ICF1-Syndrome-Associated DNMT3B Mutations Prevent De Novo Methylation at a Subset of Imprinted Loci during iPSC Reprogramming

Parent-of-origin-dependent gene expression of a few hundred human genes is achieved by differential DNA methylation of both parental alleles. This imprinting is required for normal development, and defects in this process lead to human disease. Induced pluripotent stem cells (iPSCs) serve as a valua...

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Published in:Biomolecules (Basel, Switzerland) Switzerland), 2023-11, Vol.13 (12), p.1717
Main Authors: Verma, Ankit, Poondi Krishnan, Varsha, Cecere, Francesco, D'Angelo, Emilia, Lullo, Vincenzo, Strazzullo, Maria, Selig, Sara, Angelini, Claudia, Matarazzo, Maria R, Riccio, Andrea
Format: Article
Language:English
Subjects:
Chromosomes
CRISPR
DNA methylation
DNA methyltransferase
DNMT3B
Enzymatic activity
Epigenetics
Fibroblasts
Gene expression
Genes
Genomes
Genomic imprinting
ICF syndrome
Immunodeficiency
Mutation
Patients
Pluripotency
Stem cells
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Summary:Parent-of-origin-dependent gene expression of a few hundred human genes is achieved by differential DNA methylation of both parental alleles. This imprinting is required for normal development, and defects in this process lead to human disease. Induced pluripotent stem cells (iPSCs) serve as a valuable tool for in vitro disease modeling. However, a wave of de novo DNA methylation during reprogramming of iPSCs affects DNA methylation, thus limiting their use. The ( ) gene is highly expressed in human iPSCs; however, whether the hypermethylation of imprinted loci depends on DNMT3B activity has been poorly investigated. To explore the role of DNMT3B in mediating de novo DNA methylation at imprinted DMRs, we utilized iPSCs generated from patients with immunodeficiency, centromeric instability, facial anomalies type I (ICF1) syndrome that harbor biallelic hypomorphic mutations. Using a whole-genome array-based approach, we observed a gain of methylation at several imprinted loci in control iPSCs but not in ICF1 iPSCs compared to their parental fibroblasts. Moreover, in corrected ICF1 iPSCs, which restore DNMT3B enzymatic activity, imprinted DMRs did not acquire control DNA methylation levels, in contrast to the majority of the hypomethylated CpGs in the genome that were rescued in the corrected iPSC clones. Overall, our study indicates that DNMT3B is responsible for de novo methylation of a subset of imprinted DMRs during iPSC reprogramming and suggests that imprinting is unstable during a specific time window of this process, after which the epigenetic state at these regions becomes resistant to perturbation.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom13121717