Genome wide analysis of the Ssn6-Tup11/Tup12 co-repressor complex in the fission yeast Schizosaccharomyces pombe
Author: Fagerström Billai, Fredrik
Date: 2007-03-08
Location: Sal MB416, Moas Båge, Södertörns Högskola, Alfred Nobels allé 7, Huddinge
Time: 10.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
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thesis.pdf (5.851Mb)
Abstract
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.
List of papers:
I. Fagerstrom-Billai F, Wright AP (2005). "Functional comparison of the Tup11 and Tup12 transcriptional corepressors in fission yeast." Mol Cell Biol 25(2): 716-27
Pubmed
II. Fagerstrom-Billai F, Durand-Dubief M, Ekwall K, Wright AP (2007). "Individual subunits of the Ssn6-Tup11/12 corepressor are selectively required for repression of different target genes." Mol Cell Biol 27(3): 1069-82. Epub 2006 Nov 13
Pubmed
III. Durand-Dubief M, Sinha I, Fagerstrom-Billai F, Bonilla C, Wright A, Grunstein M, Ekwall K (2007). "Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing." (Manuscript)
I. Fagerstrom-Billai F, Wright AP (2005). "Functional comparison of the Tup11 and Tup12 transcriptional corepressors in fission yeast." Mol Cell Biol 25(2): 716-27
Pubmed
II. Fagerstrom-Billai F, Durand-Dubief M, Ekwall K, Wright AP (2007). "Individual subunits of the Ssn6-Tup11/12 corepressor are selectively required for repression of different target genes." Mol Cell Biol 27(3): 1069-82. Epub 2006 Nov 13
Pubmed
III. Durand-Dubief M, Sinha I, Fagerstrom-Billai F, Bonilla C, Wright A, Grunstein M, Ekwall K (2007). "Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing." (Manuscript)
Issue date: 2007-02-15
Rights:
Publication year: 2007
ISBN: 978-91-7357-120-3
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