Biology subjects

Henderson, S.

Publications and source records attributed to Henderson, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Evolutionary Rewiring of Root Cell-Type Nitrogen Responses

Nitrate induces widespread transcriptional reprogramming in plants, but how transcription factors coordinate these responses across cell types and evolve across species with divergent root patterning remains unclear. Using single-cell transcriptomics in Arabidopsis thaliana and Solanum lycopersicum (tomato) under varying nitrate conditions, we demonstrate that many transcriptional responses are cell type and developmental stage-specific. Arabidopsis NIN-LIKE PROTEIN 7 (NLP7) directly modulates both broadly expressed and cell-type-specific targets, but is not required to establish the cell type specific nature of these patterns. Comparative analysis reveals evolutionary shifts; key nitrogen programs are localized to different cell types in tomato, with the exodermis as a major regulatory hub. Identification of tomato NLP7a and NLP7b direct targets at cellular resolution supports their role in direct modulation of cell type N-transcriptional programs. This is evidenced by NLP7-controlled exodermal cell wall remodeling in low nitrate, highlighting functional conservation despite divergent cellular topographies.

plant biology↗

bioRxiv2026

Denaturing purifications support direct interaction between PRC2 and RNA in cells

Polycomb Repressive Complex 2 (PRC2) maintains repression of genes specific for other cell differentiation states. PRC2 binds RNA in vitro with a preference for G-rich sequences. UV-based crosslinking coupled with immunoprecipitation (CLIP) experiments have shown that PRC2 also binds RNA in cells. Recently, Guo et al reported that a stringent denaturing variant of CLIP called CLAP did not detect PRC2 RNA binding in cells. We present a reanalysis of CLAP data that supports direct interaction of PRC2 with RNA in cells. CLAP for Halo-tagged PRC2 subunits from mixed populations of human and mouse cells specifically enriched for RNA from the species in which the proteins were tagged. The lack of apparent PRC2 RNA binding in Guo and colleagues analysis stems from a scaling step that deflates enrichment scores for low-complexity CLAP samples. Our findings pave the way for studies seeking to determine the physiological roles of PRC2 RNA binding activity.

genomics↗

bioRxiv2026

Molecular and Structural Characterization Reveals Divergent Extracellular Vesicle Profiles Between Wild Type and Alzheimer's Disease Cerebrocortical Organoids

Alzheimers disease (AD) is a neurodegenerative disorder affecting millions of patients globally. Despite significant efforts from researchers in recent decades, there are still many unanswered questions about AD pathogenesis. AD patient brains manifest changes in extracellular vesicles (EVs) secreted from diseased neurons, and the effect of this phenomenon remains poorly understood. EVs contain a variety of biomolecules and play a critical role in cell-to-cell communication in all eukaryotic organisms. Here, we report a thorough characterization of small EVs purified from cultures of human cerebrocortical organoids. These organoids are differentiated from human patient-derived stem cells that bear a familial AD mutation in the presenilin 1 (PSEN1) gene, or from an isogenic wildtype (WT) control. The organoid conditioned media was aspirated from cultures and processed for EV enrichment using a non-invasive technique that requires no cellular disruption. EVs purified from AD organoid conditioned media have a wider size distribution and show differential expression of tetraspanins CD63, CD9, and CD81 when compared to WT organoid-derived EVs. AD organoid-derived EVs can have single, double, and even triple membranes and display luminal fibrillar material. A deep proteomic profiling of the EVs reveals several statistically significant differences, including evidence for modifications in secretory autophagy. EV isolates from both WT and AD organoids show strong binding to amyloid detecting dyes, both in bulk fluorescence and fluorescence microscopy assays. After a 1-week co-culture of AD organoids with WT organoids, there is evidence of endosomal membrane transfer between the isogenic cultures with an increase in amyloid-{beta} peptides in the WT organoids. These observations support the notion that non-cell-autonomous spread of amyloid-containing EVs in human AD brains can be modeled in a cerebral organoid system.

neuroscience↗

bioRxiv2025

Diversification dynamics of the Palaeozoic actinopterygian radiation

Ray-finned fish are the most speciose vertebrate group today, but the dynamics of their early diversification are contentious. Their fossil record suggests a first radiation in the Carboniferous following the Late Devonian mass extinction events. Conversely, recent phylogenetic hypotheses imply a radiation originating in the Late Devonian, but lack the taxonomic breadth required to robustly test this. This necessitates phylogeny-free inference of actinopterygian diversification rates from fossil occurrences, itself challenging due to complex systematics, incomplete occurrence databases, and severe spatiotemporal sampling biases. Here, we analyse a comprehensive dataset of Palaeozoic actinopterygian genera and species using approaches that accommodate spatial and temporal sampling variation. We detect elevated actinopterygian diversification in the Late Devonian, with substantially greater lineage survival across the Hangenberg extinction event than indicated by the raw fossil record. Surprisingly, we detect no positive shifts in origination across the event, refuting previous hypotheses of explosive actinopterygian radiation in its wake. Instead, cryptic survival of diversified lineages appears responsible for the robust signal of increased diversity across different geographic scales in the Carboniferous. Nonetheless, these trends are overwhelmingly driven by low palaeolatitude Euramerican fossil assemblages, highlighting the ongoing spatial limitations of the actinopterygian fossil record.

paleontology↗

bioRxiv2025

High-quality genome assembly for the genetically improved Abbassa Nile tilapia enables the reconstruction of X and Y haplotypes

The success of the Nile tilapia (Oreochromis niloticus) as an aquaculture species is partly the result of continuous selective breeding leading to high performing strains. These elite strains have been derived from breeding populations of diverse origins and crosses with other Oreochromis species. Owing to the complex and unique evolutionary histories of each strain, existing reference genomes of wild populations are unsuitable to implement genomic selection for beneficial traits such as growth or environmental resilience in aquaculture programmes. Here we generated a high-quality genome assembly and annotation of the WorldFish Genetically Improved Abbassa Nile tilapia (GIANT) elite strain using a combination of PacBio HiFi, and Omni-C Illumina sequencing. As a male Abbassa Nile tilapia was used for the generation of the genome assembly, we reconstructed both X and Y haplotypes, identifying both amhY and amh{Delta}y on LG23 indicating that Abbassa likely shares the same sex determination system as GIFT, and thereby differs from the existing reference genome, whose sex determination loci are located on LG1.

genomics↗

bioRxiv2025

Temporal Propagation of Neural State Boundaries in Naturalistic Context

Our senses receive a continuous stream of complex information, which we segment into discrete events. Previous research has related such events to neural states: temporally and regionally specific stable patterns of brain activity. The aim of this paper was to investigate whether there was evidence for top-down or bottom-up propagation of neural state boundaries. To do so, we used intracranial measurements with high temporal resolution while subjects were watching a movie. As this is the first study of neural states in intracranial data in the context of event segmentation, we also investigated whether known properties of neural states could be replicated. The neural state boundaries indeed aligned with stimulus features and between brain areas. Importantly, we found evidence for top-down propagation of neural state boundaries at the onsets and offsets of clauses. Interestingly, we did not observe a consistent top-down or bottom-up propagation in general across all timepoints, suggesting that neural state boundaries could propagate in both a top-down and bottomup manner, with the direction depending on the stimulus input at that moment. Taken together, our findings provide new insights on how neural state boundaries are shared across brain regions and strengthen the foundation of studying neural states in electrophysiology.

neuroscience↗

bioRxiv2024

Epigenetic investigation of multifocal small intestinal neuroendocrine tumours reveals accelerated ageing of tumours and epigenetic alteration of metabolic genes

BackgroundSmall intestinal neuroendocrine tumours (SI-NETs) are the most common malignancy of the small intestine and around 50% of patients present in clinic with multifocal disease. Recent investigations into the genomic architecture of multifocal SI-NETs have found evidence that these synchronous primary tumours evolve independently of each other. They also have extremely low mutational burden and few known driver genes, suggesting that epigenetic dysregulation may be driving tumorigenesis. Very little is known about epigenetic gene regulation, metabolism and ageing in these tumours, and how these traits differ across multiple tumours within individual patients. MethodsIn this study, we performed the first investigation of genome-wide DNA methylation in multifocal SI-NETs, assessing multiple primary tumours within each patient (n=79 primary tumours from 14 patients) alongside matched metastatic tumours (n=12) and normal intestinal epithelial tissue (n=9). We assessed multifocal SI-NET differential methylation using a novel method, comparing primary tumours with matched normal epithelial tissue and an enterochromaffin-enriched cell line to enrich for tumour-specific effects. This method reduced the identification of false positive methylation differences driven by cell composition differences between tumour and normal epithelial tissue. We also assessed tumour ageing using epigenetic clocks and applied metabolic predictors in the dataset to assess methylation variation across key metabolic genes. ResultsWe have identified 12,392 tumour-specific differentially methylated positions (Bonferroni corrected p<0.05) which were enriched for neural pathways. The expression levels of the genes associated with top sites were also found to be significantly altered in SI-NETs. Age acceleration was observed across SI-NETs and a variability in epigenetic age of tumours within each patient, which we believe is reflecting the order in which tumours have developed. This is supported by the correlation of age acceleration with somatic mutational count in the tumours. We have identified SI-NET associated alterations to the methylation patterns in key metabolic genes compared to matched normal tissue, which is more pronounced in metastatic tumours and tumours harbouring chromosome 18 loss of heterozygosity, indicating metabolic differences in these tumour subtypes. ConclusionsWe have identified accelerated ageing and changes to regulation of metabolic genes, alongside an epigenetic signature of multifocal SI-NETs. These findings add to our understanding of multifocal SI-NET biology and their molecular differences which may be instrumental in the development of these elusive tumours.

cancer biology↗

bioRxiv2024

Chromosome-scale genome assembly and de novo annotation of Alopecurus aequalis.

Alopecurus aequalis is a winter annual or short-lived perennial bunchgrass which has in recent years emerged as the dominant agricultural weed of barley and wheat in certain regions of China and Japan, causing significant yield losses. Its robust tillering capacity and high fecundity, combined with the development of both target and non-target-site resistance to herbicides means it is a formidable challenge to food security. Here we report on a chromosome-scale assembly of A. aequalis with a genome size of 2.83 Gb. The genome contained 33,758 high-confidence protein-coding genes with functional annotation. Comparative genomics revealed that the genome structure of A. aequalis is more similar to Hordeum vulgare rather than the more closely related Alopecurus myosuroides and has undergone an expansion of cytochrome P450 genes, a gene family involved in non-target-site herbicide resistance.

plant biology↗

bioRxiv2024

Root traits and tree functional groups determine variability in root exudation and N uptake rates in mature temperate trees

While root exudation has the potential to affect soil biogeochemistry profoundly, the process is rarely quantified in mature, field-grown trees. We measured rates of carbon (C) exudation in 11 trees species that exhibit divergent root traits, including gymnosperms and angiosperms that associate with either arbuscular mycorrhizal (AM) or ectomycorrhizal (EcM) fungi. Our goal was to explore how tree species, plant functional groups and root traits collectively influence exudation patterns. Intraspecific variation in exudation rates was larger than interspecific variation, and neither functional groups nor morphological traits alone could sufficiently explain variation in this flux. EcM-associated gymnosperms exuded 2.4 times more C than EcM angiosperms and 1.5 times more than AM gymnosperms. Exudation rates correlated positively with specific root length (SRL) and specific root area (SRA), and were correlated with root tissue density and root diameter in EcM-associated species. Mixed-effect models revealed that exudation rates were best determined by a combination of phylogenetic group, tree-mycorrhizal type and SRA, though a large portion of unexplained variation suggests that contemporary environmental and local edaphic conditions are likely important. Collectively, our results reveal that exudation is a complex physiological process governed by multiple factors and cannot be fully explained by functional groups or root traits alone. Instead, a combined consideration of these factors and new experimental approaches may be needed before exudation patterns can be linked to plant trait frameworks and incorporated into large-scale models.

ecology↗

bioRxiv2024

STAG3 promotes exit from pluripotency through post-transcriptional mRNA regulation in the cytoplasm.

STAG proteins are key regulators of the cohesin complex and are often linked to alterations in cell identity and disease. Among the mammalian STAG paralogs, STAG3 has been less extensively studied beyond its known roles in meiosis. In this work, we demonstrate that STAG3 is expressed in mouse embryonic stem cells (mESCs) and primordial germ cell-like cells (PGCLCs), where it is required for cell fate decisions. Distinct from the other STAG proteins, STAG3 mediates its effects in the cytoplasm, facilitating the post-transcriptional regulation of gene expression. Furthermore, STAG3 localises to the centrosome independently of cohesin and interacts with proteins involved in mRNA localisation and stability. The knockdown of STAG3 in mESCs using siRNAs results in the destabilisation of the centrosome and the key P-body RNA-induced silencing complex (RISC) component TNRC6C, leading to the derepression of P-body localised mRNAs, such as DPPA3. Our results propose a model in which STAG3 collaborates with RNA-binding proteins (RBPs) and specific target mRNAs to control post-transcriptional gene expression and facilitate the transition from pluripotency in mESCs. Given that STAG3 is upregulated in various cancers, our results provide a novel perspective on how STAG proteins might contribute to cell identity and disease.

cell biology↗

bioRxiv2024

De novo annotation of the wheat pangenome reveals complexity and diversity of the hexaploid wheat pan-transcriptome

Wheat is the most widely cultivated crop in the world with over 215 million hectares grown annually. However, to meet the demands of a growing global population, breeders face the challenge of increasing wheat production by approximately 60% within the next 40 years. The 10+ Wheat Genomes Project recently sequenced and assembled to chromosome level the genomes of nine wheat cultivars to develop our understanding of genetic diversity and selection within the pan-genome of wheat. Here, we provide a wheat pan-transcriptome with de novo annotation and differential expression analysis for these wheat cultivars, across multiple different tissues and whole seedlings sampled at dusk/dawn. Analysis of these de novo annotations facilitated the discovery of genes absent from the Chinese Spring reference, identified genes specific to particular cultivars and defined the core and dispensable genomes. Expression analysis across cultivars and tissues revealed conservation in expression between a large core set of homeologous genes, but also widespread changes in subgenome homeolog expression bias between cultivars. Co-expression network analysis revealed the impact of divergence of sub-genome homeolog expression and identified cultivar-specific expression profiles. In a case study utilising both the newly constructed wheat pan-genome and pan-transcriptome we demonstrate prevalent variation in the prolamin superfamily and immune-reactive proteins across the pan-cultivars.In summary, this work provides both a valuable resource for the wider wheat community and reveals diversity in gene content and expression patterns between global wheat cultivars.

genomics↗

bioRxiv2023

Convergent evolution of monocyte differentiation in adult skin permits repair of the Langerhans cell network

Langerhans cells (LCs) maintain tissue and immunological homeostasis at the epidermal barrier site. They are unique among phagocytes in functioning both as embryo-derived, tissue-resident macrophages that influence skin innervation and repair, and as migrating professional antigen presenting cells, a capability classically assigned to dendritic cells (DCs). Here we report the mechanisms that determine this dual identity. Using ablation of embryo-derived LCs in murine adult skin and tracked differentiation of incoming monocyte-derived replacements, we reveal intrinsic intra-epidermal heterogeneity. We demonstrate that monocyte-dendritic cell progenitor (MDP)-derived monocytes are selected for survival in the skin environment. Within the epidermis, the hair follicle niche subsequently provides an initial site of LC commitment, likely via Notch signaling, prior to metabolic adaptation and survival of differentiated monocyte-derived LCs. In human skin, we show that embryo-derived (e)LCs in newborns retain transcriptional evidence of their macrophage origin, but this is superseded by distinct DC-like immune modules after post-natal expansion of eLCs. Thus, intrinsic and extrinsic adaptations to adult skin niches replicate conditioning of eLC at birth, permitting repair of the unique LC network.

immunology↗

bioRxiv2022

Sampling biases obscure the early diversification of the largest living vertebrate group

Extant ray-finned fishes (Actinopterygii) dominate marine and freshwater environments, yet their spatiotemporal diversity dynamics following their origin in the Palaeozoic are poorly understood. Previous studies investigate face-value patterns of richness, with only qualitative assessment of potential biases acting on the Palaeozoic actinopterygian fossil record. Here, we investigate palaeogeographic trends and apply richness estimation techniques to a recently-assembled occurrence database for Palaeozoic ray-finned fishes. We reconstruct patterns of local richness of Palaeozoic actinopterygians, alongside sampling standardised estimates of global diversity. We identify substantial fossil record biases, such as geographic bias in the sampling of actinopterygian occurrences centred around Europe and North America. Similarly, estimates of diversity are skewed by extreme unevenness in the abundance distributions of occurrences, reflecting past taxonomic practices and historical biases in sampling. Increasing sampling of poorly represented regions and expanding sampling beyond the literature to include museum collection data will be critical in obtaining accurate estimates of Palaeozoic actinopterygian diversity. In conjunction, applying diversity estimation techniques to well-sampled regional subsets of the global dataset may identify accurate local diversity trends.

paleontology↗

bioRxiv2022

How to resolve conflicting conservation objectives: A decision support tool for the global selection of multi-purpose protected areas

The establishment and maintenance of protected areas (PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting protected areas based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences, as well as real-time comparison of the selected areas that result from such different priorities. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between species protection and ecosystem integrity. Outputs indicate that decision makers frequently face trade-offs among conflicting objectives. Nevertheless, we show that transparent decision-support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.

ecology↗

bioRxiv2021

Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF{beta}-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

cancer biology↗

bioRxiv2021

The Th1 cell regulatory circuitry is largely conserved between human and mouse

Gene expression programmes controlled by lineage-determining transcription factors are often conserved between species. However, infectious diseases have exerted profound evolutionary pressure, and therefore the genes regulated by immune-specific transcription factors might be expected to exhibit greater divergence due to exposure to species-specific pathogens. T-bet (Tbx21) is the immune-specific lineage-defining transcription factor for T helper type I (Th1) immunity, which is fundamental for the immune response to intracellular pathogens but also underlies inflammatory diseases. We therefore compared T-bet genomic targets between mouse and human CD4+ T cells and correlated T-bet binding patterns with species-specific gene expression. Remarkably, we show that the vast majority of T-bet regulated genes are conserved between mouse and human, either via preservation of a binding site or via an alternative binding site associated with transposon-linked insertion. We also identified genes that are specifically targeted by T-bet in humans or mice and which exhibited species-specific expression. These results provide a genome-wide cross-species comparison of T-bet target gene regulation that will enable more accurate translation of genetic targets and therapeutics from pre-clinical models of inflammatory disease into human clinical trials.

immunology↗

bioRxiv2020

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

In both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.

immunology↗

bioRxiv2020

A population of CD4+ T cells with a naive phenotype stably polarized to the TH1 lineage

T-bet is the lineage-specifying transcription factor for CD4+ T helper type 1 (TH1) cells. T-bet has also been found in other CD4+ T cell subsets, including TH17 cells and TREG, where it modulates their functional characteristics. However, we lack information on when and where T-bet is expressed during T cell differentiation and how this impacts T cell function. To address this, we traced the ontogeny of T-bet-expressing cells using a fluorescent fate-mapping mouse line. We demonstrate that T-bet is expressed in a subset of CD4+ T cells with naive cell surface markers and that this novel cell population is phenotypically and functionally distinct from conventional naive CD4+ T cells. These cells are also distinct from previously described populations of memory phenotype and stem cell-like T cells. Naive-like T-bet-experienced cells are polarised to the TH1 lineage, predisposed to produce IFN{gamma} upon cell activation, and resist repolarisation to other lineages in vitro and in vivo. These results demonstrate that lineage-specifying factors can function to polarise T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T helper response.

immunology↗