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Transcriptional regulators are prevalent among identified prions inSaccharomyces cerevisiae, however, it is unclear how prions affect genome-wide transcription.We show here that the prion ([SWI⁺]) and mutant (swi1∆)forms of Swi1, a subunit of the SWI/SNF chromatin-remodeling complex, confer dramatically distinct transcriptomic profiles. In [SWI⁺] cells, genes encoding for 34 transcription factors (TFs) and 24 Swi1-interacting proteins can undergo transcriptional modifications. Several TFs show enhanced aggregation in [SWI⁺] cells. Further analyses suggest that such alterations are key factors in specifying the transcriptomic signatures of [SWI⁺] cells. Interestingly,swi1∆and [SWI⁺] impose distinct and oftentimes opposite effects on cellular functions. Translation-associated activities, in particular, are significantly reduced inswi1∆cells. Although bothswi1∆and [SWI⁺] cells are similarly sensitive to thermal, osmotic and drought stresses, harmful, neutral or beneficial effects were observed for a panel of tested chemical stressors. Further analyses suggest that the environmental stress response (ESR) is mechanistically different betweenswi1∆and [SWI⁺] cells—stress-inducible ESR (iESR) are repressed by [SWI⁺] but unchanged byswi1∆while stress-repressible ESR (rESR) are induced by [SWI⁺] but repressed byswi1∆. Our work thus demonstrates primarily gain-of-function outcomes through transcriptomic modifications by [SWI⁺] and highlights a prion-mediated regulation of transcription and phenotypes in yeast.