Red Cell Research Group

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Red Cell Research Group, Division of Blood Cancers

Goal

To identify regulators of red cell production and function including globin switching

Research Focus and Tools

• Globin switching
• ENU mutagenesis in the mouse

L-R: Fiona Brown, Stefan Sonderegger, David Curtis, Stephen Jane, Loretta Cerruti

Lung section from an ENU mouse mutant of the phosphatase SHIP1 showing macrophages with eosinophilic Ym1 crystals

Research Overview

Globin switching - Defining the molecular mechanisms underpinning fetal (gamma) globin gene silencing may provide strategies for reactivation of gamma-gene expression, a major therapeutic objective in patients with beta-thalassemia and sickle cell disease. Our laboratory has identified and defined the NF-E2 transcription factor complex as a critical regulator of the beta globin locus. The laboratory is now focusing on the therapeutic potential of targeting PRMT5, a critical component of the complex that represses gamma globin.

ENU-mutagenesis - Chemical mutagenesis has been used to identify genetic pathways in lower organism for more than 20 years. We have recently used ENU mutagenesis in the mouse to generate mouse lines with defects in red blood cells. The laboratory has over 20 different mutant lines, revealing surprising insights into how red cells are produced and function

Projects and Opportunities

• Protein arginine methyltransferase 5 – a new target for sickle cell disease and lymphoid malignancies
• Using forward genetics to understand the regulation of red blood cells

For current project opportunity descriptions please visit our honours page

Selected Publications

Rank G, Sutton R, Marshall V, Lundie RJ, Caddy J, Romeo T, Fernandez K, McCormack MP, Cooke BM, Foote SJ, Crabb BS, Curtis DJ, Hilton DJ, Kile BT and Jane SM. Novel roles for erythroid Ankyrin-1 revealed through an ENU-induced null mouse mutant. Blood 113: 3352-3362, 2009. (IF 10.89)

Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD, Cunningham JM and Jane SM. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A coupling histone and DNA methylation in gene silencing. Nature Structural Molecular Biology 16: 304-311, 2009. (IF 11.085)

Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression. Rank G, Cerruti L, Simpson RJ, Moritz RL, Jane SM, Zhao Q. Blood 116:1585-92, 2010. (IF 10.56)

Nhu-Y N. Nguyen NN, Maxwell MJ, Ooms LM, Davies EM, Hilton AA, Collinge JE, Hilton DJ, Kile BT, Mitchell CA, Hibbs ML, Jane SM and Curtis DJ. An ENU-induced mouse mutant of SHIP1 reveals a critical role of the stem cell isoform for suppression of macrophage activation. Blood 117:5362-71, 2011. (IF 10.56)