Histone architecture of stem-cell memory T cells reveals progressive remodeling of epigenetic landscape after activation of CD8 T cells

To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed after T cell activation, we investigated the genomic landscape of histone modifications in antigen-experienced CD8+ T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in distinct subsets of CD8+ T cells-naïve, stem cell memory, central memory, and effector memory-to gain insight into how histone architecture is remodeled during the differentiation of activated T cells. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers regions associated with T cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified stem cell memory T cell from other antigen-experienced CD8+ T cell subsets. Taken together, our results suggest that antigen-experienced T cells may undergo chromatin remodeling in a progressive fashion that may have implications for our understanding of peripheral T cell ontogeny and the formation of immunological memory. Gene expression profiles were analyzed in four subsets of peripheral CD8+ T cells: naive (TN; CD62L+CD44-), stem-cell memory (TSCM; CD62L+CD44-Sca1+), central memory (TCM; CD62L+CD44-), and effector memory (TEM; CD62L-CD44-) T cells. Each of the four subsets was done in triplicate, for a total of 12 arrays.