Biology subjects

Lozano-Urena, A.

Publications and source records attributed to Lozano-Urena, A..

4 recordsLinked to original sources

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

Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling

The etiology of Alzheimers disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but the molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction in the AD-affected brain might lead to reduced production of neuron-derived paracrine factors acting through receptors necessary for adult SVZ neurogenesis (ASN). To test this hypothesis, we focused on the TrkB receptor, which can transduce signals from the neurotrophins BDNF and NT4/5, since TrkB is known to regulate the ASN process and its function becomes altered in AD. Here we show that ASN is impaired in the SVZ of homozygous 5xFAD (h5xFAD) mice. This impairment is prevented by administering an AAV.PHP.eB vector that expresses in neurons the transcription factor E2F4 carrying the Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated to exert multifactorial effects in this mouse model of AD. The use of culture media conditioned by primary cortical neurons expressing E2F4DN was able to recover the proliferative and differentiative capacity of neural stem cells (NSCs) isolated from h5xFAD mice. This effect was blocked by inhibiting the TrkB receptor. Accordingly, TrkB activation mimicked the effect of the E2F4DN-conditioned medium on the proliferative and differentiative capacity of h5xFAD NSCs, a finding consistent with the upregulation of NT4/5 expression in the E2F4DN-transduced neurons. We conclude that the activation of TrkB by neurotrophins released by E2F4DN-expressing neurons can recover the ASN phenotype in 5xFAD mice. Therefore, the multifactorial therapeutic capacity of E2F4DN includes the recovery of impaired ASN through the upregulation of TrkB signaling in NSCs.

neuroscience↗

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↗

bioRxiv2022

Imprinted genes Cdkn1c and Igf2 interact to promote terminal differentiation of adult NSCs

Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Insulin-like growth factor 2 (Igf2), is an imprinted gene that shows biallelic expression only in the vascular compartment contributing to neural stem cells (NSCs) maintenance in the subventricular zone (SVZ) niche. The effects of this factor in adult NSCs differentiation are not well defined. We show here that IGF2 promotes cell fate commitment of NSCs by inducing the expression of another imprinted gene, the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), which encodes for p57 protein, eliciting cell cycle exit and terminal differentiation into astrocytes, neurons and oligodendrocytes. Using a conditional mouse model with Cdkn1c-deficient neural progenitors, we confirm that IGF2 and p57 interact in a common pathway to regulate the differentiation program of adult NSCs. This occurs through a mechanism involving the PI3K-Akt pathway that mediates regulation of p57 expression. We also show that the imprinted state of the Cdkn1c gene is not altered after IGF2 treatment confirming maternal expression of the gene in NSCs. Our results identify a molecular mechanism by which a paracrine factor produced and secreted by the neurogenic niche compartment can modulate Cdkn1c dosage to trigger differentiation of adult NSCs.

neuroscience↗