Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells [SYSTEMS IMMUNOLOGY]

Abstract

Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.

Footnotes

  • This work was supported by the Plan Nacional de I+D+I 2008–2011 and the European Union Fondos Feder, Instituto de Salud Carlos III (Grants PI12/02587 and PI16/01318), Red Española de Investigación Renal (Grants RD12/0021/0018, RD12/0021/0021, and RD16/0009/0020), and Plan de Ciencia, Tecnología e Innovación 2013–2017 del Principado de Asturias (GRUPIN-14-030). CIC bioGUNE support was provided by The Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2007–2015), the Innovation Technology Department of Bizkaia County, and the CIBER (Biomedical Research Networking Centre) program at Instituto de Salud Carlos III.

  • The sequences presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE83159 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE83159).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BLIMP1
    B lymphocyte–induced maturation protein 1
    CEBPD
    CCAAT/enhancer binding protein δ
    ChIP
    chromatin immunoprecipitation
    DEG
    differentially expressed gene
    DMR
    differentially methylated region
    EM
    effector memory
    EOMES
    eomesodermin
    FC
    fold change
    FDR
    false discovery rate
    GO
    gene ontology
    H3K9Ac
    acetylated lysine 9 in histone H3
    H3K9me3
    trimethylated lysine 9 in histone H3
    KEGG
    Kyoto Encyclopedia of Genes and Genomes
    PRF1
    perforin 1
    TEMRA
    terminally differentiated EM
    TSS
    transcription start site
    ZSCAN1
    zinc finger and SCAN domain containing protein 18.
  • Received June 24, 2016.
  • Accepted November 13, 2016.

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