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
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
Recombination of mitochondrial genomes: what can we learn from chigger mites? This project will bring three benefits to Australia. First, it will enhance Australia's research capacity in the fields of organelle genomics and evolutionary biology. Second, it will yield highly skilled young researchers: a postdoctoral fellow (Shao), a PhD student and two BSc Honours students. Third, it will generate new knowledge about genome recombination in animal mitochondria. Recombination is a fundamental, yet ....Recombination of mitochondrial genomes: what can we learn from chigger mites? This project will bring three benefits to Australia. First, it will enhance Australia's research capacity in the fields of organelle genomics and evolutionary biology. Second, it will yield highly skilled young researchers: a postdoctoral fellow (Shao), a PhD student and two BSc Honours students. Third, it will generate new knowledge about genome recombination in animal mitochondria. Recombination is a fundamental, yet poorly understood issue in mitochondrial genomics and evolutionary biology. Knowledge from this project will also improve our understanding of other important issues that are associated with animal mitochondria; like the mechanisms of mitochondrial disease and ageing, and the evolution of modern humans and other animals.Read moreRead less
New models for the role of chromatin in controlling inducible gene expression. This proposal aims to test novel models of how packaging of DNA in the nucleus plays a fundamental role in gene expression. Understanding these concepts is important in the context of successful gene therapy where major hurdles need to be overcome. This work also has implications for somatic cell therapy since it is important to understand how genes are expressed in order to successfully reprogram cells. Both of these ....New models for the role of chromatin in controlling inducible gene expression. This proposal aims to test novel models of how packaging of DNA in the nucleus plays a fundamental role in gene expression. Understanding these concepts is important in the context of successful gene therapy where major hurdles need to be overcome. This work also has implications for somatic cell therapy since it is important to understand how genes are expressed in order to successfully reprogram cells. Both of these areas are important to the Biotechnology industry. Answering questions about higher order chromatin structure in gene transcription will provide cutting edge, innovative knowledge that will have international significance. Read moreRead less
Chromatin structure and pervasive transcription. This project aims to understand mechanisms that repress pervasive transcription and to identify chromatin characteristics that repress transcription initiation outside the promoter regions. Chromatin characteristics, such as position, occupancy and turnover-rate of nucleosomes, establish an elaborate genomic indexing mechanism, which defines functional units in the genome. Defects in this process increase pervasive transcription, toxic accumulatio ....Chromatin structure and pervasive transcription. This project aims to understand mechanisms that repress pervasive transcription and to identify chromatin characteristics that repress transcription initiation outside the promoter regions. Chromatin characteristics, such as position, occupancy and turnover-rate of nucleosomes, establish an elaborate genomic indexing mechanism, which defines functional units in the genome. Defects in this process increase pervasive transcription, toxic accumulation of non-coding transcripts and genomic instability. This work aims to understand eukaryotic genome organisation and may have long-term therapeutic implications for cancer and ageing-related diseases.Read moreRead less
Understanding co-activator function in transcriptional regulation. A change in gene expression underpins all cell fate decisions yet there is scant knowledge about how transcription factors (TF), the master regulators of transcription, specifically interact with some, but not all, transcription cofactors to nuance gene expression. Aims: Using innovative molecular technologies we will identify and characterise the shared and unique relationships between TF and cofactors. Significance: This study ....Understanding co-activator function in transcriptional regulation. A change in gene expression underpins all cell fate decisions yet there is scant knowledge about how transcription factors (TF), the master regulators of transcription, specifically interact with some, but not all, transcription cofactors to nuance gene expression. Aims: Using innovative molecular technologies we will identify and characterise the shared and unique relationships between TF and cofactors. Significance: This study is important to every biological process in plants and animals driven by a change in gene expression. Expected Outcomes: This study will increase our biological knowledge in transcription control. Benefit: The knowledge gained has future applications in genomics and broad implications for biotechnology and industry.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
Silencing the X chromosome: why and how. The project aims to understand why we have X chromosome inactivation, and examine the fundamental molecular mechanisms of how it is achieved. The project will explore RNA-mediated epigenetic modification of whole chromosomes with innovative molecular methods in placental mammals, and also iconic Australian mammals, to transform our understanding of X chromosome inactivation. Further understanding whole chromosome silencing, will inform future research int ....Silencing the X chromosome: why and how. The project aims to understand why we have X chromosome inactivation, and examine the fundamental molecular mechanisms of how it is achieved. The project will explore RNA-mediated epigenetic modification of whole chromosomes with innovative molecular methods in placental mammals, and also iconic Australian mammals, to transform our understanding of X chromosome inactivation. Further understanding whole chromosome silencing, will inform future research into potential therapies for chromosomal trisomies.Read moreRead less