Biology subjects

Romero-Exposito, F. J.

Publications and source records attributed to Romero-Exposito, F. J..

5 recordsLinked to original sources

bioRxiv2026

In vivo functional classification of PTEN variants reveals context-dependent oncogenicity and interindividual variability

Gene variants, secondary mutations, and stochastic individual variability complicate cancer diagnosis, prognosis, and treatments. Here, we systematically assess the functional impact of PTEN cancer-related missense mutations in mammalian cell lines, yeast, and Caenorhabditis elegans. While cell-based assays revealed alterations in lipid phosphatase activity, CRISPR-based engineering of orthologous mutations in C. elegans enabled classification of variants based on organismal phenotypes and transcriptional profiles, providing a rapid framework to predict oncogenic potential. We further show that secondary mutations, such as gain-of-function of cdc-25.1/CDC25A, can enhance the phenotypic impact of specific daf-18/PTEN variants, revealing context-dependent oncogenicity. Finally, single-worm transcriptomic analyses uncovered substantial interindividual variability among isogenic animals with identical cdc-25.1 and daf-18 mutations, linking transcriptional states to divergent phenotypic outcomes. Together, our results establish C. elegans as a powerful in vivo platform to integrate genetic, functional, and transcriptional information for the interpretation of cancer-associated variants.

cancer biology↗

bioRxiv2024

Circadian clock disruption engages the DREAM complex in suppressing cellular health.

Circadian clock disruption and lack of sleep impair organismal health, but remedies remain elusive. Here, we used multi-omics, molecular and functional assays in C. elegans, human retinal cells and mouse brain to identify the DREAM complex as a conserved mediator of sleep and clock benefits at the cellular level. We show that DREAM abundance is under circadian control with high levels seen during wakefulness. DREAM elevation confers increased chromatin compaction and shields DNA from damage while altering fundamental cellular processes such as translation, stress responses and OXPHOS. Conversely, DREAM levels are lowered during sleep enabling cellular maintenance and repair. When sleep or clock are altered, DREAM levels remain high, and repair activities remain suppressed triggering cellular and organismal deterioration that can be reversed by genetic and pharmacological inhibition of DREAM in vivo and in vitro. We thus reveal the potential of DREAM inhibitors to replicate the benefits of sleep in sleep-deprived and clock-impaired organisms.

physiology↗

bioRxiv2024

Desynchronization between timers provokes transient arrest during C. elegans development

In multicellular organisms, development entails the progression of diverse cellular processes that need to be temporally coordinated. During C. elegans postembryonic development, the events of molting and cell divisions progress in parallel during four larval stages and are modulated by external cues such as temperature and nutrient availability. While seam cell divisions occur predominantly before ecdysis of the cuticle, the order of the events can change, suggesting that they are controlled by independent mechanisms. Here, we have analyzed the impact of reduced insulin signaling in molting and in stage-specific cell divisions. We find that reduced insulin signaling in the daf-2(e1370) allele delays both of these events but has a larger impact on the timing of cell divisions, thus increasing the desynchrony between the events. The relative delay in seam cell divisions leads to a delay in the initiation of the subsequent stage of the molting program, providing a mechanism for resynchronization of developmental processes to the beginning of the larval stages.

developmental biology↗

bioRxiv2021

Differential regulation of developmental stages supports a linear model for C. elegans postembryonic development

The repetitive nature of C. elegans postembryonic development is considered an oscillatory process, a concept that has gained traction from regulation by a circadian clock gene homolog. Nevertheless, each larval stage has a defined duration and entails specific events. We have measured the duration of each stage of development for over 2,500 larvae, under varied environmental conditions known to alter overall developmental rate. Our results show that distinct developmental stages respond differently to environmental perturbations, including changes in temperature, in food quantity and quality, and amount of insulin signaling. Furthermore, our high-resolution measurement of the effect of temperature on the stage-specific duration of development has unveiled novel features of temperature dependence in C. elegans postembryonic development. Altogether, our results support a model of linear progression of C. elegans development, with the duration of each stage determined by a unique program.

developmental biology↗

bioRxiv2020

Social chemical communication determines recovery from L1 arrest via DAF-16 activation

In a population, chemical communication determines the response of animals to changing environmental conditions, what leads to an enhanced resistance against stressors. In response to starvation, the nematode Caenorhabditis elegans arrest post-embryonic development as L1 larva right after hatching. As arrested L1 larvae, C. elegans become more resistant to diverse stresses, allowing them to survive for several weeks expecting to encounter more favorable conditions. However, prolonged periods in L1 arrest lead to the accumulation of detrimental signs of aging, which ultimately provoke animal death. When arrested L1s feed, they undergo a recovery process to erase these harmful signs before resuming the developmental program. L1 arrested larvae secrete unidentified soluble compounds that improve survival to starvation. This protection is proportional to larval population density. Thus, animals arrested at high densities display an enhanced resistance to starvation. Here we show that this chemical communication also influences recovery after prolonged periods in L1 arrest. Animals at high density recovered faster than animals at low density. We found that the density effect on survival depends on the final effector of the insulin signaling pathway, the transcription factor DAF-16. Moreover, DAF-16 activation was higher at high density, consistent with a lower expression of the insulin-like peptide DAF-28 in the neurons. The improved recovery of animals after arrest at high density depended on soluble compounds present in the media of arrested L1s. In a try to find the nature of these compounds, we investigated the disaccharide trehalose as putative signaling molecule, since its production is enhanced during L1 arrest and it is able to activate DAF-16. We detected the presence of secreted trehalose in the medium of arrested L1 larvae at a low concentration. The addition of this concentration of trehalose to animals arrested at low density was enough to rescue DAF-28 production and DAF-16 activation to the levels of animals arrested at high density. However, despite activating DAF-16, trehalose was not capable of reversing survival and recovery phenotypes, suggesting the participation of additional signaling molecules. We finally identified GUR-3 as a possible trehalose receptor in C. elegans. With all, here we describe a molecular mechanism underlying social communication that allows C. elegans to maintain arrested L1 larvae ready to quickly recover as soon as they encounter nutrient sources.

developmental biology↗