Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice.
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.
Merkenschlager
Matthias
M
Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK. matthias.merkenschlager@csc.mrc.ac.uk
Amoils
Shannon
S
Roldan
Esther
E
Rahemtulla
Amin
A
O'connor
Eric
E
Fisher
Amanda G
AG
Brown
Karen E
KE
D000483:Alleles; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis / Q000235:genetics*; D016827:CD8 Antigens / Q000032:analysis / Q000235:genetics*; D019070:Cell Lineage; D002503:Centromere / Q000378:metabolism*; D002874:Chromosome Mapping; D020868:Gene Silencing; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000502:physiology
D015704:CD4 Antigens; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell