Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8+ T Cell Differentiation

• Specific H3K4me3 and H3K27me3 patterns identify functionally related CTL genes
• Many CTL-specific transcription factors are bivalent for H3K4me3 and H3K27me3
• Bivalent loci largely resolve to a permissive signature rapidly after activation
• H3K4me2 identifies a subset of rapidly transcribed immune-specific gene loci

SummaryThe molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation. Upon differentiation into effector and/or memory CTLs, the majority of these gene loci lose repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naive T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTLs. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved via distinct epigenetic mechanisms.

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