A Structural And Functional Basis For The Regulation Of Gene Expression By Nuclear Retention Of RNA
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
The nuclear retention mechanism is a novel way used by cells to control which genes are made into proteins - a fundamental process for all diseases, particularly cancers. This project will employ cutting edge structural and proteomic techniques to determine the molecular details underpinning nuclear retention. These insights will be important for the development of new tissue-restricted gene therapy applications and drugs targeting the cancers that rely on this mechanism.
Structure-function Analysis Of Nuclear Receptor And Cofactor Action: Evidence For A Role In Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a pr ....Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.Read moreRead less
Co-ordinated Action of ATM and DNA-PK in DNA damage recognition. The aim of this project is to investigate the mechanism of repair of double straind breaks in DNA sustained after radiation damage. Specifically we will focus on two proteins ATM (mutated in the genetic disorder ataxia-telangiectasia) and DNA-PK mutated in scid mice. There two proteins recognize double straind breaks in DNA and signal this damage to the DNA repair machinery of the cell and to cell cycle checkpoints. The emphasis ....Co-ordinated Action of ATM and DNA-PK in DNA damage recognition. The aim of this project is to investigate the mechanism of repair of double straind breaks in DNA sustained after radiation damage. Specifically we will focus on two proteins ATM (mutated in the genetic disorder ataxia-telangiectasia) and DNA-PK mutated in scid mice. There two proteins recognize double straind breaks in DNA and signal this damage to the DNA repair machinery of the cell and to cell cycle checkpoints. The emphasis here will be in the relationship between the two proteins in co-ordinating the repair of breaks in DNA. This information will be important in understanding mechanisms for maintaining the integrity of the genome.Read moreRead less
ARC Centre for Kangaroo Genome. In this Australian-led Kangaroo Genome Project, we will map and characterize the tammar wallaby genome at the molecular level. Marsupial genomes are uniquely valuable because they provide comparisons that reveal new human genes, regulatory sequences and marsupial-specific genes. These will deliver new products and information useful for medicine, industry, agriculture and conservation. We will construct integrated genetic and physical maps of the genome, clone the ....ARC Centre for Kangaroo Genome. In this Australian-led Kangaroo Genome Project, we will map and characterize the tammar wallaby genome at the molecular level. Marsupial genomes are uniquely valuable because they provide comparisons that reveal new human genes, regulatory sequences and marsupial-specific genes. These will deliver new products and information useful for medicine, industry, agriculture and conservation. We will construct integrated genetic and physical maps of the genome, clone the whole genome as large inserts in BAC vectors, and build a "golden path" with minimal overlap. We will construct libraries of expressed genes from tammar tissues and array them for use in analysing gene expression.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
Functional Analysis Of The P160 Myb-binding Protein - A Regulator Of Multiple Transcription Factors?
Funder
National Health and Medical Research Council
Funding Amount
$376,697.00
Summary
The c-myb gene is a key molecular regulator of normal blood cell production, but alterations to this gene can also lead to leukaemia. The protein (Myb) encode by the c-myb gene acts as a transcription factor, ie, it controls the activity of other genes. There is good evidence that interactions with other proteins can regulate the activity of Myb. Our laboratory has identified what we believe is one such protein - p160 - that binds to a part of Myb that reduces its activity, and thus that is like ....The c-myb gene is a key molecular regulator of normal blood cell production, but alterations to this gene can also lead to leukaemia. The protein (Myb) encode by the c-myb gene acts as a transcription factor, ie, it controls the activity of other genes. There is good evidence that interactions with other proteins can regulate the activity of Myb. Our laboratory has identified what we believe is one such protein - p160 - that binds to a part of Myb that reduces its activity, and thus that is likely to be responsible for regulating Myb. However, it has recently become apparent that p160 interacts with a number of other transcription factors in addition Myb. The primary aim of this project is to elucidate precisely how p160 interacts with Myb and what the consequences of this interaction are. A range of experimental approaches, which range from in vitro to genetic studies, will be employed to do this. We will test a specific role of p160 suggested by our preliminary studies - that of a transporter of transcription factors between the nucleus and the cytoplasm of the cell. Because of the wide range of transcription factors that p160 interacts with, its effects on the function of the cell are likely to be profound. For this same reason, it is difficult to specifically predict the possible medical-health implications of this work However, what we know to date is consistent with a role for p160 as a tumour suppressor gene. Moreover, parts of this project aim to generate genetic information and tools which will help in determining whether p160 does play such a role and generally, in identifying any other associations of p160 with particular diseases.Read moreRead less
Epigenetic silencing in vertebrates: evolution and function from the bottom-up. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional genomics in Australia, with the research priority of Frontier Technologies for Building and Transforming Australian Industries and priority goals in Breakthrough Science and Frontier Technologies. This project focuses on important biological questions surrounding gene regulation and sex chromosome evolution. Inte ....Epigenetic silencing in vertebrates: evolution and function from the bottom-up. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional genomics in Australia, with the research priority of Frontier Technologies for Building and Transforming Australian Industries and priority goals in Breakthrough Science and Frontier Technologies. This project focuses on important biological questions surrounding gene regulation and sex chromosome evolution. International attention has already resulted in genome characterization of Australian icons (wallaby, Tasmanian devil and platypus), more research on these, and other Australian animals, will further highlight the importance of Australian fauna and impact positively on our scientific profile.Read moreRead less
Origin and evolution of genes on the human X chromosome. Two groups of functionally related genes are found on the human X chromosome in disproportionately high numbers. I will test whether an uneven distribution of genes is common in mammalian genomes, or whether the human X is special. I will test hypotheses of how the gene groups arose on the human X by comparing their location and expression patterns in other mammals, and other vertebrates. It will then be clear whether the ancestral autosom ....Origin and evolution of genes on the human X chromosome. Two groups of functionally related genes are found on the human X chromosome in disproportionately high numbers. I will test whether an uneven distribution of genes is common in mammalian genomes, or whether the human X is special. I will test hypotheses of how the gene groups arose on the human X by comparing their location and expression patterns in other mammals, and other vertebrates. It will then be clear whether the ancestral autosome was ?chosen?, whether it ?selfishly? accumulated these genes, or whether the function of genes changed in response to selective pressures.Read moreRead less
Small is beautiful: Did gene-rich regions of mammal chromosomes evolve from microchromosomes? Most birds and reptile genomes feature many tiny microchromosomes. These are not junk, as previously thought, but contain most of the genes. Mammals lack microchromosomes, but contain gene-rich regions with similar attributes. We suggest that microchromosomes originated by genome duplication, and evolved into the gene-rich regions of mammalian chromosomes. We will test this hypothesis by comparing seque ....Small is beautiful: Did gene-rich regions of mammal chromosomes evolve from microchromosomes? Most birds and reptile genomes feature many tiny microchromosomes. These are not junk, as previously thought, but contain most of the genes. Mammals lack microchromosomes, but contain gene-rich regions with similar attributes. We suggest that microchromosomes originated by genome duplication, and evolved into the gene-rich regions of mammalian chromosomes. We will test this hypothesis by comparing sequences and genes in microchromosomes of birds, reptiles and monotremes. This will clarify the origin and evolution of the ?microgenome?, establish its suitability as a model for vertebrate genome organisation, and demonstrate whether microchromosomes are the ancestors of the gene-rich regions of mammalian chromosomes.Read moreRead less
Origin and Evolution of Mammalian Dosage Compensation. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional comparative genomics in Australia, with the research priority of 'Frontier Technologies for Building and Transforming Australian Industries' and priority goals in 'Breakthrough Science and Frontier Technologies'. This project addresses fundamental questions about the evolution of mammalian X-chromosome inactivation, of importance as a mo ....Origin and Evolution of Mammalian Dosage Compensation. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional comparative genomics in Australia, with the research priority of 'Frontier Technologies for Building and Transforming Australian Industries' and priority goals in 'Breakthrough Science and Frontier Technologies'. This project addresses fundamental questions about the evolution of mammalian X-chromosome inactivation, of importance as a model for epigenetic change, and sex chromosomes, which has engaged some of the greatest genetic minds over nearly a century. Therefore my results will attract wide international interest and impact positively on Australia's scientific profile, and further highlight the importance of Australian mammals.Read moreRead less