Biology subjects

Williams, H.

Publications and source records attributed to Williams, H..

11 recordsLinked to original sources

bioRxiv2025

Blocking Minor Intron Splicing Disrupts DNA Repair and Overcomes Therapy Resistance in Prostate and Breast Cancer

The minor spliceosome (MiS) is a specialized RNA-processing machinery upregulated in cancer, promoting oncogene expression. We uncovered an adaptive resistance mechanism driven by secretion of extracellular vesicles enriched in U6atac snRNA, which amplifies MiS activity and promotes therapy resistance. Here, we show that U6atac snRNA, a crucial MiS component, reverses this process when depleted, revealing it as a druggable vulnerability in therapy-resistant prostate and breast cancers. U6atac knockdown triggers R-loop-mediated DNA damage while impairing repair by downregulating key DNA repair factors, disabling both homologous recombination and non-homologous end joining. This dual effect sensitizes prostate and breast tumors to PARP inhibitors, cisplatin, and radiation, independent of BRCA status. Across multiple in vitro and in vivo models, MiS targeting demonstrates tumor-selective activity with minimal toxicity. These findings position U6atac as a central regulator of genome stability and establish MiS targeting as a promising approach to potentiate genotoxic therapy and overcome resistance. Statement of significanceU6atac, a minor spliceosome component, is a crucial regulator of genome stability in cancer. Its knockdown triggers R-loop-driven DNA damage, downregulates DNA repair genes, and sensitizes tumors to DNA-damaging therapies while simultaneously blocking resistance mechanisms. Thus, minor spliceosome knockdown is a tumour-selective and broadly applicable therapeutic strategy.

cancer biology↗

bioRxiv2023

In vivo validation of late-onset Alzheimer's disease genetic risk factors

Structured AbstractO_ST_ABSIntroductionC_ST_ABSGenome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimers disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. MethodsCandidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. ResultsWe created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DiscussionThese results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.

neuroscience↗

bioRxiv2023

Metabolomics profiling reveals distinct, sex-specific signatures in the serum and brain metabolomes in the mouse models of Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSIncreasing evidence suggests that metabolic impairments contribute to early Alzheimers disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation. METHODSWe investigated differences of serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at six months of age. RESULTSWe identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSIONSeveral of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of APOE4 carriers and replicating the serum metabolic imprint of the APOE4 genotype. Our work thus represents a significant step towards translating metabolic dysregulation from model organisms to human AD.

neuroscience↗

bioRxiv2023

Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval

Long QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions. LQTS represents a significant clinical challenge due to its complex genetic underpinning and propensity for fatal arrhythmias. In this study, we generated induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMCs) of six patients with extreme polygenic scores for short and long corrected QT intervals. iPSC lines were rigorously validated for genomic integrity through karyotyping and targeted mutation analysis specific to a lengthened or shortened QT interval. Pluripotency was confirmed by expression of key markers TRA 1-60, TRA 1-81, SOX2, OCT4, NANOG, and REX1 via quantitative PCR and immunofluorescence. Subsequent cardiac induction successfully generated cardiomyocytes that were further characterized. This patient-specific approach will enable us to better understand variable expressivity and penetrance of LQTS. Rigorously validated iPSC lines serve as a vital resource for elucidating the molecular mechanisms underlying LQTS. Our study provides a robust and clinically relevant resource to facilitate our understanding the genetic and cellular complexity of LQTS.

genetics↗

bioRxiv2023

New resources for environmental genomics in the wild Mediterranean grass B. distachyon

AO_SCPLOWBSTRACTC_SCPLOWClosely related to economically important crops, the grass Brachypodium distachyon has been originally established as a pivotal species for grass genomics but more recently flourished as a model for developmental biology. Grasses encompass more than 10,000 species and cover more than 40% of the world land area from tropical to temperate regions. Given that grasses also supply about a fifth of the worlds dietary protein as cereal grains, unlocking the sources of phenotypic variation in B. distachyon is hence of prime interest in fundamental and applied research in agronomy, ecology and evolution. We present here the B. distachyon diversity panel, which encompasses 332 fully sequenced accessions covering the whole species distribution from Spain to Iraq. By combining population genetics, niche modeling and landscape genomics, we suggest that B. distachyon recolonized Europe and the Middle East following the last glacial maximum. Consequently, the species faced new environmental conditions which led to clear associations between bioclimatic variables and genetic factors as well as footprints of positive selection in the genome. Altogether, this genomic resource offers a powerful alternative to Arabidopsis thaliana to investigate the genetic bases of adaptation and phenotypic plasticity in plants and more specifically in monocots.

ecology↗

bioRxiv2022

Backtracking: Improved methods for identifying the source of a deliberate release of Bacillus anthracis from the temporal and spatial distribution of cases

Reverse epidemiology is a mathematical modelling tool used to ascertain information about the source of a pathogen, given the spatial and temporal distribution of cases, hospitalisations and deaths. In the context of a deliberately released pathogen, such as Bacillus anthracis (the disease-causing organism of anthrax), this can allow responders to quickly identify the location and timing of the release, as well as other factors such as the strength of the release, and the realized wind speed and direction at release. These estimates can then be used to parameterise a predictive mechanistic model, allowing for estimation of the potential scale of the release, and to optimise the distribution of prophylaxis. In this paper we present two novel approaches to reverse epidemiology, and demonstrate their utility in responding to a simulated deliberate release of B. anthracis in ten locations in the UK and compare these to the standard grid-search approach. The two methods - a modified MCMC and a Recurrent Convolutional Neural Network - are able to identify the source location and timing of the release with significantly better accuracy compared to the grid-search approach. Further, the neural network method is able to do inference on new data significantly quicker than either the grid-search or novel MCMC methods, allowing for rapid deployment in time-sensitive outbreaks. Author summaryIn this paper we demonstrate three methods for estimating the source location and timing of a deliberate release of Bacillus anthracis based on the temporal and spatial distribution of cases. Two of our proposed methods, a modified MCMC approach and a neural network based approach, provide significant improvements over previous methods by directly addressing the problematic parameter-likelihood surface, and, in the case of the neural network approach, addressing the slow deployment speeds of existing methods. Our results represent a major step forward in the accuracy and speed of epidemiological back-calculation.

systems biology↗

bioRxiv2020

Revealing grand-paternal programming of lipid metabolism using a novel computational tool

While the consequences of poor maternal diet on the offspring’s cardio-metabolic health have been studied in detail, the role of the father’s diet on the health of his offspring is poorly understood. We used a known mouse model to establish the impact of an isocaloric paternal low-protein high-carbohydrate diet on the offspring’s lipid metabolism. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate male and female offspring, in serum, liver, brain, heart and abdominal adipose tissues by Mass Spectrometry and Nuclear Magnetic Resonance. Using a purpose-built computational tool for analysing lipid metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of alterations associated with paternal diet. These elucidate a mechanism for the defective physiological behaviour of systems at risk of cardio-metabolic disease.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2020

A novel tool for standardizing clinical data in a realism-based common data model

Standardizing clinical information in a common data model is important for promoting interoperability and facilitating high quality research. Semantic Web technologies such as Resource Description Framework can be utilized to their full potential when a clinical data model accurately reflects the reality of the clinical situation it describes. To this end, the Open Biomedical Ontologies Foundry provides a set of ontologies that conform to the principles of realism and can be used to create a realism-based clinical data model. However, the challenge of programmatically defining such a model and loading data from disparate sources into the model has not been addressed by pre-existing software solutions. The PennTURBO Semantic Engine is a tool developed at the University of Pennsylvania that works in conjunction with data aggregation software to transform source-specific RDF data into a source-independent, realism-based data model. This system sources classes from an application ontology and specifically defines how instances of those classes may relate to each other. Additionally, the system defines and executes RDF data transformations by launching dynamically generated SPARQL update statements. The Semantic Engine was designed as a generalizable RDF data standardization tool, and is able to work with various data models and incoming data sources. Its human-readable configuration files can easily be shared between institutions, providing the basis for collaboration on a standard realism-based clinical data model.

bioinformatics↗

bioRxiv2019

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

BackgroundLate-onset Alzheimers disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimers have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes.\n\nResultsThis resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter(R) Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of three mouse models based on LOAD genetics, carrying APOE4 and TREM2*R47H alleles, demonstrated overlaps with distinct human AD modules that, in turn, are functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq shows strong correlation between gene expression changes independent of experimental platform.\n\nConclusionsTaken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models.

neuroscience↗

bioRxiv2018

Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multi-modal imaging investigation

Young adult APOE-{varepsilon}4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (half APOE-{varepsilon}4 carriers, the other half APOE-{varepsilon}3{varepsilon}3/{varepsilon}2{varepsilon}3; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. Diffusion tractography was used to quantify the microstructure (mean diffusivity, MD; fractional anisotropy, FA) of the parahippocampal cingulum bundle (PHCB), which links pDMN and the medial temporal lobe. APOE-{varepsilon}4 carriers had lower MD and higher FA relative to non-carriers in PHCB. Further, PHCB microstructure was selectively associated with pDMN activity during a scene discrimination task known to be sensitive to Alzheimers disease (AD). These findings are consistent with a lifespan view of AD risk, where early-life structural and functional brain changes in specific, vulnerable networks leads to increased neural activity that may ultimately trigger amyloid-{beta} deposition.

neuroscience↗

bioRxiv2017

HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

biochemistry↗