Transcriptional responses to proteotoxic stressors are profoundly diverse and tissue-specific.

Cells counteract proteotoxic conditions by launching transcriptional stress responses. While synthesis of heat shock proteins (HSPs) upon acute stress is well characterized, how distinct proteotoxic conditions reshape the transcriptome remains poorly understood. Here, we analyse polyA+ RNA expression under heat shock, HSP90 inhibition, and polyglutamine (polyQ) aggregation. We find fundamentally distinct transcriptional responses to proteotoxic stressors and a systemic deficiency of mice under chronic stress to launch acute responses. While heat shock and HSP90 inhibition induce chaperones, polyQ aggregation increases expression of RNAs linked to transcription repression, chromatin remodeling, and autophagy. Analysing wild-type and Huntington's Disease (HD) mice reveals tissue-specific transcriptional adaptations to polyQ, including repressed cell-type specific functions and altered energy metabolism. Despite profound reprogramming, remarkably few genes exhibit consistently increased (Acy3, Abhd1, Tmc3) or decreased (Fos) RNA levels across HD brain regions. These results emphasize cellular background in disease manifestation and support energy metabolism and detoxifying enzymes as therapeutic targets in late-stage HD. Moreover, the systemic deficiency of chronically stressed mice to launch responses challenges strategies that rely on induced transcription. Altogether, we characterize transcription signatures to proteotoxic stresses, identify key trans-activators driving proteotoxic stress responses, provide an interactive gene-by-gene viewer of global changes, and delineate tissue-specific transcription programs in HD mice.