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Stem Cell Group

About us

Research Focus

The primary focus of our research program is to better understand how genes that drive blood and mesenchymal stem cell development are regulated.

Our research is in the following core areas:

  1. Investigating transcription factor interactions that drive haematopoietic stem cell (HSC) and mesenchymal stem cells (MSC) development, self-renewal and differentiation
     
  2. Investigating interactions between the core transcription factor networks in HSCs and MSCs with cell signalling pathways associated with their development and maintenance
     
  3. Investigating links between the transcription factor network in embryonic HSCs and in leukaemic cells
     
  4. Investigating the pathogenesis of myelodysplasia (MDS) with a view to drug development
     

Research Interests

Interactions between Transcription Factor Networks and Cell Signaling Pathways during Early Blood Development
We have shown that the expression of Gata2, Fli1 and Scl genes are dramatically upregulated in mesodermal haematopoietic progenitors and form a cross regulating protein-DNA regulatory sub-circuit. Following its activation, this sub-circuit is predicted to maintain expression of each of the component transcription factors without need for a continuous extracellular stimulus. Therefore sufficient concentrations of these transcription factors, all of which are critical for normal haematopoiesis, can be maintained in haematopoietic stem cells so that they can regulate downstream target genes. Bmp4 is a likely stimulus that initiates Gata2 and Fli1 expression which we predict would be sufficient to activate the circuit. Our aim is to integrate the Gata2/Fli1/Scl sub-circuit with known mediators and master regulators of haematopoiesis. In particular, investigate whether the Gata2/Fli1/Scl gene regulatory network kernel regulates expression of mediators of the Bmp signalling pathway.

Tissue specific regulation of gene expression
To understand how tissues develop in the embryo, it is of fundamental importance to know how tissues switch on and off genes that are required for their biological identity and function. Promoter driven basal rates of gene expression are generally insufficient for mammalian development. Transcription factors bind distal enhancers and corporate with promoter complexes to boost the activity of the basal transcriptional machinery. A question that has not been adequately addressed is whether different tissues use distinct enhancers to regulate expression of the same gene and how expression is fine-tuned to suit individual needs. Our aim is to determine whether different cell types use distinct enhancers to regulate expression of the same gene. We will analyze sequence motifs within these tissue specific enhancers to build computational algorithms that will allow genome-wide prediction of gene regulatory elements that target blood, endothelial and mesenchymal progenitors.

Clinical database and biorepository for Myelodysplastic and Myeloproliferative disorders
A specialist haematology clinic will be established at the Prince of Wales Hospital for the investigation, management and prospective study of patients with myeloproliferative and myelodysplastic syndromes.

Team

Collaborators

Dr Brian Huntly, Cambridge University

Grants & Funding

Grants

 Project

Source

Duration

Funding

Epigenetic therapy in Myelodysplasia and Chronic Myelomonocytic Leukaemia (CIA)

NHMRC 2012-2014 $656,175

Drug Resistance in Paediatric Leukaemia (CIB)

NHMRC 2012-2014 $450,000

 Tissue specific regulation of gene expression (CIA)

ARC

2009-2011

$278,000

 Transcriptional regulation of haematopoietic stem cell development (CIA)

NHMRC

2008-2010

$544,000

 Interactions between transcription factor networks and cell signalling pathways (CIA)

NHMRC

2009-2011

$566,500

 Dissecting the embryonic blood-endothelial regulatory code and
 investigating its role in leukaemia (CIA)

NHMRC

2010-2012

$623,500

 Determining the transcriptional program of a leukaemogenic
 transcription factor in normal and leukaemic cells (CIA)

NHMRC

2011-2013

$621,732

 Upregulation of Dyskerin augments telomerase activity in
 haematopoietic cells (CIB)

NHMRC

2011-2013

$359,208

 Do Leukaemic cells use stem cell enhancers to express
 oncogenic transcription factors? (CIA)

Leukaemia Foundation

2010

$98,000

 Pathogenesis of Myelodysplasia (CIA)

Leukaemia Foundation

2009-2011

$150,000

 Epigenetic changes associated with pharmacotherapy in
 Myelodysplasia (CIA)

Cancer Institute of NSW

2010

$50,000

 Identifying transcriptional regulatory complexes in leukaemia (CIB)

Cancer Institute of NSW

2011

$50,000

 Major Equipment Grant (CIA)

UNSW/NHMRC

2010

$338,000

 Major Equipment Grant (CIA)

UNSW/NHMRC

2011

$142,000

Research conducted by Stem Cell Group is being sponsored by the following agencies:

Group contacts