Biology subjects

Hall, H.

Publications and source records attributed to Hall, H..

10 recordsLinked to original sources

bioRxiv2026

Tau-induced elevation in promoter-proximal RNA polymerase II pausing is linked to decreased expression of long neuronal genes in a Drosophila tauopathy model.

Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.

molecular biology↗

bioRxiv2025

Podoplanin expression identifies human airway basal cells with higher progenitor cell potential

Basal cells are key to maintaining and repairing a functioning airway epithelium. Understanding how basal cells maintain normal airways provides a foundation for interpreting their dysfunction in disease states and for the development of novel therapies. The airway epithelium exists in a dynamic state in which basal stem cells replace lost luminal mucosecretory and multiciliated cell types via an intermediate suprabasal cell state. The ability to isolate basal cells with high progenitor cell potential would be beneficial in regenerative medicine applications, but the molecular identity of this population is unclear. Here, we evaluate candidate surface markers to isolate human basal cells. As an individual marker, we found that podoplanin (PDPN) had a favorable sensitivity and specificity compared with integrin alpha 6 (ITGA6) or nerve growth factor receptor (NGFR). We found that KRT5-expressing basal cells could be subdivided into those with high or low PDPN expression; KRT5-negative cells did not express PDPN. In vitro, PDPN-high basal cells had higher colony-forming capacity, increased population doubling potential and formed larger colonies than PDPN-low basal cells. PDPN-high basal cells expressed higher levels of TP63, as well as other genes expressed by quiescent or resting basal cells identified in single cell RNA sequencing studies. PDPN-low basal cells expressed genes associated with a differentiating basal cell state, including KRT4, NOTCH3 and serpin B family genes. Our results demonstrate that PDPN expression can identify basal cells with high progenitor cell potential, enabling high efficiency sorting of airway stem cells.

cell biology↗

bioRxiv2025

Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis

The genes encoding transcription factor RUNX1 and its binding partner CBFB have been reported to be mutated in human breast cancer. Here, we provide evidence that Runx1 loss of function results in accelerated disease onset and tumour development in mouse models of breast cancer, in keeping with a tumour suppressor role for RUNX1 in this disease setting. Combined deletion of Runx1 and the related family member Runx2 resulted in mammary epithelial cells becoming exquisitely sensitive to WNT-driven transformation, with the emergence of multiple tumours early in life. Clonogenic assays indicated that Runx1 ablation induced a stem cell like phenotype in mammary epithelial cells, whilst transcriptome analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co- deleted. Interestingly, altered Runx expression in the mammary epithelium also drove profound alterations in the tumour microenvironment, impacting the immune landscape. These results highlight that Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Loss of Runx2 itself did not result in tumour promotion, yet the dramatic effects of combined Runx1 and Runx2 loss suggest that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.

cancer biology↗

bioRxiv2022

A phloem-localized Arabidopsis metacaspase (AtMC3) improves drought tolerance

Increasing drought phenomena pose a serious threat to agricultural productivity. Although plants have multiple ways to respond to the complexity of drought stress, the underlying mechanisms of stress sensing and signalling remain unclear. The role of the vasculature, in particular the phloem, in facilitating inter-organ communication is critical. Here, we investigated the role of AtMC3, a phloem-specific member of the metacaspase family, in osmotic stress responses in Arabidopsis thaliana. Overexpression of AtMC3 conferred drought tolerance by enhancing the differentiation of the metaphloem sieve elements and maintaining higher levels of vascular-mediated transportation, whilst plants lacking the protein showed an impaired response to drought and inability to respond effectively to the hormone abscisic acid. Analyses of the proteome in plants with altered AtMC3 levels revealed differential abundance of proteins related to osmotic stress. Overall, our data highlight the importance of AtMC3 and vascular plasticity in fine-tuning early drought responses at the whole plant level without affecting growth or yield.

plant biology↗

bioRxiv2021

The Clock:cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

The aging eye experiences physiological changes that include decreased visual function and increased risk of retinal degeneration. Although there are transcriptomic signatures in the aging retina that correlate with these physiological changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. Here, we integrated ATAC-seq and RNA-seq data to identify 61 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 61 age-regulated transcription factors include two circadian regulators, Clock and cycle, that showed sustained increases in activity during aging. When we disrupted Clock activity in adult photoreceptors, we observed changes in expression of 15 - 20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that loss of Clock activity leads to changes in activity of 31 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, disruption of Clock activity in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.

genomics↗

bioRxiv2021

Proper control of R-loop homeostasis is required for maintenance of gene expression and neuronal function during aging

Age-related loss of cellular function and increased cell death are characteristic hallmarks of aging. While defects in gene expression and RNA metabolism have been linked with age-associated human neuropathies, it is not clear how the changes that occur in aging neurons contribute to loss of gene expression homeostasis. R-loops are RNA-DNA hybrids that typically form co-transcriptionally via annealing of the nascent RNA to the template DNA strand, displacing the non-template DNA strand. Dysregulation of R-loop homeostasis has been associated with both transcriptional impairment and genome instability. Importantly, a growing body of evidence links R-loop accumulation with cellular dysfunction, increased cell death and chronic disease onset. Here, we characterized the R-loop landscape in aging Drosophila melanogaster photoreceptor neurons and showed that bulk R-loop levels increased with age. Further, genome-wide mapping of R-loops revealed that transcribed genes accumulated R-loops over gene bodies during aging, which correlated with decreased expression of long and highly expressed genes. Importantly, while photoreceptor-specific down-regulation of Top3{beta}, a DNA/RNA topoisomerase associated with R-loop resolution, lead to decreased visual function, overexpression of Top3{beta} or nuclear-localized RNase H1, which resolves R-loops, enhanced positive light response during aging. Together, our studies highlight the functional link between dysregulation of R-loop homeostasis, gene expression and visual function during aging.

molecular biology↗

bioRxiv2021

Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Upon damage, IL-1{beta} signalling-dependent modulation of Jag1/2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives reprogramming and acquisition of differentiation plasticity. We identify a core role for the transcription factor Fosl2/Fra2 in secretory cell fate conversion to alveolar type 2 (AT2) cells retaining the distinct genetic and epigenetic signatures of secretory lineages. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate the functional role of a IL-1{beta}-Notch-Fosl2 axis for the fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration.

cell biology↗

bioRxiv2021

Quantitative proteomic and metabolomic profiling reveals altered mitochondrial metabolism and folate biosynthesis pathways in the aging Drosophila eye

Aging is associated with increased risk of ocular disease, suggesting that age-associated molecular changes in the eye increase its vulnerability to damage. Although there are common pathways involved in aging at an organismal level, different tissues and cell types exhibit specific changes in gene expression with advanced age. Drosophila melanogaster is an established model system for studying aging and neurodegenerative disease, that also provides a valuable model for studying age-associated ocular disease. Flies, like humans, exhibit decreased visual function and increased risk of retinal degeneration with age. Here, we profiled the aging proteome and metabolome of the Drosophila eye, and compared these data with age-associated transcriptomic changes from both eyes and photoreceptors to identify alterations in pathways that could lead to age-related phenotypes in the eye. Notably, the proteomic and metabolomic changes observed in the aging eye are distinct from those observed in the head or whole fly, suggesting that tissue-specific changes in protein abundance and metabolism occur in the aging fly. Our integration of the proteomic, metabolomic and transcriptomic data reveals that changes in metabolism, potentially due to decreases in availability of B vitamins, together with chronic activation of the immune response, may underpin many of the events observed in the aging Drosophila eye. We propose that targeting these pathways in the genetically tractable Drosophila system may help to identify potential neuroprotective approaches for neurodegenerative and age-related ocular diseases.

biochemistry↗

bioRxiv2018

Metagenomic profiling of ticks: identification of novel rickettsial genomes and detection of tick-borne canine parvovirus

BackgroundAcross the world, ticks act as vectors of human and animal pathogens. Ticks rely on bacterial endosymbionts, which often share close and complex evolutionary links with tick-borne pathogens. As the prevalence, diversity and virulence potential of tick-borne agents remain poorly understood, there is a pressing need for microbial surveillance of ticks as potential disease vectors.\n\nMethodology/Principal FindingsWe developed a two-stage protocol that includes 16S-amplicon screening of pooled samples of hard ticks collected from dogs, sheep and camels in Palestine, followed by shotgun metagenomics on individual ticks to detect and characterise tick-borne pathogens and endosymbionts. Two ticks isolated from sheep yielded an abundance of reads from the genus Rickettsia, which were assembled into draft genomes. One of the resulting genomes was highly similar to Rickettsia massiliae strain MTU5. Analysis of signature genes showed that the other represents the first genome sequence of the potential pathogen Candidatus Rickettsia barbariae. Ticks from a dog and a sheep yielded draft genome sequences of strains of the Coxiella-like endosymbiont Candidatus Coxeilla mudrowiae. A sheep tick yielded sequences from the sheep pathogen Anaplasma ovis, while Hyalomma ticks from camels yielded sequences belonging to Francisella-like endosymbionts. From the metagenome of a dog tick from Jericho, we generated a genome sequence of a canine parvovirus.\n\nSignificanceHere, we have shown how a cost-effective two-stage protocol can be used to detect and characterise tick-borne pathogens and endosymbionts. In recovering genome sequences from an unexpected pathogen (canine parvovirus) and a previously unsequenced pathogen (Candidatus Rickettsia barbariae), we demonstrate the open-ended nature of metagenomics. We also provide evidence that ticks can carry canine parvovirus, raising the possibility that ticks might contribute to the spread of this troublesome virus.\n\nAuthor SummaryWe have shown how DNA sequencing can be used to detect and characterise potentially pathogenic microorganisms carried by ticks. We surveyed hard ticks collected from domesticated animals across the West Bank territory of Palestine. All the ticks came from species that are also capable of feeding on humans. We detected several important pathogens, including two species of Rickettsia, the sheep pathogen Anaplasma ovis and canine parvovirus. These findings highlight the importance of hard ticks and the hazards they present for human and animal health in Palestine and the opportunities presented by high-throughput sequencing and bioinformatics analyses of DNA sequences in this setting.

microbiology↗

bioRxiv2018

Cell death in cells overlying lateral root primordia contributes to organ growth in Arabidopsis

Unlike animal development, plant organ growth is widely accepted to be determined by cell division without any contribution of cell elimination. We investigated this paradigm during Arabidopsis lateral root formation when growth of the new primordia (LRP) from pericycle-derived stem cells deep inside the root is reportedly facilitated by remodeling of the walls of overlying cells without apparent cell death. However, we observed the induction of marker genes for cell types undergoing developmental cell death in several cells overlying the growing LRP. Transmission electron microscopy, time-lapse confocal and light sheet microscopy techniques were used to establish that cell death occurred at least in a subset of endodermal LRP-overlying cells during organ emergence. Significantly, organ emergence was retarded in mutants lacking a positive cell death regulator, and restored by inducing cell death in cells overlying LRP. Hence, we conclude that in the case of LRP, cell elimination contributes to organ growth.

plant biology↗