Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation.
An intronic silencer within the CD4 gene is the critical cis regulatory element for T cell subset-specific expression of CD4. We have combined transfection studies with gene targeting in mice to identify several key sequences within the silencer core that are required for gene silencing during thymocyte development. In mice, mutations in individual sites resulted in variegated, but heritable, derepression of CD4 in mature CD8(+) T lymphocytes, whereas compound mutations resulted in full derepression. These results indicate that there is partial redundancy in recruiting a chromatin remodeling machinery that results in epigenetic silencing. Mutations in single sites also resulted in partial derepression of CD4 in immature double-negative thymocytes, but there was no apparent variegation. These findings suggest two distinct modes of CD4 silencer function at different developmental stages: active repression in CD4(-)CD8(-) thymocytes, in which silencing must be reversible, and epigenetic gene silencing upon differentiation to the CD8(+) cytotoxic T cell lineage.
Taniuchi
Ichiro
I
Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. taniuchi@bioreg.kyushu-u.ac.jp
Sunshine
Mary Jean
MJ
Festenstein
Richard
R
Littman
Dan R
DR
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D019070:Cell Lineage; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D005822:Genetic Vectors; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D013950:Thymus Gland / Q000166:cytology*; D014158:Transcription, Genetic; D014162:Transfection; D019076:Transgenes
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D015500:Chloramphenicol O-Acetyltransferase