Effects Of The Atrial Natriuretic Factor Enhancer And The 5'HS4 Insulator On The Probability Of Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$534,628.00
Summary
Complex organisms contain many different types of cells, which can have completely different appearances and functions. All of these cells contain the same genes; the differences between them are achieved by the selective use of the genes. The means by which the selective use of genes is accomplished is a key to understanding how complex organisms develop, and how that development goes awry in cancer, heart disease, and other common disorders. A very large body of evidence indicates that gene re ....Complex organisms contain many different types of cells, which can have completely different appearances and functions. All of these cells contain the same genes; the differences between them are achieved by the selective use of the genes. The means by which the selective use of genes is accomplished is a key to understanding how complex organisms develop, and how that development goes awry in cancer, heart disease, and other common disorders. A very large body of evidence indicates that gene regulation is accomplished by the interaction of protein factors with segments of DNA flanking the gene. One hypothesis underlying our work is that the flanking DNA elements act primarily to increase the probability that a gene will be active rather than silent. We will ask if removing a known regulatory element from the gene for Atrial Natriuretic Factor (ANF) in mice reduces the likelihood of ANF being expressed by heart cells when the heart is stressed. This experiment will also shed new light on an extremely common disease state in humans (cardiac hypertrophy). In a second experiment, we will use a new experimental system we have developed to ask if a gene regulatory element is able to dial up the amount of expression from a gene, as well as to switch the gene on. Our previous work suggested this was not the case, but we wish to conduct a more rigorous test. Another hypothesis is that no DNA element is able to completely shield a transferred gene from the regulatory elements surrounding it. Accordingly, we will test a DNA element that has been proposed to insulate any gene from all influences of surrounding genes, and ask if it is able to create an autonomously expressing gene at any site within the genome. Because they deal with functions that are common to all genes, these experiments will provide information that should be applicable to a broad array of efforts to manipulate gene expression.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