Improving the efficiency of CRISPR gene editing in cells. Human red blood cells are well-characterised and the globin gene locus is a model system for the study of gene regulation. Gene editing technologies and delivery tools are evolving rapidly and the globin gene locus is the perfect model for gene editing optimisation. This collaboration between UNSW Sydney and CSL aims to bring together our combined expertise and new technologies to develop an optimal platform for genetic modification in a ....Improving the efficiency of CRISPR gene editing in cells. Human red blood cells are well-characterised and the globin gene locus is a model system for the study of gene regulation. Gene editing technologies and delivery tools are evolving rapidly and the globin gene locus is the perfect model for gene editing optimisation. This collaboration between UNSW Sydney and CSL aims to bring together our combined expertise and new technologies to develop an optimal platform for genetic modification in a red blood cell line. Simultaneously, this project aims to generate fundamental insights into mechanisms of human gene regulation. The technological and biological outcomes of this project will be of benefit for future gene editing applications.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE190100085
Funder
Australian Research Council
Funding Amount
$414,864.00
Summary
Elucidating a novel mechanism for coping with harmful mutations. This project aims to improve our understanding of the complex regulatory mechanisms that increase genetic and phenotypic robustness. Survival of organisms depends on their ability to cope with genetic variation. A novel process of genetic compensation has recently been identified, producing a normal phenotype in a homozygous mutant, that would be expected to have deleterious effects. This project will reveal how compensation is ach ....Elucidating a novel mechanism for coping with harmful mutations. This project aims to improve our understanding of the complex regulatory mechanisms that increase genetic and phenotypic robustness. Survival of organisms depends on their ability to cope with genetic variation. A novel process of genetic compensation has recently been identified, producing a normal phenotype in a homozygous mutant, that would be expected to have deleterious effects. This project will reveal how compensation is achieved by examining the molecular pathways that are activated following genetic mutation. This project is expected to strengthen Australian reputation in evolutionary genetics, and in turn enhance our understanding of how organisms adapt to changing environments.Read moreRead less
Transcription factors find their targets by reading the epigenetic code. This project aims to elucidate how transcription factors, proteins that regulate gene expression, find their target genes. The hypothesis is that non-DNA binding domains play an essential role in this process. This project expects to transform our understanding of transcription factor families, and how factors in families with the same DNA-binding domain manage to regulate different genes. Expected outcomes of this project ....Transcription factors find their targets by reading the epigenetic code. This project aims to elucidate how transcription factors, proteins that regulate gene expression, find their target genes. The hypothesis is that non-DNA binding domains play an essential role in this process. This project expects to transform our understanding of transcription factor families, and how factors in families with the same DNA-binding domain manage to regulate different genes. Expected outcomes of this project include revealing how accessory proteins help transcription factors identify their targets in the genome by reading epigenetic marks. This should provide significant benefits including improved design of artificial transcription factors to up- or down-regulate specific genes in research and agriculture.Read moreRead less
Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, th ....Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, the project intends to enhance the efficiency and function of these factors by designing modules to improve the stability of DNA binding and effectiveness in functionally regulating gene expression. The project outcomes could include knowledge enabling the use of genetically engineered DNA-binding proteins to artificially control gene expression, with significant scientific and economic implications.Read moreRead less
Unravelling the contributions of Denisovan DNA to the peoples of Oceania. This project aims to investigate the impact gene flow from Denisovans, an archaic hominin species, has had on individuals from Papua New Guinea and eastern Indonesia. These people owe up to 5% of their genomes to these mysterious ancestors, but the repercussions of this finding remain poorly understood. In order to identify the biological contributions these fragments of DNA make to the individuals who carry them, this pro ....Unravelling the contributions of Denisovan DNA to the peoples of Oceania. This project aims to investigate the impact gene flow from Denisovans, an archaic hominin species, has had on individuals from Papua New Guinea and eastern Indonesia. These people owe up to 5% of their genomes to these mysterious ancestors, but the repercussions of this finding remain poorly understood. In order to identify the biological contributions these fragments of DNA make to the individuals who carry them, this project aims to combine anthropological genetics with cutting-edge functional genomics in a pioneer multidisciplinary approach. Ultimately, this project may transform our understanding of both the population and evolutionary pressures that have acted upon these groups in the past 50,000 years.Read moreRead less
Endocardial sprouting and mechano-signalling in heart trabeculation. This project aims to understand how the ventricles, the pumping chambers of the mammalian heart, form during embryonic life. Critical is the elaboration of trabeculae, myocardial projections that form a sponge-like layer on the inner surface of the chamber wall and which play vital roles in contraction, oxygen and nutrient exchange, conduction and septation. The project expects to develop a deeper understanding of trabeculation ....Endocardial sprouting and mechano-signalling in heart trabeculation. This project aims to understand how the ventricles, the pumping chambers of the mammalian heart, form during embryonic life. Critical is the elaboration of trabeculae, myocardial projections that form a sponge-like layer on the inner surface of the chamber wall and which play vital roles in contraction, oxygen and nutrient exchange, conduction and septation. The project expects to develop a deeper understanding of trabeculation using high resolution, single cell methodologies, and to investigate how bio-mechanical forces from contraction or blood flow influence chambers formation.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.
Regulatory architecture of the trunk-to-tail transition. This project aims to elucidate gene regulatory mechanisms that control how the head-to-tail axis is laid down during embryonic development. The project capitalises on unique pluripotent stem cell resources and cutting-edge genomic technology developed by the team. This project expects to generate new knowledge in the area of developmental biology and gene regulation that is anticipated to have wider application to the understanding of evol ....Regulatory architecture of the trunk-to-tail transition. This project aims to elucidate gene regulatory mechanisms that control how the head-to-tail axis is laid down during embryonic development. The project capitalises on unique pluripotent stem cell resources and cutting-edge genomic technology developed by the team. This project expects to generate new knowledge in the area of developmental biology and gene regulation that is anticipated to have wider application to the understanding of evolutionary mechanisms and ultimately regenerative medicine.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
Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time t ....Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time the cardiac regulatory repertoire in zebrafish and will compare it with that of fly and mouse using cutting-edge bioinformatics pipelines. This work will unravel cardiac-specific regulatory modifications that give rise to evolutionary changes. On a broader scale, it will shed new light on the role of regulatory innovations over gene innovations in the emergence of new traits.Read moreRead less