I am a reproductive biologist whose research is focussed around understanding how the early events of conception and embryo development are controlled. Critical aspects of my research are to determine the consequences to pregnancy and adult health if the
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
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.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
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less