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

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.