Proteasome activity maintains cell-type-specific gene expression

) are transcriptionally altered, with striking overrepresentation of proteins canonically restricted in expression to specific tissues. This dysregulation is partly driven by the accumulation of the proteasome substrate and deubiquitinase OTUD5, a known chromatin and transcriptional regulator. Our results thus identify proteasome-dependent mechanisms to safeguard cell-type-specific gene expression programs and expand proteasome biology to include governance of cell identity.