Regulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation platform we call "PERSIST" which consists of nine CRISPR-specific endoRNases as RNA-level activators and repressors as well as modular OFF- and ON-switch regulatory motifs. We show that PERSIST-regulated transgenes exhibit strong OFF and ON responses, resist silencing for at least two months, and can be readily layered to construct cascades, logic functions, switches and other sophisticated circuit topologies. The orthogonal, modular and composable nature of this platform as well as the ease in constructing robust and predictable gene circuits promises myriad applications in gene and cell therapies.