Random activation of a transgene under the control of a hybrid hCD2 locus control region/Ig enhancer regulatory element.
Locus control regions such as those of human CD2 and beta-globin differ from classical enhancers in that, whereas the former confer high level, copy-dependent, position-independent expression to linked genes in transgenic mice, the latter do not, expression levels being dependent on the site of integration. We report that the position independence of the CD2 locus control region is modified by coupling it to the immunoglobulin heavy chain enhancer. Whilst in the majority of transgenic lines the Ig heavy chain enhancer has little or no effect on T cell expression of the hCD2 transgene, in others transgene expression is non-specifically extinguished in a proportion of lymphoid cells. The transgenic locus chromatin appears inaccessible to DNase I in these cells, which do not express the gene. Furthermore, mice homozygous for the hybrid hCD2-Ig heavy chain enhancer construct contain T cells with both an active and an inactive transgene. The 'decision' to express or repress the gene appears to be a random process which involves each chromosome separately, occurs at early stages in differentiation and is heritable by daughter cells. These data suggest the possibility that stochastic decisions might control a number of biological processes.
Laboratory of Molecular Immunology, National Institute for Medical Research, Ridgeway, London, UK.
J I
JI
Elliott
R
R
Festenstein
M
M
Tolaini
D
D
Kioussis
D000818:Animals; D018801:CD2 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D002874:Chromosome Mapping; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
D018801:CD2 Antigens; D002843:Chromatin; D007143:Immunoglobulin Heavy Chains; D008565:Membrane Proteins