The epigenetic control of stemness in CD8 ⁺ T cell fate commitment

Abstract

After priming, naïve CD8 T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8 T cells activated after infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell-related memory genes. Single-cell RNA sequencing revealed a defect in silencing of stem/memory genes selectively in-defective T cell effectors. As a result, -defective CD8 T cells show sustained survival and increased long-term memory reprogramming capacity. Thus, Suv39h1 plays a critical role in marking chromatin to silence stem/memory genes during CD8 T effector terminal differentiation.

Epigenetics of T cell aging

“…22 The acquisition of effector and memory T cell functions requires not only that genes involved in lineage commitment are turned on but also that genes maintaining stemness are repressed. [23][24][25][26] Consequently, DNA methylation as well as DNA demethylation and histone modifications conferring gene activation as well as repression are required for T cells to differentiate. 27 Equally important, the epigenetic code can act as the memory of cellular identity because it can be transmitted from one cell generation to the next, 28 obviously crucial for memory T cells that exhibit chromatin accessibility maps similar to effector T cells years after the inciting infection has been cleared.…”

“…Epigenetic changes occur with T cell activation and differentiation . The acquisition of effector and memory T cell functions requires not only that genes involved in lineage commitment are turned on but also that genes maintaining stemness are repressed . Consequently, DNA methylation as well as DNA demethylation and histone modifications conferring gene activation as well as repression are required for T cells to differentiate .…”

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…T cell differentiation is intimately linked to epigenetic programming, but the mechanistic role of epigenetic marks in steering T cell differentiation 40,60,61,63,69,70 and thymic selection [71][72][73][74][75] has only recently become more clear. Here we observed that ablation of Dot1L in the T cell lineage differentially affected CD4 + and CD8 + T cells.…”

The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation

“…Such observations have also been reported for specialized cases of terminal differentiation. For instance, a defect of the H3K9 trimethylase Suv39h1 maintains the re-programming capacity of CD8 + lymphocytes [13] and chromatin acetylation induces the developmental plasticity of oligodendrocyte precursors [14]. Long before these studies, it had already been shown that cellular differentiation is associated to an overall loss of DNA accessibility, measured experimentally with DNAseI [15].…”