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How does the signal for allelic exclusion transmit from the cell surface to chromatin?

Reference	BB/C508769/1
Principal Investigator / Supervisor	Dr Inga-Lill Martensson-Bopp
Co-Investigators / Co-Supervisors	Dr Anne Corcoran, Dr Martin Turner
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	425,000
Status	Completed
Type	Research Grant
Start date	13/01/2005
End date	12/01/2008
Duration	36 months

Abstract

Allelic exclusion is an active signalling process mediated by functional cell surface expression of immunoglobulin heavy and light chain that shuts down further rearrangement on the second, non-expressing allele. This process ensures the production of uniquely specific high affinity antibody producing cells. The intracellular signalling pathways connecting these cell surface events to the nucleus, or the chromatin remodelling mechanisms involved are almost completely uncharacterised. We aim to address the following questions: What are the chromatin changes required to achieve allelic exclusion? What signalling pathway (or pathways) are involved in regulating this process? What is the link between cytoplasmic signalling pathways and allelic exclusion? Our proposal is based on several new findings from our labs that make us uniquely placed to address these questions. Firstly, we have recently discovered that antisense transcription occurs extensively in the IgH locus and propose that it remodels the locus to enable VDJ recombination. Thus it is likely to be a key target for allelic exclusion. Secondly, we have demonstrated that silencing of DJ transcription is a key element in heavy chain allelic exclusion. Taken together, our observations clearly suggest a role for transcription in allelic exclusion. Thirdly, by targeted deletion of Syk, we have shown that this tyrosine kinase is essential for light chain allelic exclusion. This is the first candidate-signalling molecule with a putative role in this process. We will exploit ex vivo and in vitro cultured primary cells from normal and appropriate (allelically including) gene targeted mice. We will analyse these by RNA/DNA/immuno-FISH (fluorescent in vitro hybridisation), which enables analysis of individual alleles in single cells, and biochemical techniques incl. CHIP (chromatin immunoprecipitation) to analyse histone modifications.

Summary

unavailable

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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