Biology subjects

Femenia, T.

Publications and source records attributed to Femenia, T..

5 recordsLinked to original sources

bioRxiv2026

Rectifying Stress into Structural Memory Drives Specialization in Cells and Adaptive Computational Systems

Functional specialization in continuous systems requires balancing adaptation to environmental stress with the preservation of encoded information. Yet, the physical constraints governing how living systems reconcile selective information retention with energetic structural reorganization remain unclear-a trade-off that may offer transferable design rules for adaptive computing. Here we present a unified framework that connects cellular specialization to adaptive machine learning through principles of nonequilibrium optimization. We find that asymmetric fluctuations in key parameters act as tunable drives that, when phase-aligned, are rectified into durable functional specialization. Biologically, we show that in adipose mesenchymal cells, transient nutrient deficits trigger cytosolic pH fluctuations. These oscillations, regulated by the ATP12A proton pump, modulate nuclear compartment dynamics to coordinate mitochondrial specialization and lock in epigenetic memory for phenotype persistence. Notably, modulating ATP12A amplifies these drives, enhancing functional specialization and metabolic homeostasis in disease models. Computationally, we formalize analogous principles using a compositional framework based on operadic algebra, where structural updates act as a topological ratchet converting drive fluctuations into persistent architectures. This reveals a learning regime where gains in predictive information are accompanied by auditable residual costs for non-predictive states and reorganization. As a proof of concept, we deploy a self-organizing machine learning system that discovers latent hierarchy and reconstructs data through adaptive compartment dynamics. We show that internal organization fluctuations increase with residuals, an information-processing ledger guiding adaptive computation. Across both domains, local organization gains are directionally linked to dissipation proxies (pH variance in vivo and residuals in silico), consistent with operation under shared constraints. Overall, this work identifies asymmetric-drive rectification as a fundamental mechanism of adaptive specialization, providing thermodynamically informed design rules for both bioengineering and adaptive AI. One-Sentence SummaryAsymmetric-drive rectification is a fundamental mechanism by which cells and adaptive computational systems convert internal stress into structural memory, encoding functional specialization

biophysics↗

bioRxiv2025

Convergent Signals Encode Persistent Memory of Resilient States

Caloric restriction reduces metabolic disease and associated comorbidities. Yet, the molecular mechanisms encoding cellular memory of these benefits remain unclear. Here, we use a functional genomics approach to integrate evolutionary cues, single-cell sequencing, and metabolomics, identifying convergent signals that encode epigenetic memory of adaptive states in visceral adipose tissue natural killer (NK) cells. Cross-species analysis shows that genomic hubs linked to human accelerated regions (HARs) are conserved and active during dietary restriction, forming transcriptional compartments that regulate oxidative stress response and DNA repair genes. Targeted screens and multimodal profiling across human data and mouse models reveal convergent signals needed for persistent adaptation: cooperative transcriptional regulators (NRF2, CIRBP, NR4A2) at key HAR-linked genomic hubs, innate immune mediators (IL15-IL2RB), and metabolic cofactors from linoleic acid oxidation. Activity of these convergent signals reduces DNA damage and methylation and enhances epigenetic plasticity and cytotoxic functions, thereby decreasing tissue fibrosis and senescence while maintaining both local and systemic metabolic plasticity. Mechanistically, linoleic acid metabolism supplies acetyl-CoA to sustain H3K27ac epigenetic marks that maintain coordinated repair and cytotoxic programs after programming. IL15-IL2RB signaling links tissue metabolic state to NK cell function for coherent adaptive responses. We show that engineering of NK cells with this multimodal programming leads to long-term preservation of therapeutic phenotypes in metabolic aging models, rescuing systemic dysfunction through damaged cells clearance and leptin sensitivity. Overall, these findings establish that convergent signals encode persistent cellular phenotypes linked to metabolic plasticity, suggesting design principles for engineering therapeutic memory of cell function. One-Sentence SummaryA multimodal approach reveals how dietary and evolutionary cues can be harnessed to engineer resilient phenotype memory.

immunology↗

bioRxiv2025

Energy Conservation Drives Adaptive Specialization Through Fine-tuned Organizations

Energy conservation is at the basis of evolutionary optimization in living systems. Yet, how cells maintain function during metabolic stress while preserving adaptive capacity remains unclear. Here, we use a functional genomics approach to identify metabolic human accelerated regions (mHARs) genomic hubs (evolutionarily tuned regions) in adipose tissue that coordinate adaptive responses to nutrient deficit. During fasting, cooperative regulators PGC1A, YY1, and CTCF activate these hubs, promoting chromatin contacts that regulate lipid cycling genes such as Dgat1 and Atg4c. This activation maintains lipid and pH homeostasis while limiting oxidative stress, thereby preserving cellular plasticity. When disrupted, nutrient-stress adaptations are impaired leading to metabolic dysfunction and glucose intolerance. This is driven by NCOA7, an oxidative stress mediator that impairs lysosome function and transcriptional plasticity, triggering an inflammatory response. In cellular models, this mechanism blocks pH-mediated PGC1A droplet plasticity, further inhibiting mHAR-genomic hub activity and metabolic homeostasis. Human adipocytes show enhanced transcriptional activity of these genomic hubs compared to murine cells, with multi-enhancer mHAR regulation suppressing disease-associated variants linked to ANGPTL3 and PCSK9. Loss of this cooperative plasticity shifts cells to maladaptive responses, activating STAT1-driven disease gene expression. Our findings reveal that investigating the contextual activity of evolutionary adaptations can uncover functional hubs critical for stress resilience. This also shows that cells exploit nutrient fluctuations to drive tunable transcriptional organizations that lead to durable adaptations, identifying actionable targets for metabolic disease. One-Sentence SummaryEvolutionary tuned nuclear compartments convert nutrient stress into adaptive transcriptional organizations that preserve plasticity and suppress metabolic disease.

physiology↗

bioRxiv2023

Local recurrent circuits modulate visual center and surround interactions in the mouse superior colliculus

Center-surround interactions are fundamental to visual saliency computation, but debate continues over whether and how subcortical visual circuits actively contribute. To address this, we developed an optogenetic approach to delineate the visual center and surround zones of individual neurons in the superficial layer of the superior colliculus (SCs) using only retinal ganglion cell input. Using whole-cell recordings, we demonstrate that surround network activation suppresses center excitability, indicating that SCs circuitry is self-sufficient in driving center-surround dynamics. Through cell-type-specific trans-synaptic tracing and large-scale modeling, we identified an SCs-based circuit with two key motifs driving surround modulation: recurrent excitation and feedback inhibition. We propose that subcortical visual circuits in the SCs have evolved to perform surround suppression alongside retinal and cortical suppression, facilitating the distribution of parallel saliency computations across different levels. Significance statementThis study questions the notion that the superior colliculus (SC) merely acts as a passive recipient of saliency information from upstream circuits. We demonstrate that the SC can independently generate center-surround interactions that could contribute to visual saliency through local circuits without top-down input. This ability represents a computation that has been conserved since the dawn of vertebrate evolution. By mapping these interactions, we reveal that the mouse SC actively induces visual surround suppression. These findings suggest that phylogenetically older circuits in the SC may play a more independent role in active vision than previously acknowledged, prompting a reevaluation of visual saliency processing across subcortical brain regions.

neuroscience↗

bioRxiv2021

Metabolic resilience is encoded in genome plasticity

Metabolism plays a central role in evolution, as resource conservation is a selective pressure for fitness and survival. Resource-driven adaptations offer a good model to study evolutionary innovation more broadly. It remains unknown how resource-driven optimization of genome function integrates chromatin architecture with transcriptional phase transitions. Here we show that tuning of genome architecture and heterotypic transcriptional condensates mediate resilience to nutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fat tissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1A condensates. We find evolutionary adaptations in several dimensions; low conservation of amino acid residues within protein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stability through cis-regulatory anchoring and encoding of genome plasticity in radial chromatin organization. We show that environmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization of lipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidative stress, and fatty-acid mediated cellular acidification, enabling endurance of condensate chromatin conformations. Comparative genomics of genetic and diet perturbations reveal mammalian convergence of phenotype and structural relationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptional organization is encoded in functional divergence of metabolic disease variant-hubs, heterotypic condensate composition, and protein residues sensing metabolic variation. During fuel restriction, these features license the formation of large heterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanism maintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity through transcriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-like adaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here a general principle by which transcription uses environmental fluctuations for genome function, and demonstrate how resource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesity as an inhibitor of genome plasticity relevant for many diseases.

systems biology↗