Abstract

Precise, synthetic manipulation of the genome is key to advancing the gene and cell therapy of complex diseases. We investigate technologies that allow engineering of the epigenome beyond gene editing. By developing nuclease-dead dCas systems, repurposed from various bacterial Cas nucleases, we demonstrate their use for versatile transcription control, epigenome modifications, and spatial regulation of the genome in mammalian cells. We combine CRISPR tools with novel synthetic receptors to create multiple-input-multiple-output synthetic devices for better cancer recognition. Primary human T cells engineered with these devices greatly enhance elimination of difficult-to-treat tumor malignancies in vitro and in vivo. Novel epigenome engineering and synthetic receptors hold the promises for better cell therapies.