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Genome wide analysis of the Ssn6-Tup11/Tup12 co-repressor complex in the fission yeast Schizosaccharomyces pombe
Södertörn University, School of Life Sciences. Karolinska Institutet.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this study, we have investigated the fission yeast Ssn6-Tup11 /Tup 12 transcriptional corepressor which is involved in regulation of many genes important for a wide variety of processes. In contrast to the well characterised budding yeast Tup1 protein there are two paralogous proteins present in fission yeast, namely Tup11 and Tup12. We have shown that the two proteins can interact with each other and are expressed at similar levels, which is in line with a reported redundant function. Sequence analysis shows that the intermediate proposed histone interacting domain is highly variable between Tup11 and Tup12 indicating a diversification. Interestingly, we show that tup11 and tup12 mutants have different phenotypes on media containing KC1 and CaC12. Consistent with this functional difference, we identify a number of target genes by genome wide expression profiling that are differentially affected by tup11 - and tup12. Many of these genes are Tup12 dependent and correlate with genes that have previously been shown to respond to a range of different environmental stress conditions. The observed different physiological roles of Tup11 and Tup12 can not be explained by differential recruitment of Ssn6 which can interact independently with both Tup11 and Tup12. Most interestingly we show that the Ssn6 protein is essential in fission yeast and therefore must have a distinct role separated from Tup11 and Tup12. Surprisingly, a conditional ssn6HA-ts mutant displays the same growth phenotype as tup12, indicating a role in Tup12 dependent stress response. Consistent with the diverse phenotypes of the individual co-repressor proteins, we identify a group of genes that requires Ssn6 for their regulation which is overlapping but distinct from the group of genes that depend on Tup11 or Tup12. Genome wide chromatin immunoprecipitation shows that Ssn6 is almost invariably found in the same genomic locations as Tup11 and/or Tup12. All three co-repressor subunits are generally bound to genes that are selectively regulated by Ssn6 or Tup11/12, and thus, likely in the context of a co-repressor complex containing all three subunits. The co-repressor binds to both the intergenic and coding regions of genes, but differential localization of the co-repressor within genes does not appear to account for the selective dependence of target genes on the Ssn6 or Tup11/12 subunits. Ssn6, Tup11, and Tup12 are preferentially found at genomic locations at which histones are deacetylated, primarily by the Clr6 class I HDAC. A subset of co-repressor target genes, including direct target genes affected by Ssn6 overexpression, is in addition associated with the function of class II (Clr3) and III (Hst4 and Sir2) HDACs. Interestingly, many specific Hst4 repressed ORF targets involved in amino acid biosynthesis are also direct targets for the Ssn6-Tup11/12 co-repressor, suggesting an association with the class ill sirtuins which has not been reported previously.

Place, publisher, year, edition, pages
Stockholm: Karolinska instiutet , 2007. , 58 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:sh:diva-31991ISBN: 978-91-7357-120-3 (print)OAI: oai:DiVA.org:sh-31991DiVA: diva2:1072779
Public defence
2007-03-08, MB416, Alfred Nobels allé 7, Huddinge, 10:00 (English)
Opponent
Supervisors
Available from: 2017-02-08 Created: 2017-02-08 Last updated: 2017-02-08Bibliographically approved
List of papers
1. Functional comparison of the Tup11 and Tup12 transcriptional corepressors in fission yeast
Open this publication in new window or tab >>Functional comparison of the Tup11 and Tup12 transcriptional corepressors in fission yeast
2005 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 25, no 2, 716-727 p.Article in journal (Refereed) Published
Abstract [en]

Gene duplication is considered an important evolutionary mechanism. Unlike many characterized species, the fission yeast Schizosaccharomyces pombe contains two paralogous genes, tup11(+) and tup12(+), that encode transcriptional corepressors similar to the well-characterized budding yeast Tup1 protein. Previous reports have suggested that Tup11 and Tup12 proteins play redundant roles. Consistently, we show that the two Tup proteins can interact together when expressed at normal levels and that each can independently interact with the Ssn6 protein, as seen for Tup1 in budding yeast. However, tup11(-) and tup12(-) mutants have different phenotypes on media containing KCl and CaCl2. Consistent with the functional difference between tup11(-) and tup12- mutants, we identified a number of genes in genome-wide gene expression experiments that are differentially affected by mutations in the tup11(+) and tup12(+) genes. Many of these genes are differentially derepressed in tup11(-) mutants and are over-represented in genes that have previously been shown to respond to a range of different stress conditions. Genes specifically derepressed in tup12(-) mutants require the Ssn6 protein for their repression. As for Tupl.2, Ssn6 is also required for efficient adaptation to KCI- and CaCl2-mediated stress. We conclude that Tup11 and Tup12 are at least partly functionally diverged and suggest that the Tup12 and Ssn6 proteins have adopted a specific role in regulation of the stress response.

National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-14401 (URN)10.1128/MCB.25.2.716-727.2005 (DOI)000226287800018 ()15632072 (PubMedID)2-s2.0-11844294040 (Scopus ID)
Available from: 2011-12-21 Created: 2011-12-21 Last updated: 2017-07-19Bibliographically approved
2. Individual Subunits of the Ssn6-Tup11/12 corepressor are selectively required for repression of different target genes
Open this publication in new window or tab >>Individual Subunits of the Ssn6-Tup11/12 corepressor are selectively required for repression of different target genes
2007 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 27, no 3, 1069-1082 p.Article in journal (Refereed) Published
Abstract [en]

The Saccharomyces cerevisiae Ssn6 and Tup1 proteins form a corepressor complex that is recruited to target genes by DNA-bound repressor proteins. Repression occurs via several mechanisms, including interaction with hypoacetylated N termini of histones, recruitment of histone deacetylases (HDACs), and interactions with the RNA polymerase II holoenzyme. The distantly related fission yeast, Schizosaccharomyces pombe, has two partially redundant Tup1-like proteins that are dispensable during normal growth. In contrast, we show that Ssn6 is an essential protein in S. pombe, suggesting a function that is independent of Tup11 and Tup12. Consistently, the group of genes that requires Ssn6 for their regulation overlaps but is distinct from the group of genes that depend on Tup11 or Tup12. Global chip-on-chip analysis shows that Ssn6 is almost invariably found in the same genomic locations as Tup11 and/or Tup12. All three corepressor subunits are generally bound to genes that are selectively regulated by Ssn6 or Tup11/12, and thus, the subunit specificity is probably manifested in the context of a corepressor complex containing all three subunits. The corepressor binds to both the intergenic and coding regions of genes, but differential localization of the corepressor within genes does not appear to account for the selective dependence of target genes on the Ssn6 or Tup11/12 subunits. Ssn6, Tup11, and Tup12 are preferentially found at genomic locations at which histones are deacetylated, primarily by the Clr6 class I HDAC. Clr6 is also important for the repression of corepressor target genes. Interestingly, a subset of corepressor target genes, including direct target genes affected by Ssn6 overexpression, is associated with the function of class II (CIr3) and III (Hst4 and Sir2) HDACs.

National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-13954 (URN)10.1128/MCB.01674-06 (DOI)000243946000024 ()17101775 (PubMedID)2-s2.0-33846584595 (Scopus ID)
Available from: 2011-12-15 Created: 2011-12-15 Last updated: 2017-07-18Bibliographically approved
3. Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing
Open this publication in new window or tab >>Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing
Show others...
2007 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 26, no 10, 2477-2488 p.Article in journal (Refereed) Published
Abstract [en]

Expression profiling, ChiP-CHIP and phenotypic analysis were used to investigate the functional relationships of class III NAD(+)-dependent HDACs (Sirtuins) in fission yeast. We detected significant histone acetylation increases in Sirtuin mutants at their specific genomic binding targets and were thus able to identify an in vivo substrate preference for each Sirtuin. At heterochromatic loci, we demonstrate that although Hst2 is mainly cytoplasmic, a nuclear pool of Hst2 colocalizes with the other Sirtuins at silent regions (cen, mat, tel, rDNA), and that like the other Sirtuins, Hst2 is required for rDNA and centromeric silencing. Interestingly we found specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation. Hst2 directly represses genes involved in transport and membrane function, whereas Hst4 represses amino-acid biosynthesis genes and Tf2 retrotransposons. A specific role for Hst4 in Tf2 50 mRNA processing was revealed. Thus, Sirtuins share functions at many genomic targets, but Hst2 and Hst4 have also evolved unique functions in gene regulation.

National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-14223 (URN)10.1038/sj.emboj.7601690 (DOI)000247083100004 ()17446861 (PubMedID)2-s2.0-34249001997 (Scopus ID)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-07-18Bibliographically approved

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