TET3 protects the Dlk1-Dio3 imprinted locus from DNA hypomethylation during adult NSC reprogramming - Article Highlights Summary

Sep 29, 2026

Genomic imprinting is an epigenetic system that enforces monoallelic gene expression via DNA methylation at imprinting control regions (ICRs) and differentially methylated regions (DMRs). Reprogramming adult neural stem cells (NSCs) into iPSCs is used to test whether imprinting changes reflect epigenetic defects or required adaptations of pluripotency. RNA-seq and MeDIP-seq profiling show widespread ICR hypomethylation while the IG-DMR in the Dlk1-Dio3 cluster stays methylated. TET3 supports IG-DMR methylation through transcriptional control of Oct4 and Trim28, and selective IG-DMR imprinting is linked to full pluripotency acquisition.

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CategoryHealthcare

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Highlights

Genomic imprinting and DNA methylation dynamics

Reprogramming and pluripotency acquisition

TET3 regulation of IG-DMR methylation

Summary

Introduction

iScience Article TET3 protects the Dlk1-Dio3 imprinted locus from DNA hypomethylation during adult NSC reprogramming Graphical abstract Authors Laura L´azaro-Carot, Esteban Jim´enez-Villalba, Jordi Planells, ..., Mitsuteru Ito, Elizabeth J. Radford, Sacri R. Ferr´on Correspondence [sacramento.rodriguez@uv.es](sacramento.rodriguez@uv.es) In brief Epigenetics; Genomics; Molecular Genetics; Stem cells research; Transcriptomics Highlights • iPSCs derived from adult NSCs exhibit global loss of imprinting due to ICR hypomethylation • The IG-DMR within the Dlk1-Dio3 cluster resists hypomethylation during reprogramming • TET3 dioxigenase maintains IG-DMR methylation through Trim28 and Oct4 transcriptional control • Selective imprinting at the IG-DMR is essential for full pluripotency acquisition L´azaro-Carot et al., 2025, iScience 28, 113994 December 19, 2025 © 2025 The Author(s) . Published by Elsevier Inc. [https://doi.org/10.1016/j.isci.2025.113994](https://doi.org/10.1016/j.isci.2025.113994) ll iScience ll OPEN ACCESS Article TET3 protects the Dlk1-Dio3 imprinted locus from DNA hypomethylation during adult NSC reprogramming Laura L´azaro-Carot,1,5 Esteban Jim´enez-Villalba,1,5 Jordi Planells,1,5 Anna Lozano-Ure˜na,1,4 Jennifer Daz-Moncho,1 Raquel Montalb´an-Loro,1 Adela Lleches-Padilla,1 Martina Kirstein,1 Mitsuteru Ito,2 Elizabeth J. Radford,3 and Sacri R. Ferr´on1,6,* 1Instituto de Biotecnolog´ıa y Biomedicina (BiotecMed)/Departamento de Biologa Celular, Universidad de Valencia, 46100 Valencia, Spain 2Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK 3Department of Pediatrics, University of Cambridge, Cambridge CB2 0QQ, UK 4Present address: Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, 28002 Madrid, Spain 5These authors contributed equally 6Lead contact *Correspondence: [sacramento.rodriguez@uv.es](sacramento.rodriguez@uv.es)[ ](sacramento.rodriguez@uv.es)[https://doi.org/10.1016/j.isci.2025.113994](https://doi.org/10.1016/j.isci.2025.113994) SUMMARY Genomic imprinting is an epigenetic mechanism that controls monoallelic expression according to parental origin. Imprinted genes are regulated by DNA methylation at imprinting control regions (ICRs), differentiallymethylated regions (DMRs) that distinguish between parental alleles. Cell reprogramming into induced pluripotent stem cells (iPSCs) offers a valuable model for studying pluripotency. Thus, discerning whether genomic imprinting changes during reprogramming represent epigenetic abnormalities or essential adaptations of pluripotency is crucial. Here, we integrate RNA-seq and MeDIP-seq analysis to profile mouse iPSCs derived from adult neural stem cells (NSCs) . Our findings reveal that most ICRs undergo DNA hypomethylation in iPSCs, although the IG-DMR within the Dlk1-Dio3 imprinted cluster remains methylated, serving as an epigenetic marker of pluripotency. We further identify a non-canonical role forthe dioxygenase TET3 in maintaining IG-DMR methylation through the transcriptional regulation of Oct4 and Trim28 . These findings highlight genomic imprinting as a dynamic regulator of gene dosage during pluripotency acquisition. INTRODUCTION During mammalian development, the vast majority of genes are expressed or repressed from both alleles. However, there is a small number of genes, termed ‘‘imprinted genes’’ that are expressed monoallelicaly from either the maternally or the paternally inherited chromosomes.1 Approximately 150 imprinted genes have been described in mammals and are generally organized in clusters, although examples of singleton imprinted genes do exist.2 An imprinting cluster is usually under the control of a DNA element, called the imprinting control region (ICR), that consists of differentially DNA methylated regions (DMRs) between the two parental chromosomes.3 ,4 Deletion or alteration of an ICR results in loss of imprinting (LO

FAQs

What happens to DNA methylation of most ICRs during adult NSC reprogramming into iPSCs?

Most ICRs undergo DNA hypomethylation in iPSCs derived from adult NSCs.

Which region within the Dlk1-Dio3 imprinted cluster resists hypomethylation during reprogramming?

The IG-DMR within the Dlk1-Dio3 cluster remains methylated, acting as an epigenetic marker of pluripotency.

How does TET3 help maintain IG-DMR methylation during reprogramming?

TET3 maintains IG-DMR methylation through transcriptional regulation of Oct4 and Trim28.

Sep 29, 2026

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