Biology subjects

Jordan-Pla, A.

Publications and source records attributed to Jordan-Pla, A..

5 recordsLinked to original sources

bioRxiv2026

Polo-like kinase 1 controls activation of adult neural stem cells and represents a druggable entry-point to boost adult neurogenesis

Neural stem cells (NSCs) persist in the mammalian brain after development, but their potential for replacing neural populations lost in brain damage is dramatically restricted. Quiescence, or the ability to transition in and out of the cell cycle is a hallmark of adult NSCs. It deepens as the organism ages and is regarded as a strategy to protect the reservoirs of NSC for the long term. Deciphering the molecular code of dormancy is a major interest in cellular and molecular biology of ageing and in regenerative medicine since it has important implications for potentially manipulating NSCs to improve tissular homeostasis. In this work we have identified the mitotic kinase Polo like kinase 1 (Plk1) as a novel intrinsic regulator of the dynamic transition between NSC quiescence and activation in adult neurogenic niches. Using quantitative phosphoproteomics to pinpoint mechanistical mediators of the role of Plk1, we have identified the quiescence/activation molecular switch formed by E3 ubiquitin ligase Huwe1 and its target, the transcription factor Ascl1/Mash1, as novel effectors of Plk1 in NSCs. We discover that Plk1 restrains the accumulation of Ascl1/Mash1 by acting upstream of Huwe1, providing a direct molecular connection between completion of the cell cycle and the re-establishment of a low activation state following NSC division, which supports the concept that quiescence is an actively maintained state. Moreover we demonstrate that pharmacological inhibition of Plk1 is sufficient to enhance adult neurogenesis in vivo, identifying Plk1 as a viable target to acutely boost endogenous stem cell activation.

neuroscience↗

bioRxiv2025

YAP/TAZ create a physical niche for the maintenance of adult neural stem cell quiescence

Adult stem cells inhabit specialized niches where local and systemic cues regulate their behavior. In the mouse ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) dynamically transition between quiescence and activation and reside amidst unique deposits of extracellular matrix (ECM) known as fractones. We show that NSCs that enter quiescence in response to BMP4 secrete a complex ECM that, on its own, is capable of inducing NSC quiescence. This specific ECM triggers the nuclear translocation of Yes-associated protein (YAP), to induce further ECM remodeling and adhesion. Together, the BMP-ECM-YAP pathway creates a two-step mechanism where a soluble and transient quiescence-inducing signal leads to the formation of a physical niche to maintain the quiescent state. In the intact niche, YAP and its paralog TAZ (Transcriptional coactivator with PDZ-binding motif) essentially sustain quiescence by preserving fractones and the characteristic structural organization. Moreover, our findings reveal a previously unrecognized role for YAP/TAZ in quiescence.

neuroscience↗

bioRxiv2023

Fine-tuning Rpb4 phosphorylation modulates Rpb4/7 stoichiometry within yeast RNA polymerase II and regulates gene expression

RNA polymerase II (RNAPII) consists of 12 subunits, including Rpb4 and Rpb7, which form a heterodimeric stalk domain. In yeast, assembly of Rpb4/7 with the 10-subunit "core" is substoichiometric. Aside from its role in transcription, Rpb4/7 also binds to mRNAs co-transcriptionally (mRNA imprinting), exits the nucleus together with the mRNA, and modulates subsequent cytoplasmic processes like translation and degradation. However, the mechanisms underlying Rpb4/7 functions and its association with RNAPII remain poorly understood. In this study, we identify five phosphorylation sites in Rpb4 that regulate various steps of mRNA and snoRNA biogenesis, including transcription elongation and the polyadenylation step. We also provide evidence that the kinase Hrr25 and the phosphatase Fcp1, known to target the carboxyl-terminal domain (CTD) of Rpb1 and participate in processes at gene 3'-ends, coordinate Rpb4 phosphorylation. Inefficient Rpb4 phosphorylation leads to increased Rpb4 association with RNAPII, particularly at gene 3'-ends, suggesting that Rpb4-P promotes stalk dissociation from RNAPII either before or during transcription termination. Collectively, our findings underscore the pivotal role of dynamic Rpb4 phosphorylation in regulating Rpb4/7 stoichiometry as well as transcription elongation and termination, with an impact on mRNA imprinting.

molecular biology↗

bioRxiv2020

Xrn1 influences RNA pol II-dependent transcription elongation rates across the yeast genome and this control is particularly relevant for late elongation of regulatory genes

mRNA homeostasis is favored by crosstalk between transcription and degradation machineries. Both the Ccr4-Not and the Xrn1-decaysome complexes have been described to influence transcription. While Ccr4-Not has been shown to directly stimulate transcription elongation, the information available on how Xrn1 influences transcription is scarce and contradictory. In this study we have addressed this issue by mapping RNA polymerase II (RNA pol II) at high resolution, using CRAC and BioGRO-seq techniques in Saccharomyces cerevisiae. We found significant effects of Xrn1 perturbation on RNA pol II profiles across the genome. RNA pol II profiles at 5 exhibited significant alterations that were compatible with decreased elongation rates in the absence of Xrn1. Nucleosome mapping detected altered chromatin configuration in the gene bodies. We also detected accumulation of RNA pol II shortly upstream of polyadenylation sites by CRAC, although not by BioGRO-seq, suggesting higher frequency of backtracking before pre-mRNA cleavage. This phenomenon was particularly linked to genes with poorly positioned nucleosomes at this position. Accumulation of RNA pol II at 3 was also detected in other mRNA decay mutants. According to these and other pieces of evidence, Xrn1 seems to influence transcription elongation at least in two ways: by directly favoring elongation rates and by a more general mechanism that connects mRNA decay to late elongation.

genomics↗

bioRxiv2018

The telomeric Cdc13-Stn1-Ten1 complex regulates RNA polymerase II transcription

Specialized telomeric proteins have an essential role in maintaining genome stability through chromosome end protection and telomere length regulation. In the yeast Saccharomyces cerevisiae, the evolutionary conserved CST complex, composed of the Cdc13, Stn1 and Ten1 proteins, largely contributes to these functions. Here, we report the existence of genetic interactions between TEN1 and several genes coding for transcription regulators. Molecular assays confirmed this novel function of Ten1 and further established that it regulates the occupancies of RNA polymerase II and the Spt5 elongation factor within transcribed genes. Since Ten1, but also Cdc13 and Stn1, were found to physically associate with Spt5, we propose that Spt5 represents the target of CST in transcription regulation. Moreover, CST physically associates with Hmo1, previously shown to mediate the architecture of S phase-transcribed genes. The fact that, genome-wide, the promoters of genes down-regulated in the ten1-31 mutant are prefentially bound by Hmo1, leads us to propose a potential role for CST in synchronizing transcription with replication fork progression following head-on collisions.

molecular biology↗