The histone methyltransferase G9a is required for silencing of helper lineage genes in CD8+ T cells

During a binary cell fate decision, a progeny silences the gene expression program associated with the alternative fate. Helper versus cytotoxic lineage decision in the thymus has been studied as a model for gene silencing of alternative lineage genes, including Cd4. While RUNX3 is required for the initiation of Cd4 silencing, it remains unknown how silenced states of Cd4 and other helper lineage genes are maintained. We show that the histone methyltransferase G9a is necessary for heritable silencing of Cd4 and other helper lineage genes in CD8 T cells. Despite normal Cd4 downregulation during the development, G9a-deficient CD8 T cells fail to maintain silencing of helper lineage genes when they repeatedly divide under non-inflammatory conditions. However, Cd4 depression is prevented during division driven by elevated TCR signaling and an inflammatory cytokine signaling. These results reveal the requirement for G9a in silencing of helper lineage genes in CD8 T cells and also suggest that CD8 T cells employ an alternative mechanism to maintain their cellular identity during immune responses. Overall design: RNA-sequencing on CD4+CD8+ G9a KO, CD4–CD8+ G9a KO, and CD4–CD8+ G9a WT T cells after 4 weeks of proliferation in a lymphopenic environment. ChIP-sequencing on H3K9me3 IP''ed from Ehmt2+/+ and Ehmt2-/- CD8+ T cells cultured in vitro with antibodies to CD3 and CD28

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Verbaro DJ, Sakurai N, Kim B, Shinkai Y, Egawa T