Biology subjects

Hidalgo, D.

Publications and source records attributed to Hidalgo, D..

7 recordsLinked to original sources

bioRxiv2026

Potential benefit of loss-of-function on bacterial fitness

Escherichia coli is a well-studied organism with extensive genomic and proteomic data. This study examines how gene loss reallocates cellular resources and impacts fitness. Genes were classified based on fitness measurements as essential, important, mean-effect, or fitness-enhancing. Using proteomic data, we analyzed the relationship between protein production cost and fitness, finding that genes with a high proteomic mass fraction are more likely to affect fitness, while fitness-enhancing deletions rarely improve fitness by reducing proteomic burden. We calculated the cumulative of proteome fractions encoded by genes classified as mean-effect and compared it with the results from the ME-model simulations. The mean-effect category constitutes 31-75% of the proteome, with the highest proportion LB, while enrichment analysis of core mean-effect genes highlighted transmembrane transport as the main functional category. Furthermore, we identified a subset of genes whose deletion increased fitness compared to the mean; they generally have low expression, and many have unknown functions. AI-assisted structural analyses identified domains and conserved features compatible with DNA-binding proteins, suggesting that some may represent putative transcriptional regulators requiring further validation. RpoS, stress sigma factor controlling up to 15% of the proteome is one of the transcriptional regulators in the fitness-enhancing category. Our findings suggest that the cost of being a generalist is linked to transcriptional regulation, while molecular transport represents a high burden for nutrient readiness. ImportanceThis study provides new insights into how gene loss benefits bacteria by identifying gene categories and their associated protein fractions whose disruption does not impose large fitness penalties. Additionally, it uncovers specific fitness-enhancing genes and generates hypotheses based on structural analyses for previously uncharacterized ones. Our findings suggest that several of these genes may encode putative transcriptional regulators, highlighting a potential role for regulatory complexity in cellular efficiency. By revealing how certain gene deletions enhance fitness and which gene categories are nonessential, this work advances our understanding of bacterial adaptation and genome streamlining. These insights have broad implications for evolutionary biology, metabolic engineering, and biotechnology, offering strategies to optimize microbial function by selectively reducing genetic and regulatory burden.

systems biology↗

bioRxiv2024

Trial-by-trial inter-areal interactions in visual cortex in the presence or absence of visual stimulation

State-of-the-art computational models of vision largely focus on fitting trial-averaged spike counts to visual stimuli using overparameterized neural networks. However, a computational model of the visual cortex should predict the dynamic responses of neurons in single trials across different experimental conditions. In this study, we investigated trial-by-trial inter-areal interactions in the visual cortex by predicting neuronal activity in one area based on activity in another, distinguishing between stimulus-driven and non-stimulus-driven shared variability. We analyzed two datasets: calcium imaging from mouse V1 layers 2/3 and 4, and extracellular neurophysiological recordings from macaque V1 and V4. Our results show that neuronal activity can be predicted bidirectionally between L2/3 and L4 in mice, and between V1 and V4 in macaque monkeys, with the latter interaction exhibiting directional asymmetry. The predictability of neuronal responses varied with the type of visual stimulus, yet responses could also be predicted in the absence of visual stimulation. In mice, we observed a bimodal distribution of neurons, with some neurons primarily driven by visual inputs and others showing predictable activity during spontaneous activity despite lacking consistent visually evoked responses. Predictability also depended on intrinsic neuronal properties, receptive field overlap, and the relative timing of activity across areas. Our findings highlight the presence of both stimulus- and non-stimulus-related components in interactions between visual areas across diverse contexts and underscore the importance of non-visual shared variability between visual regions in both mice and macaques.

neuroscience↗

bioRxiv2021

Regulatory perturbations of ribosome allocation results in a trade-off between fast growth and adaptation capacity

Bacteria regulate their cellular resource allocation to enable fast growth-adaptation to a variety of environmental niches. We studied the ribosomal allocation, growth and expression profiles of two sets of fast-growing mutants of Escherichia coli K-12 MG1655 in glucose minimal medium. Mutants with only 3 of the seven copies of ribosomal RNA operons grew faster than the wild-type strain in minimal media and show similar phenotype to previously studied rpoB mutants. Higher growth rates due to increased ribosome content affected resource allocation. Expression profiles of fast-growing mutants shared downregulation of hedging functions and upregulated growth functions. Mutants showed longer diauxic shifts and reduced activity of gluconeogenic promoters during glucose-acetate shifts, suggesting reduced availability of the RNA Polymerase for expressing hedging proteome. These results show that the regulation of ribosomal allocation underlies the growth/hedging phenotypes obtained from laboratory evolution experiments. We show how two different regulatory perturbations (rRNA promoters or rpoB mutations) reshape the proteome for growth with a concomitant fitness cost HighlightsMutants with only 3 ribosomal operons grow faster than wild-type in minimal medium {Delta}4 rrn and rpoB mutants share phenotypic traits Faster growth of mutants is achieved by increased ribosome content Fast-growing mutants display reduced hedging expression and adaptation trade-offs Despite similar ribosomal content in rich medium the mutants present growth defects

systems biology↗

bioRxiv2020

The Erythropoietin Receptor Stimulates Rapid Cycling and Formation of Larger Red Cells During Mouse and Human Erythropoiesis

Erythroid terminal differentiation entails cell divisions that are coupled to progressive decreases in cell size. EpoR signaling is essential for the survival of erythroid precursors, but it is unclear whether it has other functions in these cells. Here we endowed mouse precursors that lack the EpoR with survival signaling, finding that this was sufficient to support their differentiation into enucleated red cells, but that the process was abnormal. Precursors underwent fewer and slower cell cycles and yet differentiated into smaller red cells. Surprisingly, EpoR further accelerated cycling of early erythroblasts, the fastest cycling cells in the bone marrow, while simultaneously increasing their cell size. EpoR-mediated formation of larger red cells was independent of the established pathway regulating red cell size by iron through Heme-regulated eIF2 kinase (HRI). We confirmed the effect of Epo on red cell size in human volunteers, whose mean corpuscular volume (MCV) increased following Epo administration. This increase persisted after Epo declined and was not the result of increased reticulocytes. Our work reveals a unique effect of EpoR signaling on the interaction between the cell cycle and cell growth. Further, it suggests new diagnostic interpretations for increased red cell volume, as reflecting high Epo and erythropoietic stress.

developmental biology↗

bioRxiv2019

Dissection of the 4D chromatin structure of the α-globin locus through in vivo erythroid differentiation with extreme spatial and temporal resolution

Mammalian gene expression patterns are controlled by regulatory elements, which interact within Topologically Associating Domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. We developed Tiled-C, a low-input Chromosome Conformation Capture (3C) approach, to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of matched chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. In contrast to previous reports, our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.

genomics↗

bioRxiv2018

Emergence of the erythroid lineage from multipotent hematopoiesis

Red cell formation begins with the hematopoietic stem cell, but the manner by which it gives rise to erythroid progenitors, and their subsequent developmental path, remain unclear. Here we combined single-cell transcriptomics of murine hematopoietic tissues with fate potential assays to infer a continuous yet hierarchical structure for the hematopoietic network. We define the erythroid differentiation trajectory as it emerges from multipotency and diverges from 6 other blood lineages. With the aid of a new flow-cytometric sorting strategy, we validated predicted cell fate potentials at the single cell level, revealing a coupling between erythroid and basophil/mast cell fates. We uncovered novel growth factor receptor regulators of the erythroid trajectory, including the proinflammatory IL-17RA, found to be a strong erythroid stimulator; and identified a global hematopoietic response to stress erythropoiesis. We further identified transcriptional and high-purity FACS gates for the complete isolation of all classically-defined erythroid burst-forming (BFU-e) and colony-forming progenitors (CFU-e), finding that they express a dedicated transcriptional program, distinct from that of terminally-differentiating erythroblasts. Intriguingly, profound remodeling of the cell cycle is intimately entwined with CFU-e developmental progression and with a sharp transcriptional switch that extinguishes the CFU-e stage and activates terminal differentiation. Underlying these results, our work showcases the utility of theoretic approaches linking transcriptomic data to predictive fate models, providing key insights into lineage development in vivo.

systems biology↗

bioRxiv2017

A hyperthermophilic phage decoration protein suggests common evolutionary origin with Herpesvirus Triplex proteins and an anti-CRISPR protein

Virus capsid proteins reproducibly self-assemble into regularly-shaped, stable shells that protect the viral genome from external environmental assaults, while maintaining the high internal pressure of the tightly packaged viral genome. To elucidate how capsids maintain stability under harsh conditions, we investigated the capsid components of a hyperthermophilic virus, phage P74-26. We determined the structure of a capsid protein gp87 and show that it has the same fold as trimeric decoration proteins that enhance the structural stability of capsids in many other phage, despite lacking significant sequence homology. We also find that gp87 is significantly more stable than its mesophilic homologs, reflecting the high temperature environment in which phage P74-26 thrives. Our analysis of the gp87 structure reveals that the core domain of the decoration protein is conserved in trimeric capsid components across numerous dsDNA viruses, including human pathogens such as Herpesviruses. Moreover, this core {beta}-barrel domain is found in the anti-CRISPR protein AcrIIC1, which suggests a mechanism for the evolution of this broad spectrum Cas9 inhibitor. Our work illustrates the principles for increased stability of a thermophilic decoration protein, and extends the evolutionary reach of the core trimeric decoration protein fold.

biochemistry↗