Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity
Identifieur interne : 000101 ( Main/Exploration ); précédent : 000100; suivant : 000102Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity
Auteurs : Rita Gemayel [Belgique] ; Sreenivas Chavali [Royaume-Uni] ; Ksenia Pougach [Belgique] ; Matthieu Legendre [France] ; Bo Zhu [Belgique] ; Steven Boeynaems [Belgique] ; Elisa Van Der Zande [Belgique] ; Kris Gevaert [Belgique] ; Frederic Rousseau [Belgique] ; Joost Schymkowitz [Belgique] ; M. Madan Babu [Royaume-Uni] ; Kevin J. Verstrepen [Belgique]Source :
- Molecular Cell [ 1097-2765 ] ; 2015.
Abstract
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.
Url:
DOI: 10.1016/j.molcel.2015.07.003
PubMed: 26257283
PubMed Central: 4543046
Affiliations:
- Belgique, France, Royaume-Uni
- Provence-Alpes-Côte d'Azur, Province de Flandre-Orientale, Province du Brabant flamand
- Gand, Heverlee, Louvain, Marseille
- Université d'Aix-Marseille
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Le document en format XML
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Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Babu, M Madan" sort="Babu, M Madan" uniqKey="Babu M" first="M. Madan" last="Babu">M. Madan Babu</name><affiliation wicri:level="1"><nlm:aff id="aff3">MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QH</wicri:noRegion></affiliation></author><author><name sortKey="Verstrepen, Kevin J" sort="Verstrepen, Kevin J" uniqKey="Verstrepen K" first="Kevin J." last="Verstrepen">Kevin J. 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1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Chavali, Sreenivas" sort="Chavali, Sreenivas" uniqKey="Chavali S" first="Sreenivas" last="Chavali">Sreenivas Chavali</name><affiliation wicri:level="1"><nlm:aff id="aff3">MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QH</wicri:noRegion></affiliation></author><author><name sortKey="Pougach, Ksenia" sort="Pougach, Ksenia" uniqKey="Pougach K" first="Ksenia" last="Pougach">Ksenia Pougach</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Legendre, Matthieu" sort="Legendre, Matthieu" uniqKey="Legendre M" first="Matthieu" last="Legendre">Matthieu Legendre</name><affiliation wicri:level="4"><nlm:aff id="aff4">Structural and Genomic Information Laboratory, IGS UMR7256, Centre National de la Recherche Scientifique, Aix-Marseille Université, Institut de Microbiologie de la Méditerranée (IMM), 13288 Marseille Cedex 9, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Structural and Genomic Information Laboratory, IGS UMR7256, Centre National de la Recherche Scientifique, Aix-Marseille Université, Institut de Microbiologie de la Méditerranée (IMM), 13288 Marseille Cedex 9</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Zhu, Bo" sort="Zhu, Bo" uniqKey="Zhu B" first="Bo" last="Zhu">Bo Zhu</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Boeynaems, Steven" sort="Boeynaems, Steven" uniqKey="Boeynaems S" first="Steven" last="Boeynaems">Steven Boeynaems</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Van Der Zande, Elisa" sort="Van Der Zande, Elisa" uniqKey="Van Der Zande E" first="Elisa" last="Van Der Zande">Elisa Van Der Zande</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Gevaert, Kris" sort="Gevaert, Kris" uniqKey="Gevaert K" first="Kris" last="Gevaert">Kris Gevaert</name><affiliation wicri:level="3"><nlm:aff id="aff5">Department of Medical Protein Research, VIB, 9000 Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Medical Protein Research, VIB, 9000 Ghent</wicri:regionArea><placeName><region type="province" nuts="2">Province de Flandre-Orientale</region><settlement type="city">Gand</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff6">Department of Biochemistry, Ghent University, 9000 Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biochemistry, Ghent University, 9000 Ghent</wicri:regionArea><placeName><region type="province" nuts="2">Province de Flandre-Orientale</region><settlement type="city">Gand</settlement></placeName></affiliation></author><author><name sortKey="Rousseau, Frederic" sort="Rousseau, Frederic" uniqKey="Rousseau F" first="Frederic" last="Rousseau">Frederic Rousseau</name><affiliation wicri:level="3"><nlm:aff id="aff7">Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Schymkowitz, Joost" sort="Schymkowitz, Joost" uniqKey="Schymkowitz J" first="Joost" last="Schymkowitz">Joost Schymkowitz</name><affiliation wicri:level="3"><nlm:aff id="aff7">Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Babu, M Madan" sort="Babu, M Madan" uniqKey="Babu M" first="M. Madan" last="Babu">M. Madan Babu</name><affiliation wicri:level="1"><nlm:aff id="aff3">MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QH</wicri:noRegion></affiliation></author><author><name sortKey="Verstrepen, Kevin J" sort="Verstrepen, Kevin J" uniqKey="Verstrepen K" first="Kevin J." last="Verstrepen">Kevin J. Verstrepen</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author></analytic><series><title level="j">Molecular Cell</title><idno type="ISSN">1097-2765</idno><idno type="eISSN">1097-4164</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Amberd, D C" uniqKey="Amberd D">D.C. Amberd</name></author><author><name sortKey="Burke, D" uniqKey="Burke D">D. Burke</name></author><author><name sortKey="Strathern, J N" uniqKey="Strathern J">J.N. Strathern</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Balaji, S" uniqKey="Balaji S">S. Balaji</name></author><author><name sortKey="Babu, M M" uniqKey="Babu M">M.M. Babu</name></author><author><name sortKey="Iyer, L M" uniqKey="Iyer L">L.M. Iyer</name></author><author><name sortKey="Luscombe, N M" uniqKey="Luscombe N">N.M. Luscombe</name></author><author><name sortKey="Aravind, L" uniqKey="Aravind L">L. 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Van Riper</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Belgique</li><li>France</li><li>Royaume-Uni</li></country><region><li>Provence-Alpes-Côte d'Azur</li><li>Province de Flandre-Orientale</li><li>Province du Brabant flamand</li></region><settlement><li>Gand</li><li>Heverlee</li><li>Louvain</li><li>Marseille</li></settlement><orgName><li>Université d'Aix-Marseille</li></orgName></list><tree><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Gemayel, Rita" sort="Gemayel, Rita" uniqKey="Gemayel R" first="Rita" last="Gemayel">Rita Gemayel</name></region><name sortKey="Boeynaems, Steven" sort="Boeynaems, Steven" uniqKey="Boeynaems S" first="Steven" last="Boeynaems">Steven Boeynaems</name><name sortKey="Boeynaems, Steven" sort="Boeynaems, Steven" uniqKey="Boeynaems S" first="Steven" last="Boeynaems">Steven Boeynaems</name><name sortKey="Gemayel, Rita" sort="Gemayel, Rita" uniqKey="Gemayel R" first="Rita" last="Gemayel">Rita Gemayel</name><name sortKey="Gevaert, Kris" sort="Gevaert, Kris" uniqKey="Gevaert K" first="Kris" last="Gevaert">Kris Gevaert</name><name sortKey="Gevaert, Kris" sort="Gevaert, Kris" uniqKey="Gevaert K" first="Kris" last="Gevaert">Kris Gevaert</name><name sortKey="Pougach, Ksenia" sort="Pougach, Ksenia" uniqKey="Pougach K" first="Ksenia" last="Pougach">Ksenia Pougach</name><name sortKey="Pougach, Ksenia" sort="Pougach, Ksenia" uniqKey="Pougach K" first="Ksenia" last="Pougach">Ksenia Pougach</name><name sortKey="Rousseau, Frederic" sort="Rousseau, Frederic" uniqKey="Rousseau F" first="Frederic" last="Rousseau">Frederic Rousseau</name><name sortKey="Schymkowitz, Joost" sort="Schymkowitz, Joost" uniqKey="Schymkowitz J" first="Joost" last="Schymkowitz">Joost Schymkowitz</name><name sortKey="Van Der Zande, Elisa" sort="Van Der Zande, Elisa" uniqKey="Van Der Zande E" first="Elisa" last="Van Der Zande">Elisa Van Der Zande</name><name sortKey="Van Der Zande, Elisa" sort="Van Der Zande, Elisa" uniqKey="Van Der Zande E" first="Elisa" last="Van Der Zande">Elisa Van Der Zande</name><name sortKey="Verstrepen, Kevin J" sort="Verstrepen, Kevin J" uniqKey="Verstrepen K" first="Kevin J." last="Verstrepen">Kevin J. Verstrepen</name><name sortKey="Verstrepen, Kevin J" sort="Verstrepen, Kevin J" uniqKey="Verstrepen K" first="Kevin J." last="Verstrepen">Kevin J. Verstrepen</name><name sortKey="Zhu, Bo" sort="Zhu, Bo" uniqKey="Zhu B" first="Bo" last="Zhu">Bo Zhu</name><name sortKey="Zhu, Bo" sort="Zhu, Bo" uniqKey="Zhu B" first="Bo" last="Zhu">Bo Zhu</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Chavali, Sreenivas" sort="Chavali, Sreenivas" uniqKey="Chavali S" first="Sreenivas" last="Chavali">Sreenivas Chavali</name></noRegion><name sortKey="Babu, M Madan" sort="Babu, M Madan" uniqKey="Babu M" first="M. Madan" last="Babu">M. Madan Babu</name></country><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Legendre, Matthieu" sort="Legendre, Matthieu" uniqKey="Legendre M" first="Matthieu" last="Legendre">Matthieu Legendre</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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