The Journal of Experimental Medicine
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Published 6 December 2004. doi:10.1084/jem.20041127
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1437-1444
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Centromeric Repositioning of Coreceptor Loci Predicts Their Stable Silencing and the CD4/CD8 Lineage Choice

Matthias Merkenschlager1, Shannon Amoils1, Esther Roldan1, Amin Rahemtulla4, Eric O'Connor2, Amanda G. Fisher1, and Karen E. Brown3

1 Lymphocyte Development Group, MRC Clinical Sciences Centre
2 Flow Cytometry Facility, MRC Clinical Sciences Centre
3 Chromosome Biology Group, MRC Clinical Sciences Centre
4 Department of Haematology, Faculty of Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK

Address correspondence to Matthias Merkenschlager, Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK. Phone: 44-208-383-8239; Fax: 44-208-383-8338; email: matthias.merkenschlager{at}csc.mrc.ac.uk

The differentiation of CD4+ CD8+ double positive (DP) thymocytes requires the irreversible choice between two alternative lineages, distinguished by the mutually exclusive expression of either CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8, and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization, we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predicted by the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains. These data provide evidence that lineage-specific developmental programs are established early during the transition from the DP to the single positive stage.

Key Words: lineage commitment • FISH

Abbreviations used in this paper: 3-D, three-dimensional; DP, double positive; FISH, fluorescence in situ hybridization; SP, single positive.


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