Variable Expressivity And Epigenetic Inheritance At The Axin Fused Locus In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in m ....Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in mammals. An epigenetic modification is a mark, present on some genes that determines whether the gene is expressed (switched on) or silent. Animals are thought to acquire this mark during development and it is retained throughout life except in germ cells where the mark is generally, but not always, erased. The establishment of the mark appears to be a stochastic event at the cellular level resulting in mosaic expression. The percentage of marked cells can differ from one individual to another . In theory, this could help to explain why individuals with identical genetic information, such as identical twins, can have different phenotypic characteristics. The fact that these modifications can be inherited implies that there is an alternative mode of inheritance of genetic traits which does not involve mutation but which can be carried from generation to generation in a semipermanent way. Understanding the mechanisms underlying these events is important if we wish to predict or modify the phenotype of an invidual or that of his or her offspring.Read moreRead less
Identification Of Variably Expressed Genes In Isogenic Mice And Humans
Funder
National Health and Medical Research Council
Funding Amount
$293,080.00
Summary
Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establis ....Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establishment of epigenetic modifications to the DNA. An epigenetic modification is a mark which determines whether a gene is expressed (switched on) or silent (switched off). The establishment of the mark appears to be a stochastic event which can result in different physical characteristics between genetically identical individuals. We would like to study this process in inbred mouse strains and in humans. Inbred mouse strains are maintained by inbreeding (brother-sister mating) to ensure that all individuals of the strain are isogenic (genetically identical) and in such a way that environmental variation is minimised. We will use established molecular techniques to find genes which are variably expressed among isogenic mice and humans. This work will enable us to discover genes which are sensitive to epigenetic modifications and whose epigenotype must be known if we are able to predict phenotype or disease state.Read moreRead less
The Establishment Of Epigenetic Marks At Metastable Epialleles In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$372,750.00
Summary
Occasionally, identical twins are found to have distinctly different characteristics, such as eye colour or severity of genetic disease, that clearly cannot be explained by their genetic makeup, and are unlikely to be the result of environmental differences. In genetically identical mice, similar cases exist, where some mice have a yellow coat and others a brown coat. In instances such as these, a growing body of evidence suggests that certain modifications to genes are responsible. These modifi ....Occasionally, identical twins are found to have distinctly different characteristics, such as eye colour or severity of genetic disease, that clearly cannot be explained by their genetic makeup, and are unlikely to be the result of environmental differences. In genetically identical mice, similar cases exist, where some mice have a yellow coat and others a brown coat. In instances such as these, a growing body of evidence suggests that certain modifications to genes are responsible. These modifications are not traditional DNA mutations, but are chemical modifications of the basic sequence. Currently, we do not know when these DNA modifications are established during foetal development. We will use the mouse coat colour gene mentioned above to investigate when the different physical characteristics are established in embryonic development. Indeed, there is increasing evidence that critical periods exist in human foetal development where minor environmental or nutritional changes can affect long-term health of the adult. Perhaps the establishment of the DNA modifications are under an environmental or nutritional influence. Further study of when and how the DNA modifications are set-up during embryonic development is necessary in order to understand these events.Read moreRead less
A Random Mutagenesis Screen To Identify Modifiers Of Epigenetic Phenomena In The Mouse.
Funder
National Health and Medical Research Council
Funding Amount
$680,750.00
Summary
In recent months, both the human and mouse genome projects have been completed. The main focus now for mammalian geneticists is to discover the function of the genes sequenced in these initiatives. One way to achieve this goal is by random mutagenesis followed by screening of mice for novel phenotypes. In the mouse, ethylnitosourea (ENU) is a chemical that can be used to perform the mutagenesis. ENU causes mutations in sperm. We are using ENU mutagenesis to search for genes that modify epigeneti ....In recent months, both the human and mouse genome projects have been completed. The main focus now for mammalian geneticists is to discover the function of the genes sequenced in these initiatives. One way to achieve this goal is by random mutagenesis followed by screening of mice for novel phenotypes. In the mouse, ethylnitosourea (ENU) is a chemical that can be used to perform the mutagenesis. ENU causes mutations in sperm. We are using ENU mutagenesis to search for genes that modify epigenetic states. Epigenetic modifications are alterations in the genome that do not change the DNA sequence, yet silence the expression of genes. Silencing occurs on a cell-by-cell basis within a tissue resulting in mosaic expression. Silencing can also occur between individuals of the same genetic makeup. For example, identical twins are occasionally found that have distinctly different characteristics, such as eye colour or severity of genetic disease. These differences may be the result of variable epigenetic modifications. However, very little is known about how these variable epigenetic modifications are controlled. We wish to find the proteins involved in establishing and maintaining epigenetic states. It is likely that these processes play a fundamental role in the determination of phenotype, both in normal development and disease.Read moreRead less
Epigenetic Silencing Of Retroelements In Mammalian Stem Cells: A Role For RNA Interference?
Funder
National Health and Medical Research Council
Funding Amount
$296,980.00
Summary
Now that the human genome has been sequenced, all the genes which encode the bricks and mortar of our cells have been defined. A major question remains: how are all these genes controlled and co-ordinated? What turns them on or off at precisely the right time? In this project we wish to test whether a newly-discovered mechanism of turning genes off in plants and flies also works in mammals. If we demonstrate this mechanism then it may help us to improve gene therapy - a novel form of medical tre ....Now that the human genome has been sequenced, all the genes which encode the bricks and mortar of our cells have been defined. A major question remains: how are all these genes controlled and co-ordinated? What turns them on or off at precisely the right time? In this project we wish to test whether a newly-discovered mechanism of turning genes off in plants and flies also works in mammals. If we demonstrate this mechanism then it may help us to improve gene therapy - a novel form of medical treatment in which healthy genes are used to replace defective genes in cells. Both inherited diseases, like hemophilia, and acquired diseases, like cancer, have been considered appropriate targets for gene therapies. Surprisingly, however, the promises of gene therapy have not kept up with expectations. In attempting to achieve clinically relevant results, viruses (masters of forcing infected cells to do their bidding) have been harnessed to deliver healthy genes into diseased cells. A major problem has been that the modified, safe viruses used clinically have not been efficient at achieving sustained production of healthy gene products. In examining the question of what turns gene off, we will attack the problem of sustainability of gene therapy by defining the mechanisms involved in switching gene therapy viruses off. If we can understand what switches viral genes off in cells, then we should be able to devise means to avoid the 'off switch' and thereby provide durable treatments for many types of cancer. In the studies described , we will attack this problem using a number of different, but complementary approaches.Read moreRead less
Genomic Characterisation Of Asbestos Related Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$88,099.00
Summary
Lung cancer causes more deaths in Australia than any other cancer. Smoking is the main cause, but people exposed to asbestos are also at risk, and it can be difficult to know whether a case is due to tobacco, asbestos or both. We will study lung cancer genes in people with asbestos exposure to find whether asbestos lung cancer has a specific pattern of abnormal genes (signature). If so, this could help people entitled to compensation, and also point to new treatments for asbestos lung cancer
Retrotransposon Regulation Of The Human Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$231,937.00
Summary
Complete sequencing of the human genome has revealed the positions of approximately 20,000 genes. In addition, nearly 50% of the human genome is comprised of repetitive sequences previously thought of as junk DNA. Numerous studies are now finding that this DNA actually has a variety of important functions, particularly in the control of gene activity. This project will examine the relationships between gene expression and nearby repetitive sequences during the innate immune response in humans.
STUDIES OF NF-E4, A NOVEL FETAL/ERYTHROID SPECIFIC FACTOR INVOLVED IN FETAL GLOBIN GENE REGULATION
Funder
National Health and Medical Research Council
Funding Amount
$753,810.00
Summary
Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated ....Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated clinical course. Therefore, treatment strategies which could reactivate fetal globin gene expression after birth should be explored for these diseases. To achieve this goal we must further our understanding of the normal mechanisms of developmental regulation of globin gene expression. To this end we have recently identified a novel gene which is critical for fetal globin expression. The studies we propose here will further define the function of this gene and assess its potential for gene therapy for sickle cell disease and thalassemia.Read moreRead less
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.