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The Role Of Heterochromatin In Regulating Cellular Proliferation And Development
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the ....Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit (euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell type is organised into a unique and dynamic chromatin pattern and this pattern determines the gene expression profile. This investigation will show that the critical cellular mechanism that determines the chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin. Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin formation controls the rate of cellular proliferation. This information will provide new insights into how gene expression profiles are established at precise times in early development, and offer a new strategy to inhibit the proliferation of cancer cells.Read moreRead less
Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study ....Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study the mechanism of hormonal control of apoptosis in order to identify components of the regulatory apparatus. Identification of precise factors that regulate PCD will not only provide basic understanding of hormone-controlled PCD, but any novel factors involved in the control of cellular levels of death activators or death inhibitors are potential targets for anticancer drug development. This proposal is based on our ongoing studies, which combine the powerful biochemical and cellular approaches with the in vivo studies in vinegar fly (Drosophila) to address complex issues that are often difficult to pursue by the direct use of mammalian systems. We believe that the results from this study will provide novel insights into the mechanisms of hormone-regulated control of PCD and how these control mechanisms are disrupted under pathological conditions.Read moreRead less