A5072761139- Genomics and Phylogenetic Studies
- RNA Research and Splicing
- RNA modifications and cancer
- Single-cell and spatial transcriptomics
- Cancer-related molecular mechanisms research
- Scientific Computing and Data Management
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Genomics and Chromatin Dynamics
- MicroRNA in disease regulation
- Fungal and yeast genetics research
- Molecular Biology Techniques and Applications
- Distributed and Parallel Computing Systems
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- Gene expression and cancer classification
- RNA and protein synthesis mechanisms
- Gene Regulatory Network Analysis
- Machine Learning in Bioinformatics
- Surface Chemistry and Catalysis
- Cancer Genomics and Diagnostics
- Cancer, Lipids, and Metabolism
- Microtubule and mitosis dynamics
University of Sheffield
2016-2024
University of Oxford
2012-2015
Genomics (United Kingdom)
2012-2014
Genomics England
2014
Medical Research Council
2013
Wellcome Sanger Institute
2009-2010
University of Aberdeen
2003
Institute of Medical Sciences
2003
Unique Molecular Identifiers (UMIs) are random oligonucleotide barcodes that increasingly used in high-throughput sequencing experiments. Through a UMI, identical copies arising from distinct molecules can be distinguished those through PCR amplification of the same molecule. However, bioinformatic methods to leverage information UMIs have yet formalized. In particular, errors UMI sequence often ignored or else resolved an ad hoc manner. We show common and introduce network-based account for...
CpG islands (CGIs) are associated with most mammalian gene promoters. A subset of CGIs act as polycomb response elements (PREs) and recognized by the silencing systems to regulate expression genes involved in early development. How function mechanistically nucleation sites for repressive complexes remains unknown. Here we discover that KDM2B (FBXL10) specifically recognizes non-methylated DNA recruits complex 1 (PRC1). This contributes histone H2A lysine 119 ubiquitylation (H2AK119ub1)...
New antifungal agents are urgently required to combat life-threatening infections caused by opportunistic fungal pathogens like Candida albicans . The manipulation of endogenous programmed cell death responses could provide a basis for future therapies. Here we assess the physiology in C. response environmental stresses (acetic acid and hydrogen peroxide) an agent (amphotericin B). Exposure 40-60 mM acetic acid, 5-10 peroxide, or 4-8 μg·ml -1 amphotericin B produced cellular changes...
We introduce alevin, a fast end-to-end pipeline to process droplet-based single-cell RNA sequencing data, performing cell barcode detection, read mapping, unique molecular identifier (UMI) deduplication, gene count estimation, and whitelisting. Alevin's approach UMI deduplication considers transcript-level constraints on the molecules from which UMIs may have arisen accounts for both gene-unique reads that multimap between genes. This addresses inherent bias in existing tools discard...
Abstract Despite the nuclear localization of m 6 A machinery, genomes multiple exclusively-cytoplasmic RNA viruses, such as chikungunya (CHIKV) and dengue (DENV), are reported to be extensively A-modified. However, these findings mostly based on A-Seq, an antibody-dependent technique with a high rate false positives. Here, we address presence in CHIKV DENV RNAs. For this, combine A-Seq antibody-independent SELECT nanopore direct sequencing techniques functional, molecular, mutagenesis...
Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction phagocytosis, migration, and chemotaxis monocyte-derived macrophages (MDMs) from older (>50 years old) compared younger (18-30 donors, alongside downregulation of transcription factors MYC USF1. In MDMs young knockdown or USF1 decreases phagocytosis alters the...
Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.
N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA. This has previously been shown to alter export kinetics for mRNAs though molecular details surrounding this phenomenon remain poorly understood. Recruitment TREX mRNA complex driven by transcription, 5' capping and pre-mRNA splicing. Here we identify a fourth mechanism in human cells driving association with involving m6A methylase complex. We show that recruits modified process essential their efficient...
During gene expression, RNA export factors are mainly known for driving nucleo-cytoplasmic transport. While early studies suggested that the exon junction complex (EJC) provides a binding platform them, subsequent work proposed they only recruited by cap to 5' end of RNAs, as part TREX. Using iCLIP, we show receptor Nxf1 and two TREX subunits, Alyref Chtop, whole mRNA co-transcriptionally via splicing but before 3' processing. Consequently, alters decisions Chtop regulates alternative...
Abstract Summary: Computational genomics seeks to draw biological inferences from genomic datasets, often by integrating and contextualizing next-generation sequencing data. CGAT provides an extensive suite of tools designed assist in the analysis genome scale data a range standard file formats. The toolkit enables filtering, comparison, conversion, summarization annotation intervals, gene sets sequences. can both be run Unix command line installed into visual workflow builders, such as...
Abstract Background Imprinted genes show expression from one parental allele only and are important for development behaviour. This extreme mode of allelic imbalance has been described approximately 56 human genes. Imprinting status is often disrupted in cancer dysmorphic syndromes. More subtle variation gene expression, that not parent-of-origin specific, termed 'allele-specific expression' (ASE) more common may give rise to milder phenotypic differences. Using two allele-specific...
Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and potential prognostic biomarkers. We performed in vivo transcriptome profiling pre- post-treatment prostatic biopsies from patients with advanced hormone-naive treated docetaxel androgen deprivation therapy (ADT) an aim to RNA sequencing (RNA-Seq) was on four before ~22 weeks after ADT initiation. Gene...
Highlights•TDP1 proteostasis is controlled by a UCHL3-dependent ubiquitylation mechanism•UCHL3 depletion sensitizes mammalian cells to TOP1 inhibitors•Increased TDP1 protein in rhabdomyosarcoma driven UCHL3 upregulation•Decreased spinocerebellar ataxia downregulationSummaryGenomic damage can feature DNA-protein crosslinks whereby their acute accumulation utilized treat cancer and progressive causes neurodegeneration. This typified tyrosyl DNA phosphodiesterase 1 (TDP1), which repairs...
The field of RNA-based therapeutics is rapidly evolving and targeting non-coding RNAs (ncRNAs) associated with disease becoming increasingly feasible. MicroRNAs (miRNAs) are a class small ncRNAs (sncRNAs) the first anti-miRNA drugs, e.g., Miravirsen Cobomarsen, have successfully completed phase II clinical trials. Long (lncRNAs) another that commonly dysregulated in disease. Thus, they hold potential as putative therapeutic targets or agents. LncRNAs can function through variety mechanisms,...
Abstract Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct transcriptome profiles are primarily driven by initiating events (MIE) and converge into mutually exclusive overexpression CCND1 CCND2 oncogenes. Here, with reference to their normal counterparts, we find that PC enhanced chromatin accessibility combined paired profiling can classify MIE-defined genetic subgroups. Across within different MM subgroups, ascribe regulation genes...
Abstract Background RNA inhibition by siRNAs is a frequently used approach to identify genes required for specific biological processes. However RNAi screening using hampered non-specific or off target effects of the siRNAs, making it difficult separate genuine hits from false positives. It thought that many off-target seen in experiments are due acting as microRNAs (miRNAs), causing reduction gene expression unintended targets via matches 6 7 nt 'seed' sequence. We have conducted careful...
Abstract Unique Molecular Identifiers (UMIs) are random oligonucleotide barcodes that increasingly used in high-throughout sequencing experiments. Through a UMI, identical copies arising from distinct molecules can be distinguished those through PCR amplification of the same molecule. However, bioinformatic methods to leverage information UMIs have yet formalised. In particular, errors UMI sequence often ignored, or else resolved an ad-hoc manner. We show common and introduce network-based...
<ns4:p>In the genomics era computational biologists regularly need to process, analyse and integrate large complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in pipelines or workflows, often with several branches. Large data volumes mean that processing needs be quick efficient scientific rigour requires analysis consistent fully reproducible. We have developed CGAT-core, a python package for rapid construction of workflows. CGAT-core seamlessly...
Genome sequences are essential tools for comparative and mutational analyses. Here we present the short read sequence of mouse chromosome 17 from Mus musculus domesticus derived strain A/J, castaneus CAST/Ei. We describe approaches accurate identification nucleotide structural variation in genomes vertebrate experimental organisms, show how these techniques can be applied to help prioritize candidate genes within quantitative trait loci.
The opportunistic human fungal pathogen, Candida albicans, undergoes morphological and transcriptional adaptation in the switch from commensalism to pathogenicity. Although previous gene-knockout studies have identified many factors involved this transformation, it remains unclear how these are regulated coordinate switch. Investigating morphogenetic control by post-translational phosphorylation has generated important regulatory insights into process, especially focusing on coordinated...
<ns4:p>In the genomics era computational biologists regularly need to process, analyse and integrate large complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in pipelines or workflows, often with several branches. Large data volumes mean that processing needs be quick efficient scientific rigour requires analysis consistent fully reproducible. We have developed CGAT-core, a python package for rapid construction of workflows. CGAT-core seamlessly...