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ICF1-Syndrome-Associated DNMT3B Mutations Prevent De Novo Methylation at a Subset of Imprinted Loci during iPSC Reprogramming
by Ankit Verma 1,2,+ORCID,Varsha Poondi Krishnan 2,+ORCID,Francesco Cecere 1ORCID,Emilia D'Angelo 1ORCID,Vincenzo Lullo 2ORCID,Maria Strazzullo 2ORCID,Sara Selig 3,4ORCID,Claudia Angelini 5ORCID,Maria R. Matarazzo 2,*ORCID andAndrea Riccio 1,2,*ORCID
1
Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania "Luigi Vanvitelli", 81100 Caserta, Italy
2
Institute of Genetics and Biophysics (IGB) "Adriano Buzzati-Traverso", Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy
3
Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, Israel
4
Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 31096, Israel
5
Istituto per le Applicazioni del Calcolo "Mauro Picone", Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy
*
Authors to whom correspondence should be addressed.
+
These authors equally contributed to this work.
Biomolecules 2023, 13(12), 1717; https://doi.org/10.3390/biom13121717
Submission received: 2 August 2023 / Revised: 19 November 2023 / Accepted: 23 November 2023 / Published: 28 November 2023
(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)
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Abstract
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 DNA methyltransferase 3B (DNMT3B) 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 DNMT3B 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.
Anno
2023
Autori IAC
Tipo pubblicazione
Altri Autori
Ankit Verma, Varsha Poondi Krishnan,Francesco Cecere ,Emilia D;Angelo, Vincenzo Lullo,Maria Strazzullo,Sara Selig,Claudia Angelini.Maria R. Matarazzo, Andrea Riccio
Editore
MDPI
Rivista
Biomolecules