Comparative DNA methylation profiling of ICF patients supports a functional link between ZBTB24, CDCA7 and HELLS at genomic regions with heterochromatin features
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE95040 | GEO | 2018/04/17
REPOSITORIES: GEO
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Project description:Immunodeficiency, Centromeric Instability, and Facial Anomalies Type I (ICF1) Syndrome is a rare genetic disease caused by mutations in DNMT3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B-deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 Syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1 iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1 iPSCs relevant to ICF Syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to mesenchymal stem cells (MSCs), we find virtually all CG hypomethylated regions remained hypomethylated when compared to either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 Syndrome. MethylC-seq and RNA-Seq in ICF Syndrome patient fibroblast derived induced pluripotent stem cells.
2014-11-17 | E-GEOD-46030 | biostudies-arrayexpress
Project description:DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the telomeric ICF1 phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.
2019-12-01 | GSE138265 | GEO
Project description:DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the telomeric ICF1 phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.
2019-12-01 | GSE137183 | GEO
Project description:Immunodeficiency, Centromeric Instability, and Facial Anomalies Type I (ICF1) Syndrome is a rare genetic disease caused by mutations in DNMT3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B-deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 Syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1 iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1 iPSCs relevant to ICF Syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to mesenchymal stem cells (MSCs), we find virtually all CG hypomethylated regions remained hypomethylated when compared to either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 Syndrome.
2014-11-17 | GSE46030 | 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: Not available
| S-EPMC7026229 | biostudies-literature
Project description:Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS-CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.
| S-EPMC5798369 | biostudies-literature
Project description:5-Methylcytosine (5mC) and DNA methyltransferases (DNMTs) are broadly conserved in eukaryotes but are also frequently lost during evolution. The mammalian SNF2 family ATPase HELLS and its plant ortholog DDM1 are critical for maintaining 5mC. Mutations in HELLS, its activator CDCA7, and the de novo DNA methyltransferase DNMT3B, cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, a genetic disorder associated with the loss of DNA methylation. We here examine the coevolution of CDCA7, HELLS and DNMTs. While DNMT3, the maintenance DNA methyltransferase DNMT1, HELLS, and CDCA7 are all highly conserved in vertebrates and green plants, they are frequently co-lost in other evolutionary clades. The presence-absence patterns of these genes are not random; almost all CDCA7 harboring eukaryote species also have HELLS and DNMT1 (or another maintenance methyltransferase, DNMT5). Coevolution of presence-absence patterns (CoPAP) analysis in Ecdysozoa further indicates coevolutionary linkages among CDCA7, HELLS, DNMT1 and its activator UHRF1. We hypothesize that CDCA7 becomes dispensable in species that lost HELLS or DNA methylation, and/or the loss of CDCA7 triggers the replacement of DNA methylation by other chromatin regulation mechanisms. Our study suggests that a unique specialized role of CDCA7 in HELLS-dependent DNA methylation maintenance is broadly inherited from the last eukaryotic common ancestor.
| S-EPMC10538959 | biostudies-literature
Project description:The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated with mutation of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable of analyzing single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base-pair resolution. Whole-genome bisulphite sequencing was performed to assess alteration in DNA methylation of one ICF patient and one healthy control sample at base-pair resolution.
2012-04-25 | E-GEOD-37578 | biostudies-arrayexpress
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