In this study, Ng et al. investigated the maintenance of silent gene states and how the Cd4 gene is stably repressed in CD8+T cells. Using CRISPR and shRNA screening, they identified the histone chaperone CAF-1 as a critical component for Cd4 repression and propose that the heritable silencing of the Cd4 gene in CD8+T cells exploits cooperative functions among the DNA methyltransferases, CAF-1, and histone-modifying enzymes.