International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 41 - EVOLUTIONARILY CONSERVED SEQUENCE ELEMENTS THAT POSITIVELY REGULATE INTERFERON GAMMA EXPRESSION IN T CELLS

Shnyreva M.1, Weaver WM1, Blanchette M.3, Taylor SL2, Fitzpatrick DR2, Tompa M.1, Wilson CB1

1 University of Washington, Seattle, United States, 2 Amgen Corporation, Seattle, United States, 3 McGill University, Montreal, Canada

Our understanding of mechanisms by which the expression of interferon gamma is regulated is limited. Herein, we identify two evolutionarily conserved non-coding sequence elements (IFNgCNS1 and IFNgCNS2) located ~5kb upstream and ~18kb 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, IFNgCNS1 enhanced IFN gamma production, and this was amplified further by inclusion of IFNgCNS2. 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 IFNgCNS2, the Ifng promoter and intron regions, and, though less pronounced, in IFNgCNS1 increased in parallel as naïve T cells differentiated into IFN gamma producing effector CD8 and TH1 T cells, and this was not seen in TH2 T cells. Like IFN gamma expression, these histone modifications were T-bet-dependent in CD4 but not CD8 T cells. These findings define two distal regulatory elements associated with T cell subset-specific IFN gamma expression.

[an error occurred while processing this directive]