Decoding regulatory RNA function in bacteria. All complex biological processes in bacterial cells appear to utilise regulatory small RNAs to control gene expression, but we lack a systems-level understanding of their functions and mechanisms of control. This proposal aims to address this fundamental knowledge gap using machine learning and cutting-edge, systems-level techniques to determine how small RNA sequence and structure determines function. Small RNAs have been found to control a broad ra ....Decoding regulatory RNA function in bacteria. All complex biological processes in bacterial cells appear to utilise regulatory small RNAs to control gene expression, but we lack a systems-level understanding of their functions and mechanisms of control. This proposal aims to address this fundamental knowledge gap using machine learning and cutting-edge, systems-level techniques to determine how small RNA sequence and structure determines function. Small RNAs have been found to control a broad range of traits including metabolism, biofilm formation, antibiotic tolerance, and virulence. The work proposed here will enhance our ability to predict and control bacterial gene expression with potential future impacts on bioproduction, synthetic biology, and veterinary and medical microbiology.Read moreRead less
Investigating the biogenesis and function of circular RNAs in the brain. Circular RNAs (circRNAs) are e a novel class of RNA molecules produced in a wide spectrum of eukaryotic organisms, from yeast to humans. Their expression is particularly high in the nervous system in the fruit fly, mouse and humans. What mechanisms are responsible for the tissue-specific enrichment of circular RNA expression? What are the consequences of circular RNA production on gene expression? The overall goal of the pr ....Investigating the biogenesis and function of circular RNAs in the brain. Circular RNAs (circRNAs) are e a novel class of RNA molecules produced in a wide spectrum of eukaryotic organisms, from yeast to humans. Their expression is particularly high in the nervous system in the fruit fly, mouse and humans. What mechanisms are responsible for the tissue-specific enrichment of circular RNA expression? What are the consequences of circular RNA production on gene expression? The overall goal of the proposed project is to elucidate these important aspects of circRNA biogenesis. Specifically, the project aims to (a) discover proteins that regulate circRNA expression, (b) elucidate how circRNA expression interacts with alternative splicing, and (c) identify circular RNAs that play regulatory roles in gene expression. 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
Genetic, Cellular and Molecular Analysis of Cardiac Ventricular Septation. The project aims to define the blueprint for ventricular septation in the mammalian heart – how, during heart development, a single ventricle becomes divided in two by a muscular wall, thus creating left and right pumps and electrical circuits serving the body and lung circulations separately. A proprietary mouse genetic model was created and will be used to probe the cellular and molecular mechanisms of septation using n ....Genetic, Cellular and Molecular Analysis of Cardiac Ventricular Septation. The project aims to define the blueprint for ventricular septation in the mammalian heart – how, during heart development, a single ventricle becomes divided in two by a muscular wall, thus creating left and right pumps and electrical circuits serving the body and lung circulations separately. A proprietary mouse genetic model was created and will be used to probe the cellular and molecular mechanisms of septation using new technologies able to resolve biology at a single-cell level. Outcomes may include new knowledge on heart development and evolution, including how the cardiac electrical system is formed, and how cell boundaries and tissue complexity are generated. The project may advance new technologies and create new data resources.Read moreRead less
Regulating the composition of biomolecular condensates in living cells. Biomolecular condensation is a novel organising principle of living cells, driven by ‘unmixing’ of the cellular contents into compartments. It is observed from plants to animals and is involved in diverse processes from how cells repair DNA to how they perceive signals. This project aims to reveal how human cells control the composition of condensates, which is critical for their function. It expects to uncover new regulator ....Regulating the composition of biomolecular condensates in living cells. Biomolecular condensation is a novel organising principle of living cells, driven by ‘unmixing’ of the cellular contents into compartments. It is observed from plants to animals and is involved in diverse processes from how cells repair DNA to how they perceive signals. This project aims to reveal how human cells control the composition of condensates, which is critical for their function. It expects to uncover new regulatory principles of cellular organisation by combining methods from quantitative cell biology and statistical physics. Expected benefits include building Australia’s capability in the potentially transformational field of biomolecular condensates, which has diverse future biotechnology applications in health and agriculture.Read moreRead less
Engineering a chromatin looping factor for artificial gene regulation. This project aims to define mechanisms of chromatin looping and gene activation by a widely expressed mammalian protein. The project will establish if the functions of this protein are modulated by the binding of small molecules, whether it can act in conjunction with closely related proteins, and if post-translational modifications regulate looping and gene activation. Using protein engineering the project will develop synth ....Engineering a chromatin looping factor for artificial gene regulation. This project aims to define mechanisms of chromatin looping and gene activation by a widely expressed mammalian protein. The project will establish if the functions of this protein are modulated by the binding of small molecules, whether it can act in conjunction with closely related proteins, and if post-translational modifications regulate looping and gene activation. Using protein engineering the project will develop synthetic looping factors that can switch on a wide array of target genes. The project aims to answer fundamental questions about how proteins can establish and maintain physical loops in DNA to modulate gene expression. The project will also develop research tools that might ultimately correct diseases caused by the faulty expression of genes.Read moreRead less
How novel ribosomal RNA gene repeat variants drive cellular function. The hundreds of ribosomal RNA gene repeat copies are a remarkable part of our genomes, as they encode the machinery responsible for all cellular protein synthesis and shape the structure of the nucleus. However, due to their high degree of sequence similarity, they still have not been assembled into the human genome reference. This project will resolve this impasse and furthermore uncover the functional impacts of a newly iden ....How novel ribosomal RNA gene repeat variants drive cellular function. The hundreds of ribosomal RNA gene repeat copies are a remarkable part of our genomes, as they encode the machinery responsible for all cellular protein synthesis and shape the structure of the nucleus. However, due to their high degree of sequence similarity, they still have not been assembled into the human genome reference. This project will resolve this impasse and furthermore uncover the functional impacts of a newly identified molecular diversity in the ribosomal RNA gene repeats. Outcomes include new paradigms for how the ribosomal RNA gene repeats drive protein synthesis and genome structure, and a blueprint to develop novel genomics applications for human health, biotechnology, and agriculture.Read moreRead less