Stem Cell Group
Team Leader John Pimanda
Research Focus We use bioinformatics, array-based technologies and mouse transgenics to study the transcriptional regulation of genes that control the specification and subsequent development of blood, endothelial and mesenchymal stem/progenitor cells. Our goal is to determine how the disruption of the normal gene regulatory circuitry contributes to the pathogenesis of blood stem cell disorders such as leukaemia and the myelodysplastic and myeloproliferative syndromes.
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.