Noncoding RNAs As Prognostic Markers And Therapeutic Targets In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$550,283.00
Summary
Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our labo ....Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our laboratory and others have shown that most of our genome and that of other mammals is actually expressed as noncoding RNA, which appears to be developmentally regulated. These RNAs (of which there appear to be tens of thousands, well outnumbering the protein-coding mRNAs) have been referred to as the hidden layer or dark matter of our genome, as they have barely been studied, but appear to play a central role in both normal and abnormal development in humans. There is now increasing evidence that many noncoding RNAs, including small regulatory RNAs called microRNAs, are perturbed in cancer and that these perturbations may be directly involved in, and be an accurate indicator of, cancer state and the direction of cancer progression. If this is true we need to understand the expression and functions of these RNAs in order to develop better diagnostics and perhaps powerful new therapeutics for cancer, based on RNA technology and generic delivery systems. This project will explore the patterns of noncoding RNA expression in normal breast development and in breast cancer, to identify those RNAs that direct or accompany the differentiation of these tissues, and to test the effects of interfering with their expression on these processes. These foundation studies lie at the leading edge of a new understanding of human genetics and cancer, and will provide a platform for future applications in medicine that utilize this information and understanding.Read moreRead less
Dissecting cell cycle regulation using programmable gene editing technology. This program aims to harness the unprecedented power of CRISPR-Cas13 gene-editing technology to develop high-throughput tools to explore the role of RNA regulation in cell cycle control. This project expects to generate new knowledge about cell division and RNA biology by utilizing this new technology and applying interdisciplinary approaches. Expected outcomes of this proposal include new research tools capable of broa ....Dissecting cell cycle regulation using programmable gene editing technology. This program aims to harness the unprecedented power of CRISPR-Cas13 gene-editing technology to develop high-throughput tools to explore the role of RNA regulation in cell cycle control. This project expects to generate new knowledge about cell division and RNA biology by utilizing this new technology and applying interdisciplinary approaches. Expected outcomes of this proposal include new research tools capable of broadly addressing biological questions across multiple disciplines (e.g. from health to food production). This project intends to provide significant benefits, such as enhanced biological knowledge, multidisciplinary training opportunities and will build Australia’s capability in this rapidly expanding field.Read moreRead less
Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in ....Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in doing so, will provide significant benefit by revealing the potential for iPSC to be used for functional translation of human genomics.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE230100271
Funder
Australian Research Council
Funding Amount
$463,618.00
Summary
Coordinating gene expression and cell size: the role of feedback regulation. This project aims to reveal how human cells coordinate the kinetics of messenger RNA (mRNA) transcript production, processing and degradation at the single-cell level. It expects to generate significant new biological knowledge of gene regulation by combining innovative interdisciplinary research methodologies in genetics, single-molecule imaging, mathematical modelling and quantitative cell biology. Expected outcomes i ....Coordinating gene expression and cell size: the role of feedback regulation. This project aims to reveal how human cells coordinate the kinetics of messenger RNA (mRNA) transcript production, processing and degradation at the single-cell level. It expects to generate significant new biological knowledge of gene regulation by combining innovative interdisciplinary research methodologies in genetics, single-molecule imaging, mathematical modelling and quantitative cell biology. Expected outcomes include enhanced training of researchers and to build Australia’s capability in the rapidly expanding fields of RNA biology and high-throughput microscopy. This should provide significant benefits for a myriad of applications including health, agriculture and veterinary sciences.Read moreRead less
An integrated molecular approach to human gene regulation. This proposal aims to reveal how the interaction of nuclear RNA and protein molecules control gene regulation in the face of cell stress. To understand how genetic variation leads to changes in the expression of genes, we need new insights into the fundamental principles underpinning complex gene regulatory systems. Building on the discovery of paraspeckles, novel gene regulatory structures, this project will yield insights into gene reg ....An integrated molecular approach to human gene regulation. This proposal aims to reveal how the interaction of nuclear RNA and protein molecules control gene regulation in the face of cell stress. To understand how genetic variation leads to changes in the expression of genes, we need new insights into the fundamental principles underpinning complex gene regulatory systems. Building on the discovery of paraspeckles, novel gene regulatory structures, this project will yield insights into gene regulation that will help fill these knowledge gaps. This will provide a more comprehensive understanding of RNA-mediated gene regulation, and will open up new research opportunities to target RNA based gene regulatory complexes.Read moreRead less
Investigating Hippo-regulated transcription at single molecule resolution. Signalling pathways operate throughout life to relay signals from the extracellular world to the cellular nucleus, to control transcription and elicit a response. This project aims to understand how the Hippo growth control pathway regulates transcription. Using a combination of biology, biophysics and computational biology, this project aims to quantify behaviour of the Hippo pathway transcription factors at sub-micron r ....Investigating Hippo-regulated transcription at single molecule resolution. Signalling pathways operate throughout life to relay signals from the extracellular world to the cellular nucleus, to control transcription and elicit a response. This project aims to understand how the Hippo growth control pathway regulates transcription. Using a combination of biology, biophysics and computational biology, this project aims to quantify behaviour of the Hippo pathway transcription factors at sub-micron resolution, and how Hippo signalling modulates their behaviour, interaction with the genome and function. We anticipate our discoveries will stimulate new research, e.g. testing of how other signaling pathways regulate transcription. Intended benefits are creation of jobs and new knowledge on fundamental principles of life.Read moreRead less
eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In ....eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In two parallel model systems we will study corals and reptiles to improve environmental detection while simultaneously obtaining information on their population health. This will foster more efficient conservation of endangered species that are of tremendous importance to our marine and terrestrial ecosystems.Read moreRead less
Regulatory roles of the RNA helicase DDX5 in male germline stem cells. This project aims to investigate the role of the RNA helicase DDX5 in regulating gene expression programs of male germline stem cells by utilising novel mouse models, stem cell culture and genome-wide analysis approaches. This project expects to generate new knowledge in the area of germline maintenance and adult stem cells using innovative in vivo and in vitro experimental systems. Expected outcomes of this project will incl ....Regulatory roles of the RNA helicase DDX5 in male germline stem cells. This project aims to investigate the role of the RNA helicase DDX5 in regulating gene expression programs of male germline stem cells by utilising novel mouse models, stem cell culture and genome-wide analysis approaches. This project expects to generate new knowledge in the area of germline maintenance and adult stem cells using innovative in vivo and in vitro experimental systems. Expected outcomes of this project will include gain of substantial insight into molecular mechanisms underlying germline stem cell function and gene regulation within the male germline. This should provide significant benefits, including advancement of reproductive science and development of systems applicable for animal germline preservation and manipulation.Read moreRead less
Molecular function of the ribonucleic acid binding protein RBM47 in embryonic and mature endoderm cells. This project aims to test the hypothesis that a novel ribonucleic acid (RNA) binding protein, called RBM47, regulates the processing of the RNA transcripts of genes. This project will reveal the identity and the function of these genes that are essential for controlling the growth of the embryo and the organism after birth.
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