its promoter; loss of functional Zbtb24 (BTB domain deletion) leads to early embryonic lethality in mice and dramatically reduces Cdca7 expression, which can be restored by ectopic ZBTB24 expression. Zbtb24 BTB domain deletion mouse model, transcriptome analysis, chromatin immunoprecipitation (ChIP) at CDCA7 promoter, ectopic expression rescue Human molecular genetics High 27466202
2016 Knockdown of ZBTB24 in human B cells (Raji) blocks G0/1- to S-phase cell-cycle progression and upregulates IRF-4 and Blimp-1 expression, demonstrating a role for ZBTB24 in regulating B cell proliferation via transcriptional control of these factors, independent of BCL-6. shRNA knockdown, cell-cycle analysis, gene expression analysis in human B cell line Genes and immunity Medium 27098601
2018 ZBTB24 co-occupies genomic loci with DNMT3B to regulate gene body DNA methylation; ChIP identified common binding sites, and loss-of-function approaches showed ZBTB24 directly activates CDCA7, AXIN2, and OSTC promoters and represses RNF169 and CAMKMT, with a defined 12-bp DNA binding motif. ChIP-seq, loss-of-function experiments, DNA binding motif identification, gene expression analysis Nucleic acids research High 30085123
2018 ICF2, 3, and 4 mutations (in ZBTB24, CDCA7, and HELLS respectively) affect DNA methylation at CpG-poor heterochromatin regions distinct from ICF1 (DNMT3B) targets, placing ZBTB24 in a functional pathway with CDCA7 and HELLS for heterochromatin methylation maintenance. Comparative genome-wide methylation profiling across all four ICF patient genotypes Human molecular genetics Medium 29659838
2019 Crystal structure of ZBTB24 zinc fingers 5-8 bound to a 12-bp consensus DNA sequence [CT(G/T)CCAGGACCT] revealed that ZF5-8 confer DNA binding specificity; ICF2 missense mutations C382Y and C407G in the ZF domain abolish specific DNA binding and fail to induce CDCA7 expression. X-ray crystallography, DNA binding assays, ICF2 missense mutant functional analysis, CDCA7 expression assay Nucleic acids research High 31226215
2019 The AT-hook motif and the 6th zinc-finger motif of ZBTB24 are required for heterochromatin localization, while the 6th and 7th zinc-finger motifs (not AT-hook or BTB domain) are essential for transcriptional activation of CDCA7; two ZBTB24 binding motifs in the CDCA7 promoter are required for transcriptional activation. Domain deletion analysis, immunofluorescence localization, CDCA7 promoter deletion analysis, transcriptional activation assays Genes to cells : devoted to molecular & cellular mechanisms Medium 31561277
2019 ZBTB24 deficiency upregulates TRAIL and TRAIL death receptors (TRAIL-R1/2) in human T cells, causing increased apoptosis; this is mediated through reduced CDCA7 expression, as CDCA7 overexpression rescues the apoptosis phenotype in ZBTB24-depleted T cells, placing ZBTB24 upstream of CDCA7 in the TRAIL-R apoptosis axis. shRNA knockdown of ZBTB24 and CDCA7 in Jurkat and primary T cells, CDCA7 overexpression rescue, TRAIL-R blocking experiments, apoptosis assays Biochemical and biophysical research communications Medium 31030944
2020 ZBTB24 associates with PARP1 and stimulates its auto-poly(ADP-ribosyl)ation; the ZBTB24 zinc-finger domain binds PARP1-associated poly(ADP-ribose) (PAR) chains and mediates PARP1-dependent recruitment of ZBTB24 to DNA breaks; ZBTB24 protects PAR chains from PARG-mediated degradation and facilitates PAR-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, promoting error-free NHEJ and immunoglobulin class-switch recombination. Co-immunoprecipitation of ZBTB24 with PARP1, PARP1 auto-PARylation assay, PAR chain binding assay, recruitment to DNA breaks, LIG4/XRCC4 assembly assay, B cells from ICF2 patients and Zbtb24-deficient mice, class-switch recombination assay The Journal of experimental medicine High 32865561
2023 Zbtb24 deficiency in hematopoietic lineage (Vav-Cre) causes severe loss of DNA methylation in the promoter of Il5ra, leading to its derepression, elevated CD19 phosphorylation, and hypogammaglobulinemia; heterozygous disruption of Cd19 reverts the hypogammaglobulinemia phenotype, placing ZBTB24 upstream of Il5ra methylation and CD19 signaling in B cell antibody production. Conditional knockout mouse (Vav-Cre), DNA methylation analysis at Il5ra promoter, CD19 phosphorylation assay, genetic epistasis (Cd19 heterozygous disruption rescue), immunoglobulin measurement Cellular & molecular immunology High 37990035
2024 B cell-specific deletion of Zbtb24 specifically impairs plasma cell differentiation of B1 cells (not conventional B2 cells) by attenuating heme biosynthesis partially through mTORC1; exogenous hemin supplementation rescues the B1 cell differentiation defect of Zbtb24-null cells. B cell-specific CRISPR/Cas9 Zbtb24 knockout mice, flow cytometry, in vitro B1 cell differentiation, RNA-Seq, hemin rescue experiment Cellular & molecular biology letters Medium 39277732
2025 ZBTB24 is recruited to centromeric satellite DNA where it is required to establish and maintain correct DNA methylation patterns through the recruitment of DNMT3B; this function is conserved between mouse and human cells, and disruption of ZBTB24 using an auxin-inducible degron system leads to loss of centromeric satellite DNA methylation. Constitutive Zbtb24 ICF-like mouse mutant, auxin-inducible degron system in mESCs, ChIP at centromeric satellite DNA, DNA methylation analysis, human cell analysis Human molecular genetics High 39562305
2025 The ZBTB24-CDCA7-HELLS axis maintains DNA methylation of the Dux cluster, suppressing 2C-like reprogramming in mouse ESCs; disruption of this pathway leads to Dux hypomethylation and derepression, upregulating 2C-specific genes, which is reversed by site-specific re-methylation at the Dux promoter. Genetic disruption of ZBTB24/CDCA7/HELLS in mESCs, genome-wide methylation analysis, 2C-gene expression profiling, site-specific CpG re-methylation Nucleic acids research High 40226918
2026 Missense variants (p.Val43Leu, p.Ser59Gly) in the BTB domain of ZBTB24 cause significant protein instability, resulting in loss-of-function and ICF2 syndrome with genome-wide DNA hypomethylation patterns identical to verified ICF2 patients, demonstrating that BTB domain integrity is required for ZBTB24 protein stability. Patient genetic analysis, ZBTB24 protein stability assays, whole-genome DNA methylation profiling Human molecular genetics Medium 41359419

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature cell biology 725 17891140
2005 Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Molecular and cellular biology 164 16227588
2010 A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. Experimental cell research 154 20643123
2011 Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy. Autophagy 139 21068542
2001 Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax. The Journal of biological chemistry 139 11259440
2011 Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. American journal of human genetics 131 21596365
2018 Comparative methylome analysis of ICF patients identifies heterochromatin loci that require ZBTB24, CDCA7 and HELLS for their methylated state. Human molecular genetics 63 29659838
2013 Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. Blood 63 23287860
2006 Decreased expression of tumour suppressor Bax-interacting factor-1 (Bif-1), a Bax activator, in gastric carcinomas. Pathology 54 16916719
2016 Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals. Human molecular genetics 51 27466202
2013 Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. Journal of human genetics 47 23739126
2018 ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation. Nucleic acids research 46 30085123
2011 A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Clinical genetics 39 21906047
2020 Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome. The Journal of experimental medicine 35 32865561
2019 Structural basis of specific DNA binding by the transcription factor ZBTB24. Nucleic acids research 34 31226215
2019 Bif-1 Interacts with Prohibitin-2 to Regulate Mitochondrial Inner Membrane during Cell Stress and Apoptosis. Journal of the American Society of Nephrology : JASN 32 31126972
2008 Decreased expression of Bax-interacting factor-1 (Bif-1) in invasive urinary bladder and gallbladder cancers. Pathology 32 18752120
2022 Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1. Frontiers in pharmacology 29 35418866
2012 Bif-1 suppresses breast cancer cell migration by promoting EGFR endocytic degradation. Cancer biology & therapy 29 22785202
2012 Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst. American journal of medical genetics. Part A 28 22786748
2016 Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin resistance. Scientific reports 25 26857140
2008 SRC directly phosphorylates Bif-1 and prevents its interaction with Bax and the initiation of anoikis. The Journal of biological chemistry 24 18474606
2016 Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells. Genes and immunity 20 27098601
2018 Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer. EBioMedicine 19 29759485
2017 Novel ZBTB24 Mutation Associated with Immunodeficiency, Centromere Instability, and Facial Anomalies Type-2 Syndrome Identified in a Patient with Very Early Onset Inflammatory Bowel Disease. Inflammatory bowel diseases 19 29023266
2020 BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth. Oncogene 11 32493957
2020 A young girl with hypogammaglobulinemia and granulomatous hepatitis caused by a novel mutation in ZBTB24 gene: A case based analysis. Immunobiology 10 32061411
2019 ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis. Biochemical and biophysical research communications 9 31030944
2023 Enhanced CD19 activity in B cells contributes to immunodeficiency in mice deficient in the ICF syndrome gene Zbtb24. Cellular & molecular immunology 8 37990035
2009 Bif-1 and Bax expression in cutaneous Merkel cell carcinoma. Journal of cutaneous pathology 8 19125733
2005 Bone morphogenetic protein-2 induces expression of murine zinc finger transcription factor ZNF450. Journal of cellular biochemistry 7 15526281
2022 ZBTB24 (Zinc Finger and BTB Domain Containing 24) prevents recurrent spontaneous abortion by promoting trophoblast proliferation, differentiation and migration. Bioengineered 6 35038951
2012 Bif-1 is overexpressed in hepatocellular carcinoma and correlates with shortened patient survival. Oncology letters 6 22741005
2020 Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma. Biochemistry. Biokhimiia 4 33202207
2019 Identification of ZBTB24 protein domains and motifs for heterochromatin localization and transcriptional activation. Genes to cells : devoted to molecular & cellular mechanisms 4 31561277
2016 Bif-1 promotes tumor cell migration and metastasis via Cdc42 expression and activity. Clinical & experimental metastasis 4 27730394
2019 bif1, a new BMP signaling inhibitor, regulates embryonic hematopoiesis in the zebrafish. Development (Cambridge, England) 3 30837221
2025 ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats. Human molecular genetics 2 39562305
2025 The ZBTB24-CDCA7-HELLS axis suppresses the totipotent 2C-like reprogramming by maintaining Dux methylation and repression. Nucleic acids research 2 40226918
2025 Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2. Frontiers in immunology 1 39958354
2024 Bif‑1 inhibits activation of inflammasome through autophagy regulatory mechanism. Molecular medicine reports 1 38456519
2024 A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency. Frontiers in immunology 1 39040103
2024 The ICF2 gene Zbtb24 specifically regulates the differentiation of B1 cells via promoting heme synthesis. Cellular & molecular biology letters 1 39277732
2026 Missense substitutions in the BTB domain of ZBTB24 can lead to protein instability and cause ICF2 syndrome. Human molecular genetics 0 41359419
2025 Inhibition of Bif-1 confers cardio-protection in myocardial infarction. American journal of physiology. Cell physiology 0 39982446
2025 In-depth immune profiling of a patient with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 caused by a novel mutation in ZBTB24. Clinical and experimental immunology 0 40103177
2025 Preparation of Pluronic F127 hydrogel loaded with BIF1-iRGD recombinant protein for its targeted anti-cancer effects. Research in pharmaceutical sciences 0 41341176