Y Chromosome Mechanisms In Coronary Artery Disease
Funder
National Health and Medical Research Council
Funding Amount
$369,076.00
Summary
The Y chromosome determines sex in men and until recently was not thought to contribute to heart disease. We previously found a specific type of Y chromosome that does contribute to heart disease. In the current project we plan to find the exact gene and mechanism in the search as a therapeutic target.
A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE
Funder
National Health and Medical Research Council
Funding Amount
$272,131.00
Summary
Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to dev ....Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to develop as females, as well as causing many unrelated disorders such as alpha-thalassemia. ATRX seems to be a transcription factor that controls the activity of other genes, but it is difficult to understand how it functions because it is active in all parts of the body and mutation has many different effects in humans. However, we recently discovered that in marsupial mammals that this gene has a copy on the Y chromosome (ATRY) as well as the X (ATRX). Remarkably, there is a division of labour between ATRY, which acts only in developing gonads, and ATRX, which is active everywhere else. This testis-specific ATRY gene may reveal how ATRX interacts with other genes to make a testis, without the complications of its action in other tissues. We will therefore clone and characterize ATRX-Y and its protein product to find out when and where it acts in the sex determining pathway. We will use very large cloned pieces of the marsupial genome to discover elements controlling the testis-specific expression, and we will identify the interactions of ATRY with other proteins. The testis determination pathway is a good model for the differentiation of other human organs. Our work on ATRY will show us how this class of transcription factors is activated in different tissues during development, and how it controls other genes. This will lead to a better understanding of the genetic control of human organogenesis and the effects of mutation on human 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