Deciphering the role of histone modifications in memory and exhausted CD8 T cells.

Exhausted CD8 T cells (T(EX)) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (T(MEM)) cells, T(EX) have a unique open chromatin landscape underlying a distinct gene expression program. How T(EX) transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (T(N)), T(MEM) and T(EX). We identified H3K27ac-associated super-enhancers that distinguish T(N), T(MEM) and T(EX), along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in T(N), but activated in T(MEM) or T(EX) whereas other genes poised in T(N) were repressed in T(MEM) or T(EX), indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in T(EX), suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of T(EX) compared to T(MEM) through both activating and repressive pathways.