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The molecular mechanisms that underpin acquisition and maintenance of lineage specific gene expression by virus-specific CD8+ T cells are not fully delineated. Post-translational modifications (PTMs) of genome associated histone proteins are a key mechanism for regulating gene expression. We mapped genome wide changes in histone PTM deposition during virus-specific CD8+ T cell differentiation. By comparing the location and level of deposition of a combination of H3K4me1, H3K4me2, H3K4me3, H3K27me3, H3K27Ac, chromatin accessibility and binding of the histone acetyltransferase, p300, we could map both known and putative enhancer elements that are differentially regulated between naive, effector and memory virus-specific CD8+ T cells. Using this epigenetic blueprint, we identified putative transcriptional enhancers located upstream of the Ccl5 gene, a key CD8+ T cell effector gene. We demonstrate that acquisition of Ccl5 transcription upon T cell activation is regulated via temporal and transcription factor (TF) dependent chromatin remodelling. Using chromatin conformation capture (3C) to measure enhancer-promoter interactions, we show that that TF dependent looping of these enhancer elements onto the Ccl5 promoter correlated with transcriptional activation and potential. These studies form a platform for more in depth analysis of key non-coding regulatory elements that regulate acquisition of virus-specific T cell gene expression and maintenance into memory.

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