Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8⁺ T Cell-Lineage-Specific Function

Highlights

• Virus-specific CTLs exhibit specific changes in enhancer activity upon activation

• H3K4me3 is acquired at lineage-specific enhancers in activated CTL

• H3K4me3 is deposited predominantly at TEs initially poised in the naive state

• H3K4me3⁺ enhancers are specific targets for T cell-specific transcription factors

Summary

Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ∼25,000 putative CD8⁺ T cell transcriptional enhancers (TEs) differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3⁺) chromatin signature upon differentiation. This unique TE subset exhibited characteristics of poised enhancers in the naive CD8⁺ T cell subset and demonstrated enrichment for transcription factor binding motifs known to be important for virus-specific CD8⁺ T cell differentiation. These data provide insights into the establishment and maintenance of the gene transcription profiles that define each stage of virus-specific T cell differentiation.