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ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation [Infinium]

ABSTRACT: The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in modulating gene expression, is being increasingly appreciated. We investigated the interplay between ZBTB24, a zinc-finger protein belonging to the BTB-POZ family of transcription factors, and the de novo DNA methyltransferase DNMT3B. Both factors, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting they are mechanistically linked in some way, but almost nothing is known about ZBTB24. In this study, we identified genomic targets regulated by ZBTB24, and identified its recognition motif, binding to which leads to activation. Chromatin immunoprecipitation in model cell line systems revealed common genes bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation. Genes coordinately regulated by ZBTB24 and DNMT3B are enriched for molecular mechanisms essential for cellular homeostasis, highlighting the importance of the ZBTB24-DNMT3B interplay in maintaining epigenetic patterns required for normal cellular function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111681 | GEO | 2018/07/31

REPOSITORIES: GEO

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ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation [ChiP-Seq and RNA-Seq]

Project description:The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in modulating gene expression, is being increasingly appreciated. We investigated the interplay between ZBTB24, a zinc-finger protein belonging to the BTB-POZ family of transcription factors, and the de novo DNA methyltransferase DNMT3B. Both factors, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting they are mechanistically linked in some way, but almost nothing is known about ZBTB24. In this study, we identified genomic targets regulated by ZBTB24, and identified its recognition motif, binding to which leads to activation. Chromatin immunoprecipitation in model cell line systems revealed common genes bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation. Genes coordinately regulated by ZBTB24 and DNMT3B are enriched for molecular mechanisms essential for cellular homeostasis, highlighting the importance of the ZBTB24-DNMT3B interplay in maintaining epigenetic patterns required for normal cellular function.

2018-08-01 | GSE111683 | GEO

Ablation of ZBTB24 in hematopoietic cells in mice results in antibody deficiency that mimics ICF syndrome

Project description:ICF syndrome, a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability and facial anomalies, is caused by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS. In this study we show that mice deficient for Zbtb24 in the hematopoietic lineage exhibit a phenotype that recapitulates major clinical features of ICF patients, including hypogammaglobulinemia. RNA-Seq analysis of splenic follicular B cells and marginal zone B cells identifies dozens of genes that show differential expression in the absence of Zbtb24. These include Cdca7, Taf6, Cdc40, Ostc, Crisp3 and Il5ra.

2021-10-16 | GSE184699 | GEO

Structural basis of specific DNA binding by the transcription factor ZBTB24

Project description:ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes – the other three being DNMT3B, CDCA7 and HELLS – that are mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome. The sequence is present at multiple loci, including the Cdca7 promoter region, and ZBTB24 binding is mostly associated with gene activation. Crystallography and DNA-binding data revealed that the last four of the eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 confer specificity of DNA binding. Two ICF missense mutations have been identified in the ZBTB24 ZF domain that alter zinc-binding cysteine residues. We demonstrated that the corresponding C382Y and C407G mutations in mouse ZBTB24 abolish specific DNA binding and fail to induce Cdca7 expression. Our analyses indicate, and suggest a structural basis for, the sequence specific recognition by a transcription factor centrally important for the pathogenesis of ICF syndrome.

2019-06-11 | GSE120969 | GEO

Loss of ZBTB24, a novel non-homologous end-joining protein, impairs class-switch recombination in ICF syndrome

Project description:The autosomal recessive immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite recent successes in the identification of the underlying gene defects, it is currently unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from ICF2 patients impairs non-homologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and subtype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates auto-poly(ADP-ribosyl)ation of this enzyme. The zinc finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, by binding to poly(ADP-ribose) chains ZBTB24 protects these moieties from degradation by poly(ADP-ribose) glycohydrolase (PARG). This enhances the poly(ADP-ribose)-dependent interaction between PARP1 and the LIG4/XRCC4 NHEJ complex and promotes NHEJ by facilitating the assembly of this repair complex at DNA breaks. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF syndrome.

2020-08-19 | PXD014741 | Pride

ZBTB24

Project description:ZBTB24, a gene associated with human ICF syndrome, regulates centromeric and pericentrameric heterochromatin formation

| PRJEB10266 | ENA

Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome [BiSulfite-seq]

Project description:The goal of this study was to investigate DNA methylation and gene expression changes in a zebrafish model of ICF Syndrome which were generated by mutation of ICF-gene zbtb24. Comparison of gene expression changes between wildtype and zbtb24 homozygous mutants revealed upregulation of interferon response genes following zbtb24 deletion. Upregulation of interferon response genes was blocked by mutation of the dsRNA helicase Mda5.

2018-11-28 | GSE116352 | GEO

Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome [dsRNA-seq]

2018-11-28 | GSE116359 | GEO

Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome [ssRNA-seq]

2018-11-28 | GSE116358 | GEO

ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation [Infinium]

Project description:ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation [Infinium]

| PRJNA437864 | ENA

Transcription profiling of human lymphoblastoid cell lines (LCLs) derived from ICF syndrome and normal individuals.

Project description:Genome-wide DNA methylation patterns are established and maintained by the coordinated action of three DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B. DNMT3B hypomorphic germline mutations are responsible for two-thirds of Immunodeficiency, Centromere Instability, Facial Anomalies (ICF) syndrome cases. The molecular defects in transcription, DNA methylation, and chromatin structure in ICF cells remain relatively uncharacterized. We used expressing microarrays to define the global program of gene expression to elucidate the role of DNMT3B in these processes using EBV-immortalized lymphoblastoid cell lines (LCLs) derived from ICF syndrome and normal individuals. Experiment Overall Design: 5 Normal LCLs (GM08729, GM08728, LCL1, CM304 and CM774) and 3 ICF LCLs (4088,GM08714 and 10759) were selected for RNA extraction and hybridization on Affymetrix UU133A/B microarrays.

2008-06-16 | E-GEOD-9499 | biostudies-arrayexpress

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