Biology subjects

Jimenez-Villalba, E.

Publications and source records attributed to Jimenez-Villalba, E..

3 recordsLinked to original sources

bioRxiv2025

TET2-dependent differential 5hmC deposition balances adult neural stem cell activation and differentiation

Ten-eleven translocation (TET) enzymes are key regulators of active DNA demethylation, converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and thereby shaping the epigenetic landscape and cellular identity. While their roles have been characterized in pluripotent and some multipotent stem cells, their function in adult neural stem cells (NSCs) of the subventricular zone (SVZ) remains poorly understood. Here, we show that TET2 is critical for the maintenance and differentiation of adult NSCs, orchestrating locus-specific 5hmC deposition across promoters, gene bodies, and enhancers. Importantly, 5hmC remodeling segregates into two functionally distinct programs: promoter-associated gains of 5hmC are strongly TET2-dependent and drive transcription of genes controlling neural differentiation and calcium signaling, whereas gene body- and enhancer-associated 5hmC gains partially depend on TET2 and sustain proliferative and metabolic pathways, thereby maintaining stemness. Loss of TET2 disrupts these 5hmC programs, downregulates key differentiation- and calcium-related genes, and impairs the normal differentiation-associated increase in intracellular calcium, revealing a functional consequence of altered epigenetic regulation. Together, our findings uncover a pivotal role for TET2 in coordinating complementary epigenetic and transcriptional programs that balance stemness and differentiation in adult NSCs.

neuroscience↗

bioRxiv2025

TET3 protects the Dlk1-Dio3 Imprinted Locus from DNA hypomethylation during adult NSC Reprogramming

Genomic imprinting is an epigenetic mechanism that drives monoallelic gene expression depending on parental origin. Loss of imprinting (LOI) is associated with human imprinting disorders, fetal development, and cancer progression. Imprinted genes, organized in clusters, are regulated by methylation at imprint control regions (ICRs), differentially methylated regions (DMRs) between parental chromosomes. Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) is a valuable tool for studying pluripotency and holds promise for patient-specific therapies. Discerning whether genomic imprinting changes during reprogramming represent epigenetic abnormalities or essential adaptations linked to pluripotency is crucial. Here, we perform RNA-seq and MeDIP-seq analysis on mouse iPSCs derived from neural stem cells (NSCs). Our findings reveal that ICRs undergo DNA hypomethylation, confirming widespread LOI in pluripotent cells. However, the IG-DMR within the Dlk1-Dio3 imprinted cluster resists hypomethylation, a hallmark of successful pluripotency acquisition. We also identify a non-canonical role of TET3 in IG-DMR methylation protection through transcriptional regulation of Oct4 and Trim28. These findings highlight genomic imprinting as a key mechanism of gene dosage control in pluripotency acquisition and maintenance.

cell biology↗

bioRxiv2024

Alterations of genomic imprinting appear during the reprogramming of adult neural stem cells

Genomic imprinting is an epigenetic mechanism that causes monoallelic expression of genes depending on their parental origin. Loss of imprinting (LOI) is associated with cancer progression and human imprinting disorders (IDs), impacting foetal development, metabolism and cognition. Imprinted genes, organized in clusters, rely on methylation at imprint control regions (ICRs), which are differentially methylated regions (DMRs) on both parental chromosomes. Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) is a valuable tool to understand the mechanisms associated with pluripotency and holds promise for generating patient-specific stem cells for therapeutical applications to treat different pathologies such as IDs. Here, we conduct genome-wide RNA-seq and MeDIP-seq analysis on mouse iPSCs derived from adult neural stem cells (NSCs). Our findings reveal a comprehensive alteration in iPSCs transcriptome profile, aligning with DNA hypomethylation. This correlation is pivotal in discerning which modifications in genomic imprinting during the reprogramming process represent undesirable epigenetic abnormalities that could compromiise the quality of iPSCs. Simultaneously, it helps identify genuine epigenetic modifications that are inherently linked to pluripotency, thus ensuring a clearer understanding of the factors influencing iPSC quality and pluripotent potential.

cell biology↗