Modulation of activated T cells by transient EZH2 inhibition [RNA-Seq]

The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated. However, the role of EZH2 in T cell exhaustion remains under-explored. Here, using in vitro exhaustion models, we demonstrate that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delays their dysfunctional progression and preserves T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetostat induces T-cell epigenetic reprogramming and increases the expression of the self-renewal T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. Transcriptomic profiling revealed a cell division-dependent upregulation of genes associated with thymocytes, memory and effector T cell subsets. Mapping of EZH2-associated genomic regions by ChIP-seq showed an enrichment of promoters among H2K27me3 loci reduced in abundance by tazemetostat, including those genes upregulated in taz-treated T cells.