Transcriptional Regulation of GATA-1

Lead Research Organisation: University of Oxford

Abstract

A common cause of severe anaemia that can progress to leukaemia is known as myelodysplasia. In this condition blood cell precursors are made but fail to mature properly and do not function appropriately. Understanding this disorder depends on knowing how blood cells are normally made and mature in the bone marrow.||Our interest has focused on one critical factor that is required in this process, which is called GATA-1. GATA-1 co-ordinates many aspects of the normal maturation programme of blood and we wish to aspects of it biology.

Technical Summary

A key biological question, relevant to all differentiating tissues, is how multiple cell types arise from a pluripotential cell. When this process is perturbed it leads to human disease. We are using the haemopoietic system to study this question as it provides a good scientific and clinical model. Our laboratory is focused on how the erythroid and megakaryocytic lineages are specified and mature from a progenitor cell. Our particular interest is the role key transcription factors play in these processes. In particular, the zinc-finger transcription factor GATA-1 is absolutely required for the proper maturation of both the red cell and megakaryocyte lineages. In addition, GATA-1 expression is initiated in early haematopoietic progenitor at low level but then is restricted to principally erythroid and megakaryocytic cells where it is expressed at high level.||Our aim is to understand the molecular mechanisms that result in the tissue- and developmental- specific pattern of expression. As a consequence of these studies we hope to identify the transcriptional regulators that lie upstream of GATA-1 and thus help to specify the erythroid and megakaryocyte lineages.||Our approach to this problem is to try and identify all the cis-acting elements that are required for GATA-1 expression and the trans-acting factors that bind to them. We are identifying putative cis-elements in the GATA-1 locus by DNase I hypersensitivity analysis and by pin-pointing non-coding sequence that is conserved in evolution between mouse and human. Once putative cis-elements have been identified we are testing if they have function in stable cell transfection assays and in transgenic mice. Protein-DNA interactions at functionally important elements will be then be determined. Lastly, the functional importance of selected elements will be further examined by deleting them by homologous recombination in mice.

Publications

10 25 50
 
Description 2009 Disease Team Award
Amount £2,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2010 
End 05/2014
 
Description Celgene PhD Studentship
Amount £174,000 (GBP)
Organisation Celgene 
Sector Private
Country United States of America
Start 09/2010 
End 08/2013
 
Description Leukaemia Research Specialist Programme Grant 2008
Amount £1,034,000 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2008 
End 07/2013
 
Description MRC Molecular Haematology Unit Award
Amount £520,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 03/2017
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Barts Health NHS Trust
Department Department of Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Cardiff University
Department Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Stanford University
Country United States of America 
Sector Academic/University 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation University Hospitals Birmingham NHS Foundation Trust
Department Queen Elizabeth Medical Centre, Birmingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Downs Syndrome associated preleukaemia and leukaemia 
Organisation Imperial College London
Department Centre for Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provide the majority of the research effort in this collaborative programme. We study the molecular and cellular basis of leukaemia using patient samples and mouse models that we are generating.
Collaborator Contribution We have a joint programme of work including a joint LLR Programme grant
Impact Grants 2008 Leukaemia Research 5-year Programme Grant, £1.03 M Publications (PubMed ID below): 19594743 18242315 18689547 18059480 18625887 17804520 17644747 17224656 17064858
Start Year 2006
 
Description Science Week 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Oxford Science Week is held annually to an audience of scientists and the general public.

Good feedback from schools
Year(s) Of Engagement Activity 2006,2007,2008,2009,2014
 
Description Student Presentations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Final year students present their work to the members of the Weatherall Institute of Molecular Medicine. This presentation day is held annually.

Improved student training.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010