Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells.
Our understanding of mechanisms by which the expression of IFN-gamma is regulated is limited. Herein, we identify two evolutionarily conserved noncoding sequence elements (IFNgCNS1 and IFNg CNS2) located approximately 5 kb upstream and approximately 18 kb downstream of the initiation codon of the murine Ifng gene. When linked to the murine Ifng gene (-3.4 to +5.6 kb) and transiently transfected into EL-4 cells, these elements clearly enhanced IFN-gamma expression in response to ionomycin and phorbol 12-myristate 13-acetate and weakly enhanced expression in response to T-bet. A DNase I hypersensitive site and extragenic transcripts at IFNgCNS2 correlated positively with the capacity of primary T cell subsets to produce IFN-gamma. Transcriptionally favorable histone modifications in the Ifng promoter, intronic regions, IFNgCNS2, and, although less pronounced, IFNgCNS1 increased as naïve T cells differentiated into IFN-gamma-producing effector CD8+ and T helper (TH) 1 T cells, but not into TH2 T cells. Like IFN-gamma expression, these histone modifications were T-bet-dependent in CD4+ cells, but not CD8+ T cells. These findings define two distal regulatory elements associated with T cell subset-specific IFN-gamma expression.
Shnyreva
Maria
M
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Weaver
William M
WM
Blanchette
Mathieu
M
Taylor
Scott L
SL
Tompa
Martin
M
Fitzpatrick
David R
DR
Wilson
Christopher B
CB
D000818:Animals; D002478:Cells, Cultured; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
D006657:Histones; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma