Epigenetic regulation of genomic stability and inheritance. Sperm mediate inheritance by transmitting DNA and associated chemical (epigenetic) modifications to offspring. We hypothesise that epigenetic modifications protect DNA from mutations during sperm formation. Using innovative models, our interdisciplinary team will determine whether loss of specific epigenetic modifications permits mutations in sperm and whether these mutations are transmitted to offspring. Our work will contribute to und ....Epigenetic regulation of genomic stability and inheritance. Sperm mediate inheritance by transmitting DNA and associated chemical (epigenetic) modifications to offspring. We hypothesise that epigenetic modifications protect DNA from mutations during sperm formation. Using innovative models, our interdisciplinary team will determine whether loss of specific epigenetic modifications permits mutations in sperm and whether these mutations are transmitted to offspring. Our work will contribute to understanding how new mutations arise in sperm and potentially affect offspring phenotype, adaptation and evolution. As chemicals, drugs and diet can affect epigenetic function, our studies will also contribute to determining how epigenetic inheritance affects environmental, agricultural and healthcare outcomes.Read moreRead less
Understanding how cells compact and segregate DNA in vertebrates. How a cell compacts and divides its DNA is still a major unanswered question in biology. This project will determine the way in which a cell compacts its DNA nearly ten thousand fold to allow the faithful and accurate segregation to daughter nuclei.
Gastrointestinal hormones: linking insulin dysregulation and laminitis. This project aims to identify the earliest pathogenic factors of disease by investigating two key hormones, ghrelin and GLP-2, and whether a specific genetic mutation underlies insulin dysregulation. Using innovative approaches the project will enable the identification of at-risk animals and pinpoint novel treatment strategies. In the long term improved disease treatment and prevention will reduce the suffering associated w ....Gastrointestinal hormones: linking insulin dysregulation and laminitis. This project aims to identify the earliest pathogenic factors of disease by investigating two key hormones, ghrelin and GLP-2, and whether a specific genetic mutation underlies insulin dysregulation. Using innovative approaches the project will enable the identification of at-risk animals and pinpoint novel treatment strategies. In the long term improved disease treatment and prevention will reduce the suffering associated with painful and often lethal co-morbidities.Read moreRead less
Cellular determinants of retrotransposition. This project aims to understand the processes that control retrotransposition in a genome. Transposable elements make up more than 50% of human genomes. The accumulation of retrotransposons through millions of years of evolution has shaped the genomes of all eukaryotic organisms, including humans. Researchers have elucidated mechanisms the host uses to defend the genome against insertional mutagenesis by retrotransposons, but the cellular machinery an ....Cellular determinants of retrotransposition. This project aims to understand the processes that control retrotransposition in a genome. Transposable elements make up more than 50% of human genomes. The accumulation of retrotransposons through millions of years of evolution has shaped the genomes of all eukaryotic organisms, including humans. Researchers have elucidated mechanisms the host uses to defend the genome against insertional mutagenesis by retrotransposons, but the cellular machinery and genomic environments needed for retrotransposition are undefined. This project aims to use models to uncover the mechanisms that control retrotransposition. This is expected to reveal more about human origins.Read moreRead less
Role of R-loops and double R-loops in genome organisation and transcription. The majority of our genome is converted to an extensive network of non-protein-coding RNA molecules (ncRNAs), but the function of these ncRNAs is unknown. This project aims to identify and determine the mechanism of action of nuclear ncRNA networks with a particular focus on nuclear ncRNAs that form RNA-DNA hybrids with the genomic DNA. These studies have the potential to lead to ground-breaking discoveries in our under ....Role of R-loops and double R-loops in genome organisation and transcription. The majority of our genome is converted to an extensive network of non-protein-coding RNA molecules (ncRNAs), but the function of these ncRNAs is unknown. This project aims to identify and determine the mechanism of action of nuclear ncRNA networks with a particular focus on nuclear ncRNAs that form RNA-DNA hybrids with the genomic DNA. These studies have the potential to lead to ground-breaking discoveries in our understanding of genome organisation and the mechanism of transcription control, and might provide an entirely new tool-box to manipulate genome function. This should provide significant benefits to efforts to develop innovative biotechnology and genome editing technologies in plants and animals.Read moreRead less
RNA surveillance and the initial steps of RNA biogenesis. This project aims to understand the initial steps of RNA biogenesis and how this process is linked to the chromatin environment. Although less than five per cent of our genome encodes proteins, almost the entire genome is transcribed to RNA. A large portion of these transcripts are degraded during the early steps of RNA biogenesis by the RNA surveillance machinery, but the mechanism for the recognition and degradation of these transcripts ....RNA surveillance and the initial steps of RNA biogenesis. This project aims to understand the initial steps of RNA biogenesis and how this process is linked to the chromatin environment. Although less than five per cent of our genome encodes proteins, almost the entire genome is transcribed to RNA. A large portion of these transcripts are degraded during the early steps of RNA biogenesis by the RNA surveillance machinery, but the mechanism for the recognition and degradation of these transcripts is not understood. New evidence suggests that the chromatin environment of the transcribed locus plays an important role in this process. This project will lead to significant benefits in the implementation of emerging RNA-based technologies and in understanding how genome stability is maintained.Read moreRead less
The T cell genome in 3D: linking chromatin structure to cellular function. Adaptive immune cell activation results in the acquisition and long term maintenance of specific cellular function that enables efficient immune control of infections. Using advanced cellular and genomic approaches, combined with high-resolution microscopy and cutting edge computational biology, this proposal aims to address major gaps in our knowledge about how alterations in genomic 3D architecture and targeted biochemi ....The T cell genome in 3D: linking chromatin structure to cellular function. Adaptive immune cell activation results in the acquisition and long term maintenance of specific cellular function that enables efficient immune control of infections. Using advanced cellular and genomic approaches, combined with high-resolution microscopy and cutting edge computational biology, this proposal aims to address major gaps in our knowledge about how alterations in genomic 3D architecture and targeted biochemical modifications impact cell specific gene nuclear positioning and how this regulates changes in gene expression associated with immune cell activation. An outcome will be identification of novel molecular mechanisms that will have broad applicability across cellular biology, and provide novel targets for drug development.Read moreRead less
Uncovering an evolutionary advanced mechanism of gene expression control. This project aims to uncover a new mechanism that activates gene expression in mammals, which involves unexpected connections between the core components of chromosomes and essential enzymatic machines required for the expression of genes. This project will generate new knowledge on the poorly understood process of how the extensive genomic information of multicellular organisms is selectively chosen to enable the expressi ....Uncovering an evolutionary advanced mechanism of gene expression control. This project aims to uncover a new mechanism that activates gene expression in mammals, which involves unexpected connections between the core components of chromosomes and essential enzymatic machines required for the expression of genes. This project will generate new knowledge on the poorly understood process of how the extensive genomic information of multicellular organisms is selectively chosen to enable the expression of only the required subset of genes. This will revolutionise our understanding of the mechanisms of gene control thereby shaping the field in the future. Significantly, this will allow new ways to manipulate gene expression that will impact biotechnology by providing new efficient ways to produce proteins or RNA. Read moreRead less
Who’s who in the plant gene world? As many more plant genomes are sequenced, the bottleneck is being able to interrogate and translate this data into applications for crop improvement. This project will develop and apply a population graph database, hosting genome data for the world’s major crops and their wild relatives, allowing the characterisation of gene diversity on an unparalleled scale. Analysis of this data will reveal the presence/absence and sequence diversity for classes of genes for ....Who’s who in the plant gene world? As many more plant genomes are sequenced, the bottleneck is being able to interrogate and translate this data into applications for crop improvement. This project will develop and apply a population graph database, hosting genome data for the world’s major crops and their wild relatives, allowing the characterisation of gene diversity on an unparalleled scale. Analysis of this data will reveal the presence/absence and sequence diversity for classes of genes for important agronomic traits including disease resistance, flowering time and legume nitrogen fixation which will enable plant breeders to identify and apply novel genes and allelic variants for use in breeding programmes, accelerating the production of improved crop varieties.Read moreRead less
Dynamic DNA structure states and memory formation. Activity-induced gene expression is central to neural plasticity, learning, and memory; however, the underlying mechanisms of these processes in the brain have yet to be fully resolved. The aim of this proposal is to obtain a deeper understanding of the functional relationship between genes and brain function. By elucidating the full repertoire of epigenetic mechanisms in the brain during learning and the formation of memory, it is hoped that t .... Dynamic DNA structure states and memory formation. Activity-induced gene expression is central to neural plasticity, learning, and memory; however, the underlying mechanisms of these processes in the brain have yet to be fully resolved. The aim of this proposal is to obtain a deeper understanding of the functional relationship between genes and brain function. By elucidating the full repertoire of epigenetic mechanisms in the brain during learning and the formation of memory, it is hoped that the true nature of brain adaptation across the lifespan will be revealed. Findings which may then provide new opportunities to strengthen, maintain and optimise cognitive function.Read moreRead less