Biology subjects

Jordan, A.

Publications and source records attributed to Jordan, A..

At least 19 recordsLinked to original sources

bioRxiv2026

β3-Integrin controls pericyte metabolic states and shapes tumour-stromal metabolic crosstalk in breast cancer

Pericytes are emerging as dynamic regulators of the tumour microenvironment. Yet, their role in tumour metabolism remains elusive. Here, we investigate whether {beta}3-integrin regulates pericyte metabolic state and shapes stromal-tumour metabolic interactions in breast cancer. By integrating spatial and single-cell transcriptomics from human breast tumours with multi-omics profiling of tumour-derived pericytes in vitro, we identify two {beta}3-integrin-dependent metabolic states. {beta}3-integrin-high pericytes display a metabolically active phenotype characterised by increased glycolysis and enhanced de novo serine/glycine synthesis, supporting collagen production. In contrast, {beta}3-integrin loss induces a lipid-associated state, marked by neutral lipid accumulation and lipid droplets. Mechanistically, {beta}3-integrin regulates this metabolic switch via mTOR signalling. Importantly, these states extend beyond pericytes, with adjacent cancer cells shifting towards fatty acid oxidation and lipid use near {beta}3-integrin-low pericytes. Together, our findings establish {beta}3-integrin as a key metabolic switch in pericytes and highlight their role in driving tumour metabolic plasticity.

cancer biology↗

bioRxiv2026

Mural β3-integrin signposts Stroma6, a gene signature predicting early relapse in low-risk and chemoresistant breast cancer

The Oncotype DX (ODX) assay guides adjuvant chemotherapy in ER+/HER2- breast cancer but overlooks drivers from the tumour stroma, leaving some low-risk and chemotherapy-spared patients vulnerable to rapid relapse. Here, we show that perivascular mural {beta}3-integrin protein expression predicts early (3-year) relapse in ODX low-risk patients (HR = 15.80, P = 0.010), from which we derived a translatable 6-gene stromal signature, termed Stroma6. High Stroma6 expression predicted early recurrence in the ODX low-risk discovery cohort, with zero early relapses in the low-expression group. External validation in the METABRIC dataset confirmed that Stroma6 independently predicts rapid recurrence in ODX low-risk patients (HR = 11.68, P = 0.002). Furthermore, Stroma6 utility extends to clinical chemoresistance, independently predicting early events in a pan-subtype cohort with residual disease following neoadjuvant chemotherapy (HR = 2.29, P = 0.003). Ultimately, Stroma6 is a robust prognostic signature identifying patients at high risk of early recurrence across diverse clinical contexts.

cancer biology↗

bioRxiv2026

Bifidobacterium pseudocatenulatum extracellular vesicles promote Ly6G+ granulocyte infiltration to inhibit melanoma tumour progression

Harnessing the immunomodulatory capacity of commensal bacteria is an emerging avenue in cancer therapy. Bacterial extracellular vesicles (BEVs) provide a non-replicating, nanoscale alternative to live microbes with the potential for safer systemic delivery. Here, we investigated BEVs from a novel Gram-positive strain of Bifidobacterium pseudocatenulatum (Bif-210). Intravenous administration of Bif-210 BEVs reduced B16-F10 melanoma growth in C57BL/6J mice. Mechanistically, BEVs increased tumour-infiltrating Ly6G+ granulocytes in vivo, increased CD11b+Ly6G+ and ICAM-1+Ly6G+ bone marrow populations, and induced production of the neutrophil-attracting chemokines KC/CXCL1 (mouse) and IL-8 (human). Although Ly6G+ depletion independently inhibited tumour growth, it did not combine additively with BEVs, supporting a model in which Bif-210 BEVs alter Ly6G+ granulocyte function rather than simply expanding a conventional pro-tumour granulocyte pool. BEVs activated TLR2, did not activate TLR4, and upregulated TLR2 on Ly6G+ cells, while proxy assays provided no evidence of NETosis-associated activation. Repeated intravenous BEV administration produced no overt toxicity by tissue histology, body temperature, or body weight monitoring. These findings position B. pseudocatenulatum BEVs as a promising systemic immunotherapy that recruits and re-educates granulocytes via a TLR2-centred pathway to restrain melanoma progression. HIGHLIGHTSO_LIIntravenous Bif-210 BEVs reduce established B16-F10 melanoma growth in mice. C_LIO_LIBif-210 BEVs selectively increase tumour-associated Ly6G+ granulocytes. C_LIO_LIBEV treatment and Ly6G depletion are non-additive, linking BEV activity to granulocyte biology. C_LIO_LIBif-210 BEVs expand Ly6G+ bone marrow populations and induce granulocyte-recruiting chemokines. C_LIO_LIBif-210 BEVs engage TLR2 and enhance granulocyte fitness without NETosis-associated activation. C_LI

cancer biology↗

bioRxiv2026

Tube to Tumour: an integrative epigenomic analysis of DNA methylation in high-grade serous ovarian cancer and precursor serous tubal intraepithelial carcinoma

Serous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). Yet, molecular events driving progression from STIC to HGSOC remain poorly defined. Aberrant DNA methylation is a hallmark of cancer, yet its role in early HGSOC remains unclear. We performed a comprehensive meta-analysis of publicly available Illumina Infinium DNA methylation EPIC array datasets assessing 255 samples comprising STIC, HGSOC, and histologically normal fallopian tube tissues. We mapped DNA methylation alterations during early tumorigenesis, identified conserved methylation patterns across STIC and HGSOC, and assessed RNA-sequencing data to define transcriptional consequences within genomic and epigenomic landscapes. STIC and HGSOC exhibited widespread DNA hypomethylation relative to normal tissue, accompanied by focal hypermethylation in CpG islands and 5' regulatory regions. DNA Hypomethylation intensifies during progression from STIC to HGSOC, particularly in cis-regulatory enhancer domains and intergenic regions. We identified 11,660 CpG sites and 447 genomic regions with conserved DNA methylation patterns across STIC and HGSOC. Within these, 70 genes showed coordinated DNA methylation and expression changes, including TRIM15, NKAPL, and RIPPLY3. These findings reveal that epigenetic remodelling occurs in STIC lesions, prior to malignant transformation. DNA methylation alterations at regulatory regions may drive invasion and offer novel avenues for early detection and targeted intervention.

Cancer Biology↗

bioRxiv2026

Topographic structure and function of locus coeruleus norepinephrine neurons

Norepinephrine (NE) is released throughout most of the central nervous system by neurons in the locus coeruleus (LC). We found a relationship between the morphologies, gene expression, and activity of LC-NE neurons in mice. Axonal projections of individual neurons were extensive but largely confined to subsets of brain regions. Axonal projections and graded gene expression correlated with locations of cell bodies in LC. In a behavioral task requiring ongoing learning from actions, neurons in dorsal LC projecting to the cerebral cortex were excited when mice made a different choice from the previous one and by reward prediction errors, a signal driving learning. Background activity of neurons in ventral LC was higher when mice ignored stimuli indicating potential reward availability. These observations reveal a topographically organized structure and function of a neurotransmitter system and show that it contains learning signals for flexible behavior.

neuroscience↗

bioRxiv2026

Morphoelectric Diversity and Specialization of Neuronal Cell Types in the Primate Striatum

The basal ganglia are evolutionary ancient subcortical nuclei that form interconnected loops with the neocortex and limbic system to regulate movement, learning, habit formation, emotion, and motivation. Their dysfunction contributes to major neurological and psychiatric disorders, yet most cellular-level insights derive from rodent studies, leaving knowledge gaps in humans and translationally relevant primate species. To address this, we generated multi-modal Patch-seq data linking transcriptomic identity with morphological and electrophysiological properties in macaque striatum, the input nucleus of the basal ganglia. We found underappreciated diversity among medium spiny neurons, including non-canonical types, and variation aligned with functional gradients. Interneurons also exhibited spatial variation and even greater morphoelectric diversity, highlighting their functional modularity. Despite broad evolutionary conservation, we identified primate-specific features and key differences from rodent striatal neurons. By integrating molecular classification with cellular properties that shape network function, our findings provide insights into the functional organization of the primate striatum.

neuroscience↗

bioRxiv2026

A Cross-Species Enhancer-AAV Toolkit for Cell Type-Specific Targeting Across the Basal Ganglia

The mammalian basal ganglia (BG) orchestrate motor, cognitive, and affective functions, yet cell type-specific genetic access remains limited, especially beyond rodents. Key structures implicated in movement and psychiatric disorders, including pallidum, subthalamic nucleus, and dopaminergic midbrain, lack scalable tools for cross-species targeting. Here, we present a comprehensive enhancer-AAV library enabling selective labeling and manipulation of major BG neuronal populations: striatal projection neuron subtypes, pallidal and subthalamic neurons, and midbrain dopaminergic and GABAergic populations. Using an evolutionarily informed discovery pipeline, we identified enhancers targeting canonical, non-canonical, and disease-relevant cell types, with validation demonstrating robust cross-species conservation of specificity between mouse and macaque. Computational modeling revealed sequence features predictive of in vivo performance, including motif grammar, chromatin accessibility, and evolutionary conservation, and identified distinct regulatory architectures across glial, projection, and interneuron lineages. This work establishes a comprehensive cross-species viral toolkit for the BG, unlocking previously inaccessible cell types for circuit dissection.

neuroscience↗

bioRxiv2025

Identity-stable multi-animal tracking using bidirectional segmentation with object-level memory

Tracking animal behavior in naturalistic settings is essential for understanding social dynamics and their neural underpinnings. Pose estimation methods can produce accurate keypoints using framewise inference. However, post hoc tracking steps often struggle to maintain consistent identity over time, particularly during close and rapid social interactions between visually similar animals. We present a pipeline for bidirectional video object segmentation (VOS) to correct identity swaps with much less manual annotation effort, addressing the prohibitive cost of identity correction of pose estimation data in long recordings and large cohorts. Our approach makes use of a state-of-the-art VOS algorithm, Cutie, which leverages both pixel- and object-level representations across multiple memory timescales. By comparing segmentation masks from independent forward and reverse inference runs, we identify localized zones of disagreement and flag them for manual review. When applied to more than 160 hours of dyadic vole interaction videos, our method reduces identity swaps by two orders of magnitude compared to typical pose estimation workflows and requires review of less than 0.3% of frames per video to achieve identity error-free segmentation masks and aligned keypoints. Our approach generalizes to social interactions involving three or more animals, with scalability constrained primarily by behavioral complexity (e.g., complete occlusion of multiple individuals). Our method enables scalable, long-term tracking of unmarked animals in group settings and provides a practical foundation for more naturalistic studies of social behavior. To lower the barrier for researchers facing similar tracking challenges, we provide an accessible graphical user interface for general use.

animal behavior and cognition↗

bioRxiv2025

H1.3 depletion in AML cells prompts H1.2 redistribution, chromatin remodeling and cell cycle defects

Linker histone H1 variants play critical, yet distinct, roles in chromatin organization and gene regulation. However, very little is known about their specificity in cancer cells. In this study, we investigated the specificity of the H1.3 variant in acute myeloid leukemia (AML) cells. Through chromatin mapping and transcriptomic analyses, we revealed that H1.3 was enriched explicitly in regions with a high GC content and co-localized with the repressive mark H3K27me3, supporting its role in chromatin compaction and transcriptional repression. Knockout of H1.3 induced specific changes in gene expression profiles and chromatin dynamics, characterized by the relocalization of H1.2, which was redistributed from its usual chromatin regions to the freed H1.3 regions. Consequently, locus-specific chromatin alterations associated with interferon-related signalling pathways and cell cycle deregulation were observed. Our findings emphasized an important and locus-specific function of H1.3 in AML cells. Overall, our study revealed a mechanistic connection between H1 variant imbalance, immune response activation, and cell cycle regulation, with implications for our understanding of epigenetic regulation in cancer cells.

genomics↗

bioRxiv2025

vassi - verifiable, automated scoring of social interactions in animal groups

Behavioral biologists, from neuroscientists to ethologists, rely on observation and scoring of behavior. In the past decade, numerous methods have emerged to automate this scoring through machine learning approaches. Yet, these methods are typically specified towards laboratory settings with only two animals, or employed in cases with well-separated behavioral categories. Here, we introduce the vassi Python package, focusing on supervised classification of directed social interactions and cases in which continuous variation in behavior means categories are less distinct. Our package is broadly applicable across species and social settings, including single individuals, pairs and groups, and implements a validation tool to separate behavioral edge cases. vassi has comparable performance to existing approaches on a behavioral classification benchmark, the CALMS21 mouse resident-intruder dataset, and we demonstrate its applicability on a novel, more naturalistic and complex dataset of cichlid fish groups. Our approach highlights future challenges in extending supervised behavioral classification to more naturalistic settings, and offers a methodological framework to overcome these challenges. Lay Summaryvassi (verifiable, automated scoring of social interactions) is a flexible, Python-based framework for automated behavioral classification and its verification through interactive visualization. vassi enables researchers to quantify directed social interactions in animal groups in naturalistic settings, bridging the gap between traditional ethology and modern computational tools.

animal behavior and cognition↗

bioRxiv2025

Exercise serum promotes DNA damage repair and upregulates DNA repair gene PNKP in colon cancer cells

Exercise protects against colon cancer progression, but the underlying biological mechanisms remain incompletely understood. One proposed mechanism is the release of bioactive molecules into the interstitium and systemic circulation during exercise, which may act directly on precancerous or tumour cells to suppress DNA damage, inhibit proliferation, and preserve genomic stability. Here, we evaluated the effects of exercise-conditioned human serum on DNA damage kinetics and transcriptomic signatures in colon cancer cells. Blood samples were collected from 30 participants (age 50-78 years, body mass index [≥]25 kg/m2) before and immediately after a maximal incremental cycling test. LoVo cells were exposed to pre- or post-exercise serum, treated with 2 Gy irradiation, and assessed for {gamma}-H2AX foci over 24 hours. Compared to pre-exercise serum, post-exercise serum significantly reduced {gamma}-H2AX foci at 6 hours (p=0.024) and decreased the area under the curve (AUC, p=0.014), indicating accelerated DNA repair. Post-exercise serum also increased expression of the DNA repair protein PNKP in LoVo cells, both with and without irradiation (p=0.007 and p=0.029, respectively). Transcriptomic analysis revealed upregulation of mitochondrial energy metabolism and downregulation of cell cycle and proteasome-related pathways. These findings suggest that acute exercise elicits systemic responses that enhance DNA repair and shift colon cancer cells towards a less proliferative transcriptomic state under sublethal genotoxic stress, offering a potential mechanistic explanation for the protective effects of exercise against colorectal carcinogenesis.

cancer biology↗

bioRxiv2025

Gene regulatory mechanisms underlying evolutionary adaptations of homologous neuronal cell types

How nervous systems coordinate the generation of specific neuron types with gene expression plasticity and how these mechanisms impact cell type evolution is unknown. Here we use Caenorhabditis species to study neuron-type robustness, plasticity and evolution, using VC4 and VC5 cholinergic motoneurons as models. In C. elegans, we found that epigenetic silencing through histone 3 lysine 9 methylation (H3K9me) is necessary to suppress the expression of the serotonin reuptake gene mod-5/Sert and a serotonergic phenotype in these cells. In contrast, we observed that VC4 and VC5 neurons in the Angaria group of species of the Caenorhabditis genus have evolved an intense serotonergic staining. This phenotype is caused by the emergence of a new enhancer in the mod-5/Sert locus, which has been recruited to the ancestral neuron-type gene regulatory network. Enhancer transfer from C. angaria is sufficient to impose a constitutive serotonergic fate in C. elegans. Remarkably, acquiring this new trait modulates egg-laying responses to high levels of exogenous serotonin, which can be found in specific environments. Finally, we discovered that the repression of the serotonergic fate in C. elegans VC4 and VC5 neurons is indeed a plastic trait that can be adjusted in specific environmental growth conditions to elicit egg-laying behaviours similar to those observed in Angaria species. Our work identifies gene regulatory mechanisms that coordinate the generation of robust neuron-type-specific programs with plastic gene expression responses. These findings identify a gene regulatory framework underlying the evolution of neuron-type-specific features and the emergence of novel behaviours.

evolutionary biology↗

bioRxiv2025

Differential regulation of histone H1 subtypes by N6-methyladenosine RNA methylation.

Histone H1 is involved in the regulation of chromatin structure and gene expression. Up to seven H1 subtypes or variants are expressed in human somatic cells. The H1 complement, defined as the subtype composition and proportions in each cell, is highly variable depending on the cell type, cell cycle stage, developmental context, and several diseases such as cancer. This variability results from the combined action of multiple regulatory processes. Epitranscriptomic modifications have emerged as a new regulatory layer capable of controlling all aspects of mRNA metabolism. In this work, we examined the role of the most prevalent mRNA modification, N6 methyladenosine (m6A), in the regulation of H1 subtypes. MeRIP-seq showed that H1-0 and H1-4 are enriched in m6A, whereas H1-2 displays intermediate levels of this mark. Integration of the functional studies involving m6A inhibition and partial depletion of these m6A readers led us to propose the first model of the differential regulation of H1 subtypes by m6A. In this model, m6A promotes the degradation of H1-0 mRNA mediated by YTHDF2, while it enhances the stability of H1-2 mRNA through IGF2BP1 binding and its translation by the combined action of IGF2BP1 and hnRNPD. In the case of H1-4, m6A promotes its transcription and stimulates its translation via hnRNPD binding. These findings suggest that m6A participates in the subtype-specific regulation of H1 variants, adding another layer to their complex regulation and contributing to the variability of the H1 complement in cancer. KeypointsO_LIHistone transcripts have different levels of m6A. C_LIO_LIWe analyzed the function of m6A in H1-0, H1-2, and H1-4 and identified its readers. C_LIO_LIWe propose the first model of the role of m6A in the subtype-specific regulation of histone H1. C_LI

molecular biology↗

bioRxiv2024

Population comparisons reveal more social interactions are correlated with larger brains in the Lake Tanganyikan cichlid Neolamprologus brevis

The Social Brain Hypothesis (SBH) proposes that complex social environments drive the evolution of larger brains and specific neuroanatomical adaptations. This relationship can be difficult to study in the wild, because species that differ in social organization may also diverge in morphology, ecology, phylogeny, and other life history parameters. Here we use two populations of the shell-dwelling cichlid Neolamprologus brevis with contrasting social environments to test whether increased social complexity is associated with larger brain sizes or specific regional adaptations. Behavioral observations revealed similarly low feeding rates in both populations, but significantly more frequent social interaction frequencies in the population one of the populations. This population had larger total brain volumes relative to body size, with a disproportionately larger telencephalon and a smaller hypothalamus, suggesting region-specific adaptations to social demands. By integrating behavioral quantification and neuroanatomical analysis, our study highlights the importance of sociality as a driver of brain evolution and demonstrates the utility of cichlid fish as a model for testing the SBH in non-mammalian systems. These findings provide empirical support for the SBH and underscore the value of combining behavioral and morphological data in evolutionary neuroethology.

animal behavior and cognition↗

bioRxiv2024

Multiple within species comparisons show Tanganyikan cichlid fish have larger brains in less structurally complex habitats

Many studies have found a link between higher habitat structural complexity and increased relative brain size in vertebrates. Here we explore this relationship in a multi-species comparison, comparing ten species of wild cichlids that differ in their social and territorial behaviour, but which occur across four ecologically similar but structurally diverse rocky habitats. This design allows us to perform repeated intra-specific comparisons, avoiding confounds associated with comparisons across species boundaries. We sampled 147 fish, analysing brain size and architecture while controlling for body mass and species-specific variability and compared this with habitat complexity, quantified using underwater video and three-dimensional reconstructions. Our results challenge the Clever Foraging Hypothesis (CFH), which posits that greater habitat complexity correlates with larger brain sizes. Contrary to CFH, fish from the least complex habitat had significantly larger brains. Additionally, brain architecture analysis indicated a significant enlargement of the cerebellum in fish from less complex habitats, whereas the hypothalamus showed a non-significant negative trend. Taken together, these results indicate that lower habitat complexity may impose higher cognitive demands on spatial memory and navigation due to limited refuges and increased predation risk. This study highlights the need to reconsider the assumed linear positive relationship between environmental complexity and brain development, suggesting that simpler environments might also impose significant cognitive and ecological challenges that drive brain evolution. Our findings underscore the importance of considering intra-species variability and the specific ecological and cognitive demands of different habitats in studies of brain evolution.

evolutionary biology↗

bioRxiv2024

Chromosome-level Assemblies of Three Candidatus Liberibacter solanacearum Vectors: Dyspersa apicalis, Dyspersa pallida, and Trioza urticae (Hemiptera: Psylloidea)

Psyllids are major vectors of plant diseases, including Candidatus Liberibacter solanacearum (CLso), the bacterial agent associated with zebra chip disease in potatoes and carrot yellows disease in carrot. Despite their agricultural significance, there is limited knowledge on the genome structure and genetic diversity of psyllids. In this study, we provide chromosome-level genome assemblies for three psyllid species known to transmit CLso: Dyspersa apicalis (carrot psyllid), Dyspersa pallida, and Trioza urticae (nettle psyllid). As D. apicalis is recognised as the primary vector of CLso by carrot growers in Northern Europe, we also resequenced populations of this species from Finland, Norway, and Austria. Genome assemblies were constructed using PacBio HiFi and Hi-C sequencing data, yielding genome sizes of: 594.01 Mbp for D. apicalis; 587.80 Mbp for D. pallida; and 655.58 Mbp for T. urticae. Over 90% of sequences anchored into 13 pseudo-chromosomes per species. The assemblies for D. apicalis and D. pallida exhibited high completeness, capturing over 92% of conserved Hemiptera single-copy orthologues, as assessed by Benchmarking Universal Single-Copy Orthologues (BUSCO) analysis. Furthermore, we identified sequences of the primary psyllid symbiont, Candidatus Carsonella ruddii, in all three species. Comparative genomic analyses demonstrated synteny with other psyllid species. Notably, we observed significant expansions in gene families, particularly those linked to potential insecticide detoxification, within the Dyspersa lineage. Resequencing efforts also revealed the existence of multiple subpopulations of D. apicalis across Europe. These high-quality genome resources will support future research on genome evolution, insect-plant-pest interactions, and strategies for disease management. SignificancePsyllid species are significant agricultural pests, known for transmitting plant diseases like Candidatus Liberibacter solanacearum (CLso), which causes zebra chip in potatoes and carrot yellows. However, genomic data on psyllids are limited. In this study, we present high-quality, chromosome-level genome assemblies for three psyllid species: Dyspersa apicalis, Dyspersa pallida, and Trioza urticae. We generated genome assemblies with over 90% of sequences anchored to 13 pseudo-chromosomes. Comparative analyses revealed gene expansions, particularly in detoxification pathways, suggesting adaptations within the Dyspersa lineage. Population resequencing of D. apicalis across Europe uncovered genetic subpopulations. These genomes will advance understanding of psyllid biology and inform disease management strategies.

genomics↗

bioRxiv2024

Antimicrobial and antibiofilm activity of human recombinant H1 histones against bacterial infections

Histones possess significant antimicrobial potential, yet their activity against biofilms remains underexplored. Moreover, concerns regarding adverse effects limit their clinical implementation. We investigated the antibacterial efficacy of human recombinant histone H1 subtypes against Pseudomonas aeruginosa PAO1, both planktonic and in biofilms. After the in vitro tests, toxicity and efficacy were assessed in a P. aeruginosa PAO1 infection model using Galleria mellonella larvae. Histones were also evaluated in combination with ciprofloxacin and gentamicin. Our results demonstrate antimicrobial activity against of all three histones against P. aeruginosa PAO1, with H1.0 and H1.4 showing efficacy at lower concentrations. The bactericidal effect was associated with a mechanism of membrane disruption. In vitro studies using static and dynamic models showed that H1.4 had antibiofilm potential by reducing cell biomass. Neither H1.0 nor H1.4 showed toxicity in G. mellonella larvae, and both increased larvae survival when infected with P. aeruginosa PAO1. Although in vitro synergism was observed between ciprofloxacin and H1.0, no improvement over the antibiotic alone was noted in vivo. Differences in antibacterial and antibiofilm activity were attributed to sequence and structural variations among histone subtypes. Moreover, the efficacy of H1.0 and H1.4 was influenced by the presence and strength of the extracellular matrix. These findings suggest histones hold promise for combating acute and chronic infections caused by pathogens such as P. aeruginosa. ImportanceThe constant increase of multidrug-resistant bacteria is a critical global concern. The inefficacy of current therapies to treat bacterial infections is attributed to multiple mechanisms of resistance, including the capacity to form biofilms. Therefore, the identification of novel and safe therapeutic strategies is imperative. This study confirms the antimicrobial potential of three histone H1 subtypes against both Gram-negative and Gram-positive bacteria. Furthermore, histones H1.0 and H1.4 demonstrated in vivo efficacy without associated toxicity in an acute infection model of Pseudomonas aeruginosa PAO1 in Galleria mellonella larvae. The bactericidal effect of these proteins also resulted in reduction in biomass of P. aeruginosa PAO1 biofilms. Given the clinical significance of this opportunistic pathogen, our research provides a comprehensive initial evaluation of the efficacy, toxicity, and mechanism of action of a potential new therapeutic approach against acute and chronic bacterial infections.

microbiology↗

bioRxiv2023

The transcription factor Sfp1 imprints specific classes of mRNAs and links their synthesis and cytoplasmic decay

To function effectively as an integrated system, the transcriptional and post-transcriptional machineries must communicate through mechanisms that are still poorly understood. Here we focus on Sfp1, known to regulate transcription of proliferation-related genes. We show that Sfp1 can regulate transcription either by binding to promoters, like most known transcription activators, or by binding to the transcribed regions (gene bodies), probably via RNA polymerase II (Pol II). We further studied the first mode of Sfp1 activity and found that, following promoter binding, Sfp1 binds to gene bodies and affects Pol II configuration, manifested by dissociation or conformational change of its Rpb4 subunit and increased backtracking. Surprisingly, Sfp1 binds to a subset of mRNAs co-transcriptionally and stabilizes them. The interaction between Sfp1 and its client mRNAs is controlled by their respective promoters and coincides with Sfp1s dissociation from chromatin. . Intriguingly, Sfp1 dissociation from the chromatin correlates with the extent of the backtracked Pol II. We propose that, following promoter recruitment, Sfp1 accompanies Pol II and regulates backtracking. The backtracked Pol II is more compatible with Sfp1s relocation to the nascent transcripts, whereupon Sfp1 accompanies these mRNAs to the cytoplasm and regulates their stability. Thus, Sfp1s co-transcriptional binding imprints the mRNA fate, serving as a paradigm for the cross-talk between the synthesis and decay of specific mRNAs. The interplay between Sfp1s two modes of transcription regulation remains to be examined.

molecular biology↗