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Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.

Gemayel R, Chavali S, Pougach K, Legendre M, Zhu B, Boeynaems S, van der Zande E, Gevaert K, Rousseau F, Schymkowitz J, Babu MM, Verstrepen KJ - Mol. Cell (2015)

Bottom Line: Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes.Quantitative proteomic analysis reveals that the Ssn6 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.

No MeSH data available.


Related in: MedlinePlus

Model for a Functional Role of Variable Q-Rich Repeats in the Transcriptional Regulator Ssn6Variation in the number of Q-rich repeats in Ssn6 may primarily affect the Hsp70 (Ssa2)-mediated folding dynamics of this transcriptional regulator and its interaction with Tup1 and other regulators. The ensuing functional changes in Ssn6 result in repeat-length-dependent variation in the expression of genes involved in various cellular processes. These expression changes underlie phenotypic diversity (e.g., flocculation strength).
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fig6: Model for a Functional Role of Variable Q-Rich Repeats in the Transcriptional Regulator Ssn6Variation in the number of Q-rich repeats in Ssn6 may primarily affect the Hsp70 (Ssa2)-mediated folding dynamics of this transcriptional regulator and its interaction with Tup1 and other regulators. The ensuing functional changes in Ssn6 result in repeat-length-dependent variation in the expression of genes involved in various cellular processes. These expression changes underlie phenotypic diversity (e.g., flocculation strength).

Mentions: TRs are present in ∼20% of genes in the human genome, yet their functional significance is still not fully understood. In this study, we provide a detailed and direct investigation of the outcome of Q-rich repeat variation in a physiological context. We engineered S. cerevisiae strains that only differ in the number of repeats in the transcriptional regulator SSN6 (CYC8) to mimic the natural repeat variation as well variations outside the natural range. We provide evidence that even moderate variations in Ssn6 repeat number result in detectable functional changes. These are likely caused by changes in Ssn6 solubility and interaction with other proteins, including its prime partner Tup1 (Figure 6). Our study thus shows that Q-rich repeat variation results in changes in TF stability and interaction, which in turn leads to changes in the expression of its target genes and the phenotypes they control, supporting the notion that repeats could function as evolvable genetic tuning knobs of TF function (King et al., 1997).


Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.

Gemayel R, Chavali S, Pougach K, Legendre M, Zhu B, Boeynaems S, van der Zande E, Gevaert K, Rousseau F, Schymkowitz J, Babu MM, Verstrepen KJ - Mol. Cell (2015)

Model for a Functional Role of Variable Q-Rich Repeats in the Transcriptional Regulator Ssn6Variation in the number of Q-rich repeats in Ssn6 may primarily affect the Hsp70 (Ssa2)-mediated folding dynamics of this transcriptional regulator and its interaction with Tup1 and other regulators. The ensuing functional changes in Ssn6 result in repeat-length-dependent variation in the expression of genes involved in various cellular processes. These expression changes underlie phenotypic diversity (e.g., flocculation strength).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543046&req=5

fig6: Model for a Functional Role of Variable Q-Rich Repeats in the Transcriptional Regulator Ssn6Variation in the number of Q-rich repeats in Ssn6 may primarily affect the Hsp70 (Ssa2)-mediated folding dynamics of this transcriptional regulator and its interaction with Tup1 and other regulators. The ensuing functional changes in Ssn6 result in repeat-length-dependent variation in the expression of genes involved in various cellular processes. These expression changes underlie phenotypic diversity (e.g., flocculation strength).
Mentions: TRs are present in ∼20% of genes in the human genome, yet their functional significance is still not fully understood. In this study, we provide a detailed and direct investigation of the outcome of Q-rich repeat variation in a physiological context. We engineered S. cerevisiae strains that only differ in the number of repeats in the transcriptional regulator SSN6 (CYC8) to mimic the natural repeat variation as well variations outside the natural range. We provide evidence that even moderate variations in Ssn6 repeat number result in detectable functional changes. These are likely caused by changes in Ssn6 solubility and interaction with other proteins, including its prime partner Tup1 (Figure 6). Our study thus shows that Q-rich repeat variation results in changes in TF stability and interaction, which in turn leads to changes in the expression of its target genes and the phenotypes they control, supporting the notion that repeats could function as evolvable genetic tuning knobs of TF function (King et al., 1997).

Bottom Line: Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes.Quantitative proteomic analysis reveals that the Ssn6 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.

No MeSH data available.


Related in: MedlinePlus