{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZBTB24 is a zinc‐finger and BTB domain–containing transcription factor whose mutations are causative for Immunodeficiency, Centromeric Instability, and Facial anomalies (ICF) syndrome type 2. Studies have demonstrated that ZBTB24 plays a critical role in regulating DNA methylation at juxtacentromeric repeats and heterochromatin organization, thereby influencing lymphocyte maturation and function. In ICF2 patients, loss‐of‐function mutations in ZBTB24 lead to a constellation of immunological defects, including impaired B‐cell development and disrupted B–T cell interactions, which together contribute to the clinical syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, ZBTB24 functions as a transcriptional regulator by directly binding to DNA and modulating gene expression. It is instrumental in activating the transcription of CDCA7, another ICF‐related gene, thereby establishing a regulatory link between distinct ICF subtypes. Detailed functional studies, including mouse models and transcriptome analyses, have shown that the AT-hook and specific zinc-finger motifs of ZBTB24 are indispensable for its proper localization to heterochromatin and for initiating gene activation. In addition, ZBTB24 interacts with epigenetic writers such as DNMT3B and with DNA repair proteins like PARP1, thereby contributing to gene body methylation and ensuring error-free non-homologous end joining during immunoglobulin class-switch recombination. These findings underscore its central role in maintaining genomic integrity and proper immune cell function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical roles in immune cells, the functional specificity of ZBTB24 is further highlighted by its selective regulation of genomic methylation patterns; while it is crucial for centromeric and pericentromeric methylation, subtelomeric heterochromatin appears to be maintained independently of its activity. Moreover, altered expression of ZBTB24 has been linked to defects in cell proliferation, differentiation, and migration in other cell types, such as trophoblasts, where its downregulation correlates with impaired cell function in recurrent spontaneous abortion. These diverse activities underscore the multifaceted regulatory capacity of ZBTB24 in governing both chromatin architecture and gene expression networks vital for cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jessica C de Greef, Jun Wang, Judit Balog, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2011.04.018"}], "href": "https://doi.org/10.1016/j.ajhg.2011.04.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21596365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21596365"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Corry M R Weemaes, Maarten J D van Tol, Jun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.40"}], "href": "https://doi.org/10.1038/ejhg.2013.40"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23486536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23486536"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Guillaume Velasco, Giacomo Grillo, Nizar Touleimat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative methylome analysis of ICF patients identifies heterochromatin loci that require ZBTB24, CDCA7 and HELLS for their methylated state."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy130"}], "href": "https://doi.org/10.1093/hmg/ddy130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29659838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29659838"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "E Chouery, J Abou-Ghoch, S Corbani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2011.01783.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2011.01783.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21906047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21906047"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "M L van den Boogaard, P E Thijssen, C Aytekin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.12979"}], "href": "https://doi.org/10.1111/cge.12979"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28128455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28128455"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Haoyu Wu, Peter E Thijssen, Eleonora de Klerk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddw243"}], "href": "https://doi.org/10.1093/hmg/ddw243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27466202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27466202"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hirohisa Nitta, Motoko Unoki, Kenji Ichiyanagi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jhg.2013.56"}], "href": "https://doi.org/10.1038/jhg.2013.56"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23739126"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23739126"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Joyce J Thompson, Rupinder Kaur, Carlos P Sosa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gky682"}], "href": "https://doi.org/10.1093/nar/gky682"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30085123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30085123"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Horst von Bernuth, Ethiraj Ravindran, Hang Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Orphanet J Rare Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13023-014-0116-6"}], "href": "https://doi.org/10.1186/s13023-014-0116-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25330735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25330735"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Angela Helfricht, Peter E Thijssen, Magdalena B Rother, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20191688"}], "href": "https://doi.org/10.1084/jem.20191688"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32865561"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32865561"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "J Liang, R Yan, G Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Immun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/gene.2016.18"}], "href": "https://doi.org/10.1038/gene.2016.18"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27098601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27098601"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xiao-Yuan Qin, Jing Feng, Ge Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2019.04.147"}], "href": "https://doi.org/10.1016/j.bbrc.2019.04.147"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31030944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31030944"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Sharmin Aktar, Hiroyuki Sasaki, Motoko Unoki "}, {"type": "b", "children": [{"type": "t", "text": "Identification of ZBTB24 protein domains and motifs for heterochromatin localization and transcriptional activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Cells (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/gtc.12723"}], "href": "https://doi.org/10.1111/gtc.12723"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31561277"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31561277"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Shir Toubiana, Guillaume Velasco, Adi Chityat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Subtelomeric methylation distinguishes between subtypes of Immunodeficiency, Centromeric instability and Facial anomalies syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy265"}], "href": "https://doi.org/10.1093/hmg/ddy265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30010917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30010917"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Haibo Ruan, Zhenzhen Dai, Jinyu Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZBTB24 (Zinc Finger and BTB Domain Containing 24) prevents recurrent spontaneous abortion by promoting trophoblast proliferation, differentiation and migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.2019655"}], "href": "https://doi.org/10.1080/21655979.2021.2019655"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35038951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35038951"}]}]}]}