# TET3 protects the Dlk1-Dio3 imprinted locus from DNA hypomethylation during adult NSC reprogramming

## TL;DR

This study shows that TET3 helps maintain DNA methylation at a specific genomic region during the reprogramming of adult neural stem cells into pluripotent stem cells.

## Contribution

The study reveals a new role for TET3 in preserving methylation at the Dlk1-Dio3 imprinted locus during reprogramming.

## Key findings

- Most imprinting control regions lose DNA methylation in iPSCs derived from adult NSCs.
- The IG-DMR within the Dlk1-Dio3 cluster remains methylated during reprogramming.
- TET3 maintains IG-DMR methylation by regulating Oct4 and Trim28 transcription.

## Abstract

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), differentially methylated 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 for the 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.

•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

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

Epigenetics; Genomics; Molecular Genetics; Stem cells research; Transcriptomics