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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198705 | GEO | 2023/11/28

REPOSITORIES: GEO

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