This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
Molecular Basis Of Transgenerational Epigenetic Inheritance In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$477,965.00
Summary
While it has long been recognised that it is not just DNA, but chromosomes, that are passed from the gametes to the embryo, the non-DNA component was thought to carry no information with respect to the offspring's ultimate phenotype. However, there is now evidence that the non-DNA component, the epigenetic component, can play a role in the inheritance of phenotype in mammals. This study will attempt to determine the molecular nature of this phenomenon.
Retrotransposons As Controlling Elements In Mammals: A Screen For Expression In Somatic Cells And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mamma ....Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mammals. A large body of evidence demonstrates that transposons can disrupt gene expression. To prevent this from occurring, most organisms have evolved mechanisms to keep transposons silent. However, fragmentary evidence indicates that transposons are at least sometimes expressed in normal and cancer cells. We hypothesize that activity of transposons in mammals alters gene expression sufficiently to cause variation between individuals, and that altered gene expression can cause disease (particularly cancer) and some manifestations of aging. As a first step toward testing this hypothesis, it is essential to acquire more complete information on the expression of transposons in normal and diseased cells. Furthermore, if transposon expression is closely linked to the development or progression of cancer or aging, then the ability to monitor such expression could have diagnostic utility. DNA array technology is coming into wide use to compare patterns of gene expression in different types of cells. We propose to adapt this method to the study of transposon expression. We will clone examples of all known classes of mouse and human transposon, and study transposon expression in: 1. Normal mice, at intervals from the earliest phase of development to old age, and 2. Human cancers of a variety of types. These studies will provide information of fundamental significance for mammalian biology, and also have the potential to lead to improved diagnosis of disease.Read moreRead less
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
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
microRNA are non-coding RNAs with fundamental functions in biology and emerging roles in disease. Hundreds of microRNA have been found and they control gene expression by destroying RNA or controlling their translation into cellular proteins. We will characterise their mechanisms of action and the cellular factors that are involved. Understanding the way microRNA work is a key question in gene regulation research and will aid the development of therapeutic strategies invovling small RNA.
Probing The Cellular Functions Of The Translation Factor P97
Funder
National Health and Medical Research Council
Funding Amount
$370,307.00
Summary
The protein p97 takes part in the synthesis of cellular proteins from messenger RNA, a central step in gene expression. We will characterise p97 function as cells progress through their cycle of growth and division, and during responses to stress. Cellular stress is important in many diseases, such as viral infection, diabetes, heart disease, cancer, or complications during major surgery. Knowledge of p97 function may help us to better understand and treat these diseases.