Variable glutamine-rich repeats modulate the function of the transcriptional regulator SSN6

Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation, remain unknown. Here, we demonstrate that Q-rich repeats are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6p (Cyc8p) result in systematic, repeat-length dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6p increases with its repeat number, until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6p repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator’s innate function, with the inherent risk of pathogenic repeat expansions. Overall design: Transcriptome profiles of two biological replicates of each SSN6 tandem repeat number variant and the WT grown in a glucose-rich medium (4% glucose - glu4) or in a glucose-starved medium (0 % glucose - glu0)