Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA375804 | ENA |
REPOSITORIES: ENA
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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
Project description:The chromatin-remodeling enzyme helicase lymphoid-specific (HELLS) interacts with cell division cycle-associated 7 (CDCA7) on nucleosomes and is involved in the regulation of DNA methylation in higher organisms. Mutations in these genes cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, which also results in DNA hypomethylation of satellite repeat regions. We investigated the functional domains of human CDCA7 in HELLS using several mutant CDCA7 proteins. The central region is critical for binding to HELLS, activation of ATPase, and nucleosome sliding activities of HELLS-CDCA7. The N-terminal region tends to inhibit ATPase activity. The C-terminal 4CXXC-type zinc finger domain contributes to CpG and hemimethylated CpG DNA preference for DNA-dependent HELLS-CDCA7 ATPase activity. Furthermore, CDCA7 showed a binding preference to DNA containing hemimethylated CpG, and replication-dependent pericentromeric heterochromatin foci formation of CDCA7 with HELLS was observed in mouse embryonic stem cells; however, all these phenotypes were lost in the case of an ICF syndrome mutant of CDCA7 mutated in the zinc finger domain. Thus, CDCA7 most likely plays a role in the recruitment of HELLS, activates its chromatin remodeling function, and efficiently induces DNA methylation, especially at hemimethylated replication sites.
2024-06-23 | GSE270227 | GEO
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
Project description:CDCA7, encoding a protein with a C-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of peri/centromeric satellite DNA. Previous work suggests that the CDCA7 CRD is implicated in DNA binding, which plays a key role in directing the DNA methylation mechinery to peri/centromeric regions. To identify potential genomic targets of CDCA7, we performed ChIP-Seq using CDCA7 knockout (KO) mouse embryonic stem cells (mESCs) stably expressing HA-tagged wild-type (WT) or ICF mutant (R285H) mCDCA7.
2024-07-31 | GSE255395 | GEO
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
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 | GSE116359 | GEO
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 | GSE116358 | GEO
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
Project description:ICF syndrome (Immunodeficiency, Centromeric instability and Facial anomalies) is a rare genetic disorder characterized by severe immunodeficiency that leads to lethal infections in early childhood. In addition, more than half of affected individuals show mild to severe intellectual disability at very early onset. Two genes explain the majority of the ICF cases, DNMT3B and ZBTB24, defining ICF1 and ICF2 subtypes. Despite unifying clinical features, ICF patients display variability in molecular and phenotypic defects with no clear genotype/phenotype correlation. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. Among the disease models, patient-derived iPSCs were acknowledged as a powerful tool enabling the study of ICF syndrome etiology during early development. Here, we show the generation of a novel ICF2 disease model by reprogramming CD34+ cells derived from patient peripheral whole blood into iPSCs. We provide the molecular and phenotypical characterization of the disease model. In particular, we examined the DNA methylation profiles at genome-wide level, demonstrating that iPSCs recapitulate the methylation defects specifically associated with ZBTB24 deficiency. We discuss these results and compare them with the molecular features identified in ICF1-patient derived iPSCs caused by DNMT3B loss of function.
2024-05-31 | GSE262957 | GEO
Project description:We are interested in deciphering the mechanism by which DNA methylation in late B cell differentiation affects humoral immune response. We were using enzymatic-methyl sequencing (EM-seq) and chose to study a very rare immunodeficiency called ICF type 4, where a point mutation in a gene encoding the protein HELLS causes a lack of both circulating antibodies and memory B cells in human. HELLS is a chromatin remodeler, that allows for DNA methylation to occur.
2023-07-27 | E-MTAB-12609 | biostudies-arrayexpress