Variable glutamine-rich repeats modulate transcription factor activity

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 domains 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 Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. 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

How do regulatory networks evolve and expand throughout evolution?

Throughout evolution, regulatory networks need to expand and adapt to accommodate novel genes and gene functions. However, the molecular details explaining how gene networks evolve remain largely unknown. Recent studies demonstrate that changes in transcription factors contribute to the evolution of regulatory networks. In particular, duplication of transcription factors followed by specific mutations in their DNA-binding or interaction domains propels the divergence and emergence of new networks. The innate promiscuity and modularity of regulatory networks contributes to their evolvability: duplicated promiscuous regulators and their target promoters can acquire mutations that lead to gradual increases in specificity, allowing neofunctionalization or subfunctionalization.publisher: Elsevier articletitle: How do regulatory networks evolve and expand throughout evolution? journaltitle: Current Opinion in Biotechnology articlelink: http://dx.doi.org/10.1016/j.copbio.2015.02.001 content_type: article copyright: Copyright © 2015 The Authors. Published by Elsevier Ltd.status: publishe

Noise and Epigenetic Inheritance of Single-Cell Division Times Influence Population Fitness

The fitness effect of biological noise remains unclear. For example, even within clonal microbial populations, individual cells grow at different speeds. Although it is known that the individuals’ mean growth speed can affect population-level fitness, it is unclear how or whether growth speed heterogeneity itself is subject to natural selection. Here, we show that noisy single-cell division times can significantly affect population-level growth rate. Using time-lapse microscopy to measure the division times of thousands of individual S. cerevisiae cells across different genetic and environmental backgrounds, we find that the length of individual cells’ division times can vary substantially between clonal individuals and that sublineages often show epigenetic inheritance of division times. By combining these experimental measurements with mathematical modeling, we find that, for a given mean division time, increasing heterogeneity and epigenetic inheritance of division times increases the population growth rate. Furthermore, we demonstrate that the heterogeneity and epigenetic inheritance of single-cell division times can be linked with variation in the expression of catabolic genes. Taken together, our results reveal how a change in noisy single-cell behaviors can directly influence fitness through dynamics that operate independently of effects caused by changes to the mean. These results not only allow a better understanding of microbial fitness but also help to more accurately predict fitness in other clonal populations, such as tumors.publisher: Elsevier articletitle: Noise and Epigenetic Inheritance of Single-Cell Division Times Influence Population Fitness journaltitle: Current Biology articlelink: http://dx.doi.org/10.1016/j.cub.2016.03.010 content_type: article copyright: © 2016 Elsevier Ltd.status: publishe

Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity

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 domains 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 Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. 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.publisher: Elsevier articletitle: Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity journaltitle: Molecular Cell articlelink: http://dx.doi.org/10.1016/j.molcel.2015.07.003 content_type: article copyright: Copyright © 2015 The Authors. Published by Elsevier Inc.status: publishe

Selecting and generating superior yeasts for the brewing industry

status: publishe