Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR.
Coreceptor expression is tightly regulated during thymocyte development. Deletion of specific Cd8 enhancers leads to variegated expression of CD8alphabeta heterodimers in double-positive thymocytes. Here we show CD8 variegation is correlated with an epigenetic 'off' state, linking Cd8 enhancer function with chromatin remodeling of the adjacent genes Cd8a and Cd8b1 (Cd8). The zinc finger protein MAZR bound the Cd8 enhancer and interacted with the nuclear receptor corepressor N-CoR complex in double-negative thymocytes. MAZR was downregulated in double-positive and CD8 single-positive thymocytes. 'Enforced' expression of MAZR led to impaired Cd8 activation and variegated CD8 expression. Our results demonstrate epigenetic control of the Cd8 loci and identify MAZR as an important regulator of Cd8 expression.
Bilic
Ivan
I
Institute of Immunology, Medical University of Vienna, Vienna 1090, Austria.
Koesters
Christina
C
Unger
Bernd
B
Sekimata
Masayuki
M
Hertweck
Arnulf
A
Maschek
Romana
R
Wilson
Christopher B
CB
Ellmeier
Wilfried
W
D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D019175:DNA Methylation; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic / Q000276:immunology; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014158:Transcription, Genetic
D016827:CD8 Antigens; C433839:CD8alphabeta antigen; D002843:Chromatin; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C485875:Zfp278 protein, mouse