Bradley is a Senior Lecturer in Comparative Biomedical Sciences. His main research focus is on the development of the immune system.
Bradley graduated from the University of California, Santa Barbara with a BA in Aquatic Biology in 1981 and an MA in Molecular Biology in 1984. He received a PhD in Microbiology from the University of Virginia in 1992. From there Bradley did postdoctoral research at the University of Chicago, and the University of California, Los Angeles. In 2000, he became a Research Assistant Professor at the University of California, Los Angeles, and in 2003 he moved to the UK to become a Senior Research Scientist at the MRC Clinical Sciences Centre within the Imperial College School of Medicine, London. In September of 2008 Bradley joined the staff at the RVC as a Senior Lecturer.
Bradley’s overall interest is in the mechanisms of regulation of gene expression that cells use during development. The primary interest is in the development of the immune system, studying how regulation of gene expression controls the key steps in lymphocyte development. Lymphocytes undergo large changes in gene expression as they mature during lymphopoiesis. Understanding the mechanisms of these changes will be important to develop therapeutics for manipulating the immune response during disease. Research interests span from the regulation of transcriptional mechanisms to post-transcriptional events regulating translation and messenger RNA stability. Bradley’s specific interests relate to the roles of microRNAs and the molecular function of the Ikaros family of transcription factor proteins.
Fig. 1. Reduced numbers of Treg cells in mice with T cell specific knockout of Dicer. a. FACS profile of Treg cells, which are CD4+ T cells expressing the α chain of the high affinity IL2 receptor (CD25) and the transcription factor FoxP3. With the Dicer knockout there is a three-fold reduction in the number of Treg cells. b. A reduced level of FoxP3 RNA from CD4+ splenocytes and thymocytes in the Dicer knockout mice as demonstrated by quantitative RT-PCR.
MicroRNAs (miRNAs) are small RNAs (~22 mers) that post-transcriptionally regulate gene expression by binding to target sequences in messages and modulating their translation, stability, and/or localization. Gene regulation by miRNAs is critical at many developmental stages in organisms ranging from worms to man. In previous work miRNA function in T cell development was examined by creating and characterizing a conditional knock out of the Dicer gene, which is the RNase required for miRNA synthesis. Loss of Dicer resulted in a depletion of regulatory T (Treg) cells, which are required for down regulation of the immune response. Bradley’s current interest is to identify the critical miRNAs, the genes they regulate, and understand how that regulation is critical for Treg development and function.
Fig. 2. Ikaros localization to regions of pericentromeric heterochromatin as demonstrated in B-cells stained with antibodies to Ikaros (red) and a FISH probe to γ−satellite DNA (green), which make up the centromeric DNA.
Ikaros is a sequence specific DNA binding protein that is essential for lymphocyte development. Despite its importance, the molecular mechanisms Ikaros uses to regulate gene expression during lymphocyte development remain largely a mystery. Ikaros has a unique characteristic in that it is localized to regions of pericentromeric heterochromatin in the interphase nucleus. These regions contain silent genes so it has been hypothesized that Ikaros recruits genes to these regions, facilitating their silencing. However, to date there is no evidence supporting this role, and it still remains a theory. Bradley is interested in studying Ikaros function by finding the genes to which Ikaros binds, characterizing the roles that associated proteins play, and determining how this affects transcriptional regulation of important genes in lymphocyte development.
- Taylor B, Cobb BS, Bruno L, Webster Z, Fisher AG, Merkenschlager M. 2009 A reappraisal of evidence for probabilistic models of allelic exclusion. PNAS. 106:516-21.
- Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, Kanellopoulou C, Jensen K, Cobb BS, Merkenschlager M, Rajewsky N, and K Rajewsky. 2008. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell. 132:860-74.
- Thompson EC, Cobb BS, Sabbattini P, Meixlsperger S, Parelho V, Liberg D, Taylor B, Dillon N, Georgopoulos K, Jumaa H, Smale ST, Fisher AG, and M Merkenschlager. 2007. Ikaros DNA binding proteins as integral components of developmental stage-specific regulatory circuits. Immunity. 26:335-344.
- Cobb BS, Hertweck A, Smith J, O’Connor E, Graf D, Cook T, Smale ST, Sakaguchi S, Livesey FJ, Fisher AG, and M Merkenschlager. 2006. A role for Dicer in immune regulation. J Exp Med. 203:2519-27.
- Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'connor E, Godwin J, Wilson CB, Brockdorff N, Fisher AG, Smale ST, and M Merkenschlager. 2005. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J Exp Med. 9:1367-73.
- Cobb BS and ST Smale. 2005. Ikaros-family proteins: in search of molecular functions during lymphocyte development. Curr Top Microbiol Immunol. 290:29-47.