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
Mechanisms By Which Chromatin Modulates Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
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 to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important ....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 to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly regulate gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer can result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialized forms of these histones (variants). We believe that these histone variants can specifically generate chromosomal domains which could in some cases expose or in other cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of these histone variants to discover the role it plays in determining the type of chromosomal domain made and the role of this domain has in turning genes on or off at precise times in early development during the formation of different specialized cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
Essential Roles Of RNA Polymerase II Transcription And DNA Damage Response Pathway In The Maintenance Of Centromere Chromatin Assembly
Funder
National Health and Medical Research Council
Funding Amount
$601,224.00
Summary
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growt ....A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growth and cancer development.Read moreRead less
Epigenetic Regulation Of Telomere Chromatin And Genome Stability
Funder
National Health and Medical Research Council
Funding Amount
$633,447.00
Summary
Telomeres are structures at the end of the chromosomes that impact cell replication. 15% of cancers, called ALT cancers, show telomere instability, increased DNA damage and are frequently mutated for the ATRX gene. ALT cancers have poor prognosis, due to the limited understanding of ALT cancer activation. This study aims to create a model of ALT activation to uncover the mechanisms that control ALT tumourigenesis. This could lead to potential ALT-specific diagnostic and therapeutic tools.
Function Of ATRX, H3.3 And PML Nuclear Bodies In The Regulation Of Telomere Chromatin Integrity
Funder
National Health and Medical Research Council
Funding Amount
$434,652.00
Summary
The telomere is required for protecting chromosome ends. During cell division and development, telomeres lose their repeats, exposing the chromosome ends to damage. The consequences of this damage are disease, cancer, and aging. By contrast, embryonic stem cells (ES) continually renew their telomeres and do not stop growing. ES cells thereby provide a means to unravel the molecular mechanisms of indefinite telomere renewal. Here we propose a novel mechanism that operates to control continual tel ....The telomere is required for protecting chromosome ends. During cell division and development, telomeres lose their repeats, exposing the chromosome ends to damage. The consequences of this damage are disease, cancer, and aging. By contrast, embryonic stem cells (ES) continually renew their telomeres and do not stop growing. ES cells thereby provide a means to unravel the molecular mechanisms of indefinite telomere renewal. Here we propose a novel mechanism that operates to control continual telomere renewal in ES cells.Read moreRead less
Epigenetic Regulation Of Core Centromere CENP-A Chromatin Integrity
Funder
National Health and Medical Research Council
Funding Amount
$318,284.00
Summary
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growt ....A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growth and cancer development.Read moreRead less
The Special Role Of Histone Variants In Regulating The Inheritance And 3-dimensional Organisation Of The Epigenome
Funder
National Health and Medical Research Council
Funding Amount
$962,716.00
Summary
It has been more than a decade since the human genome has been completely sequenced but how this genomic information is selectively utilized to direct gene expression that is unique to each of the 200 different cell types of the human body remains to be elucidated. We have new data to suggest that it is how our genome is packaged into a variety of different and dynamic 3-dimensional structures in a cell that determines cell type specific programs of gene expression