Biology subjects

Dickson, E.

Publications and source records attributed to Dickson, E..

7 recordsLinked to original sources

bioRxiv2025

Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion

The integrated stress response (ISR) is a highly conserved cellular signaling network, allowing cells to adapt and respond to various stressors. In one of the toughest cancers to date, glioblastoma multiforme (GBM) with aggressive spread and high recurrence rates, the role of the ISR is yet to be well understood - whether activation may suppress or promote this disease - and drug-treatment of GBM has thus far shown inconclusive results. In this work we use an optogenetic tool, opto- PKR, to specifically trigger ISR-activation with light with high spatiotemporal control via the PKR-kinase, avoiding potential upstream damage or side effects from drugs. Using immunofluorescence and RNA-sequencing we show that targeted ISR-activation reaches levels where both adaptive (ATF4) and terminal response (CHOP) of the ISR are activated, which show downregulation of genes associated with extracellular environment and glial cell migration, further supported by ECM-stain and scratch assays. Further, we show inhibition of aggressive spread for ISR-activated GBM spheroids in collagen 3D culture. Photopatterning of ISR-activation in spheroids demonstrates a cell intrinsic effect at tissue scale, and recovery studies indicate a tunable, non-ablative intervention space. These findings suggest a route to containment and motivate ISR-activating small molecule screening in GBM models.

cancer biology↗

bioRxiv2025

RNA-coupled CRISPR Screens Reveal ZNF207 as a Regulator of LMNA Aberrant Splicing in Progeria

Despite progress in understanding pre-mRNA splicing, the regulatory mechanisms controlling most alternative splicing events remain unclear. We developed CRASP-Seq, a method that integrates pooled CRISPR-based genetic perturbations with deep sequencing of splicing reporters, to quantitively assess the impact of all human genes on alternative splicing from a single RNA sample. CRASP-Seq identifies both known and novel regulators, enriched for proteins involved in RNA splicing and metabolism. As proof-of-concept, CRASP-Seq analysis of an LMNA cryptic splicing event linked to progeria uncovered ZNF207, primarily known for mitotic spindle assembly, as a regulator of progerin splicing. ZNF207 depletion enhances canonical LMNA splicing and decreases progerin levels in patient-derived cells. High-throughput mutagenesis further showed that ZNF207s zinc finger domain broadly impacts alternative splicing through interactions with U1 snRNP factors. These findings position ZNF207 as a U1 snRNP auxiliary factor and demonstrate the power of CRASP-Seq to uncover key regulators and domains of alternative splicing. Main PointsO_LICRASP-Seq: RNA-coupled CRISPR screen quantifying gene and domain impact on splicing C_LIO_LIProfiling of five events identified 370 genes influencing alternative splicing C_LIO_LIZNF207 regulates splicing by interacting with U1 snRNP via its zinc-finger domains C_LIO_LIZNF207 depletion corrects LMNA aberrant splicing causing progeria C_LI

genetics↗

bioRxiv2024

Trophic level associated gut length divergence evolved under sexual conflict in Lake Malawi cichlids

Variation in gastrointestinal morphology is associated with dietary specialization across the animal kingdom. Gut length generally correlates with trophic level, and increased gut length in herbivores is a classic example of adaptation to cope with diets with lower nutrient content and a higher proportion of refractory material. However, the genetic basis of gut length variation remains largely unstudied, partly due to the inaccessibility and plasticity of the gut tissue, as well as the lack of dietary diversity within traditional model organisms relative to that observed among species belonging to different trophic levels. Here, we confirm the genetic basis of gut length variation among recently evolved Lake Malawi cichlid fish species with different dietary adaptations. We then produce interspecific, inter-trophic-level hybrids to map evolved differences in intestinal length in an F2 mapping cross between Metriaclima mbenjii, an omnivore with a relatively long gut, and Aulonocara koningsi, a carnivore with a relatively short gut. We identify numerous candidate quantitative trait loci for evolved differences in intestinal length. These quantitative trait loci are predominantly sex-specific, supporting an evolutionary history of sexual conflicts for the gut. We also identify epistatic interactions potentially associated with canalization and the maintenance of cryptic variation in the cichlid adaptive radiation. Overall, our results suggest a complex, polygenic evolution of gut length variation associated with trophic level differences among cichlids, as well as conflicts and interactions that may be involved in evolutionary processes underlying other traits in cichlids. SummaryThis study examines the genetic basis of gut length variation in Lake Malawi cichlids, which exhibit different dietary adaptations. It highlights how cichlids recapitulate a broad taxonomic trend: gut length correlates with trophic level, with herbivores and omnivores having longer intestines than carnivores. By creating hybrids of Metriaclima mbenjii (omnivore) and Aulonocara koningsi (carnivore), we identify several quantitative trait loci and epistatic interactions underlying gut length differences. These genetic associations are predominantly sex-specific, suggesting historical sexual conflicts. The results indicate complex, polygenic evolution of gut morphology in these fish, and suggest evolutionary interactions and processes shaping dietary traits across species.

genetics↗

bioRxiv2024

Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN)

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies.

cancer biology↗

bioRxiv2022

Microarray profiling of hypothalamic gene expression changes in Huntington's disease mouse models

Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntingtons disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.

neuroscience↗

bioRxiv2018

Mobile genetic element-encoded hypertolerance to copper protects Staphylococcus aureus from killing by host phagocytes

Pathogens are exposed to toxic levels of copper during infection and copper tolerance may be a general virulence mechanism used by bacteria to resist host defences. In support of this, inactivation of copper-exporter genes has been found to reduce the virulence of bacterial pathogens in vivo. Here we investigate the role of copper-hypertolerance in methicillin resistant Staphylococcus aureus. We show that a copper-hypertolerance locus (copB-mco), carried on a mobile genetic element, is prevalent in a collection of invasive S. aureus strains and more widely among clonal complex 22, 30 and 398 strains. The copB and mco genes encode a copper efflux pump and a multicopper oxidase, respectively. Isogenic mutants lacking copB or mco had impaired growth in subinhibitory concentrations of copper. Transfer of a copB-mco encoding plasmid to a naive clinical isolate resulted in a gain of copper hypertolerance and enhanced bacterial survival inside primed macrophages. The copB and mco genes were upregulated within infected macrophages and their expression was dependent on the copper sensitive operon repressor CsoR. Isogenic copB and mco mutants were impaired in their ability to persist intracellularly in macrophages and were less resistant to phagocytic killing in human blood than the parent strain. The importance of copper-regulated genes in resistance to phagocytic killing was further elaborated using mutants expressing a copper-insensitive variant of CsoR. Our findings suggest that the gain of mobile genetic elements carrying copper-hypertolerance genes contributes to the evolution of virulent strains of S. aureus, better equipped to resist killing by host immune cells.

microbiology↗

bioRxiv2017

Global phylogenomics of multidrug-resistant Staphylococcus aureus sequence type 772: the Bengal Bay clone

The global spread of antimicrobial resistance has been well documented in Gram-negative bacteria and healthcare-associated epidemic pathogens, often emerging from regions with heavy antimicrobial use. However, the degree to which similar processes occur with Gram-positive bacteria in the community setting is less well understood. Here we demonstrate the recent origin and global spread from the Indian subcontinent of a multidrug resistant Staphylococcus aureus lineage, sequence type 772 (Bengal Bay clone). Short-term outbreaks occurred following intercontinental transmission, typically associated with travel and family contacts, but ongoing endemic transmission was uncommon. Instrumental in the emergence of a single dominant clade in the early 1990s was the acquisition of a multidrug resistance integrated plasmid that did not appear to incur a significant fitness cost. The Bengal Bay clone therefore combines the multidrug resistance of traditional healthcare-associated clones with the epidemiological and virulence potential of community-associated clones.

genomics↗