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The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (RNA-seq)

ABSTRACT: The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (RNA-seq)

PROVIDER: PRJNA812886 | ENA |

REPOSITORIES: ENA

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The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (WGBS)

Project description:Bi-allelic hypomorphic mutations in DNMT3B disrupt DNA methyltransferase activity and lead to Immunodeficiency, Centromeric instability, Facial anomalies syndrome, type 1 (ICF1). While several ICF1 phenotypes have been linked to abnormally hypomethylated repetitive regions, the unique genomic regions responsible for the remaining disease phenotypes remain largely uncharacterized. Here we explored two ICF1 patient-induced pluripotent stem cells (iPSCs) and their CRISPR-Cas9 corrected clones to determine whether DNMT3B correction can globally overcome DNA methylation defects and related changes in the epigenome. Hypomethylated regions throughout the genome were found highly comparable between ICF1 iPSCs carrying different DNMT3B variants, and significantly overlap with those in ICF1-peripheral blood and lymphoblastoid cell lines. These regions include large CpG island domains, as well as promoters and enhancers of several lineage-specific genes, in particular immune-related, suggesting that they are pre-marked during early development. CRISPR-corrected ICF1 iPSCs reveal that the majority of phenotype-related hypomethylated regions re-acquire normal DNA methylation levels following editing. However, at the most severely hypomethylated regions in ICF1 iPSCs, which also display the highest increased H3K4me3 levels and/or abnormal CTCF binding, the epigenetic memory persisted, and hypomethylation was uncorrected. Overall, we demonstrate that restoring the catalytic activity of DNMT3B can reverse the majority of the ICF1 aberrant epigenome. However, a small fraction of the genome is resilient to this rescue, highlighting the challenge of reverting disease states that are due to genome-wide epigenetic perturbations. Uncovering the basis for the persistent epigenetic memory will promote the development of strategies to overcome this obstacle-

2023-01-11 | GSE197924 | GEO

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (RNA-seq)

2023-01-11 | GSE197923 | GEO

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (ChIP-seq)

2023-01-11 | GSE197922 | GEO

Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction.

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

Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

2019-12-01 | GSE137183 | GEO

Disturbed methylation at multiple imprinted loci in iPSCs derived from ICF1 patients during reprogramming

Project description:DNA methylation perturbations have been a hallmark of Immunodeficiency, Centromeric instability, Facial anomalies type I (ICF1) syndrome. The early developmental abnormalities due to DNMT3B deficiency accounts for genome-wide methylation defects that have been addressed frequently in many studies. Biallelic hypomorphic DNMT3B mutations cause the ICF1 syndrome. We have investigated the role of DNMT3B in mediating methylation at imprinted loci by employing induced pluripotent stem cells (iPSC) lines derived from ICF1 patients and their derivative strains in which the DNMT3B mutations were corrected by CRISPR/Cas9 technology. For ICF1 syndrome, skin fibroblasts derived DNA were also included for comparison purposes. By employing a whole-genome array-based approach, we observed a strong hypomethylation at a subset of gDMRs and sDMRs. However, these did not fully recover methylation despite most of the other hypomethylated CpGs in the genome reverted to their epigenetic state in the corrected iPSC clones. Loss of imprinted methylation in the ICF iPSCs was accompanied by increased levels of histone H3K4 trimethylation and in some cases gene activation, which were only partially reversed upon correction. Overall our study provides a comprehensive analysis of the role of DNMT3B activity in genomic imprinting maintenance in human somatic cells and indicates a molecular mechanism explaining why imprinting defects are resistant to correction.

2023-11-28 | GSE198705 | GEO

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory

Project description:The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory

| PRJNA812879 | ENA

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (WGBS)

| PRJNA812885 | ENA

The aberrant epigenome of DNMT3B-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory (ChIP-seq)

| PRJNA812887 | ENA

The aberrant epigenome of <i>DNMT3B</i>-mutated ICF1 patient iPSCs is amenable to correction, with the exception of a subset of regions with H3K4me3- and/or CTCF-based epigenetic memory.

Project description:Bi-allelic hypomorphic mutations in DNMT3B disrupt DNA methyltransferase activity and lead to immunodeficiency, centromeric instability, facial anomalies syndrome, type 1 (ICF1). Although several ICF1 phenotypes have been linked to abnormally hypomethylated repetitive regions, the unique genomic regions responsible for the remaining disease phenotypes remain largely uncharacterized. Here we explored two ICF1 patient-derived induced pluripotent stem cells (iPSCs) and their CRISPR-Cas9-corrected clones to determine whether DNMT3B correction can globally overcome DNA methylation defects and related changes in the epigenome. Hypomethylated regions throughout the genome are highly comparable between ICF1 iPSCs carrying different DNMT3B variants, and significantly overlap with those in ICF1 patient peripheral blood and lymphoblastoid cell lines. These regions include large CpG island domains, as well as promoters and enhancers of several lineage-specific genes, in particular immune-related, suggesting that they are premarked during early development. CRISPR-corrected ICF1 iPSCs reveal that the majority of phenotype-related hypomethylated regions reacquire normal DNA methylation levels following editing. However, at the most severely hypomethylated regions in ICF1 iPSCs, which also display the highest increases in H3K4me3 levels and/or abnormal CTCF binding, the epigenetic memory persists, and hypomethylation remains uncorrected. Overall, we demonstrate that restoring the catalytic activity of DNMT3B can reverse the majority of the aberrant ICF1 epigenome. However, a small fraction of the genome is resilient to this rescue, highlighting the challenge of reverting disease states that are due to genome-wide epigenetic perturbations. Uncovering the basis for the persistent epigenetic memory will promote the development of strategies to overcome this obstacle.

| S-EPMC10069469 | biostudies-literature

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