chromosome research
summary
Our genetic material (DNA) is packaged into compact structures
known as chromosomes, through which all the activities of our genes
are regulated. Defects in chromosome number or the way chromosomes
are packaged cause a plethora of problems, such as the imbalanced
distribution of our genetic material and aberrant gene activity,
giving rise to many serious clinical outcomes including cancer,
dysmorphology, intellectual disability, infertility, and pregnancy
loss. This research aims to study the mechanisms that control the
functions of chromosomes and their underlying genes, the clinical
impact of their dysfunction, and potential interventional
strategies
group leader(s)
Professor KH Andy
Choo
Director, Genetic Disorders Theme
Murdoch Childrens Research Institute
Department of Paediatrics, University of Melbourne
The Royal Children's Hospital
Flemington Road Parkville
Victoria 3052
Australia
T +61 3 8341 6306
F +61 3 8341 6212
E andy.choo@mcri.edu.au
group leader
biography
current research projects
Project 1: Master regulator of chromosome compaction,
DNA repair and gene expression, and impact on disease
aetiology
In order for our genetic material to be faithfully segregated into
two daughter cells, the DNA must compact 10,000 fold into
chromosomes. Proper compaction of DNA also underpins the regulation
of DNA repair and global gene expression. A master regulator in
these fundamentally important processes is the multi-subunit
protein complex, condensin, for which an increasing number of
diseases have now been linked to its defect. The aims of this
project are to understand how condensin and its affiliated
components affect chromosome folding, DNA repair and global gene
expression, using integrated proteomics, biochemistry and cell
biology approaches. Specific techniques employed will include RNAi
and conditional gene knockout, expression array analysis, next gen
sequencing, and others. The knowledge gained will have major
implications for understanding the underlying causes of a wide
range of diseases.
Contact: damien.hudson@mcri.edu.au or andy.choo@mcri.edu.au
Project 2: Chromosome instability and disorders of the sex
chromosomes and sexual development
Chromosomes must be copied and distributed faultlessly into the
newly dividing cells for normal human development to occur. Failure
of the accurate segregation of chromosomes is linked to many health
problems including birth defects, cancer, premature aging and
infertility. This project aims to identify genetic and epigenetic
factors that compromise the faithful transmission of chromosomes in
humans and mice, with a focus on disorders of the sex chromosomes
and sexual development. The study will utilise state-of-the-art
genetic and epigenetic approaches and tools including live-cell
imaging, cell and chromosome sorting, proteomics, and mutant gene
identification and characterisation. Results gained from this
project have the potential to benefit the diagnosis and prevention
of a host of chromosome-related disorders.
Contact: paul.kalitsis@mcri.edu.au or andy.choo@mcri.edu.au
Project 3: Epigenetic regulation in normal and stem cells,
and in cancers
This research involves the investigation of the epigenetic
mechanisms that control gene transcription, chromatin organisation
(with particular focus on the centromere and telomere), stem cell
pluripotency and differentiation states, and cancer development.
Specific project areas are:
a) We have previously reported that normal genomic DNA can undergo
epigenetic transformation into a centromere (or neocentromere) with
major consequence in genetic perturbation that results in birth
disorders or cancer development. This study investigates the
underlying roles of different epigenetic determinants including
non-coding RNA, histone variants, and other chromatin modifiers.
The findings will impact on our understanding of fundamental
epigenetic mechanisms that regulate our chromatin environment, and
their contribution to different disease conditions.
b) How pluripotent embryonic stem (ES) cells and cancer cells
retain their capacity for indefinite proliferation is a central
question in stem cell and cancer biology. We have shown the
importance of histone variant H3.3 and ATRX (alpha thalassemia
mental retardation) in the control of telomere function in ES
cells, and the presence of H3.3 and ATRX at the telomeres of
commonly occurring human ALT (alternative lengthening of telomeres)
cancer cells. We propose and aim to test the hypothesis that ALT
and possibly other cancers utilise a similar mechanism as ES cells
in the regulation of telomere chromatin to ensure continual
proliferation. We will determine the mechanisms of action between
these chromatin regulators and how they contribute to the
regulation of telomere length in ES cells and human cancers.
team members
- Melissa Anderson - Research Assistant
- Muhammed Bakhrebah - PhD Student (UoM Paeds)
- Nicole Carson - Research Assistant
- Fiona Chang - PhD Student (UoM Paeds)
- Cw Chow - HONORARY FELLOW
- Helen Godsall - Personal Assistant
- Alison Graham - Research Assistant
- Damien Hudson - Senior Research Officer
- Danielle Irvine - Senior Research Officer
- Paul Kalitsis - Senior Research Officer
- Bo Won Kim - Research Assistant
- Ji Hun Kim - PhD Student (UoM Paeds)
- Danuta Loesch-Mdzewska - HONORARY FELLOW
- William Marrow - Undergraduate Work Experience
- Hua Ren - HONORARY FELLOW
- David Tremethick - HONORARY FELLOW
- Bob Williamson - ESTEEMED HONORARY FELLOW
- Lee Wong - HONORARY FELLOW
publications
- Marshall OJ., Choo KH. Putative CENP-B paralogues are not present at mammalian centromeres. Chromosoma (2011) PubMed
- Yik YI., Farmer PJ., King SK., Chow CW., Hutson JM., Southwell BR. Gender differences in reduced substance P (SP) in children with slow-transit constipation. PEDIATRIC SURGERY INTERNATIONAL 27 (7) : 699 - 704(2011) PubMed
- Zacharin M., Bajpai A., Chow CW., Catto-Smith A., Stratakis C., Wong MW., Scott R. Gastrointestinal polyps in McCune Albright syndrome. JOURNAL OF MEDICAL GENETICS 48 (7) : 458 - 461(2011) PubMed
- Zaratiegui M., Castel SE., Irvine DV (2nd author)., Kloc A., Ren J., Li F., de Castro E., Marín L., Chang AY., Goto D., Cande WZ., Antequera F., Arcangioli B., Martienssen RA. RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II. Nature 479 (7371) : 135 - 138(2011) PubMed