Ssn6–Tup1 interacts with class I histone deacetylases required for repression

Watson, Anjanette; Edmondson, Diane G.; Bone, James R.; Mukai, Yoshihiko; Yu, Yan; Du, Wendy; Stillman, David J.; Roth, Sharon Y.

doi:10.1101/gad.829100

Cited by 154 publications

(164 citation statements)

References 39 publications

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“…Tup1 is known to alter local chromatin structure by interacting with chromatin-modifying proteins [19][20][21] , including Hda1 22 . Hda1 is a class 2 histone deacetylase required for repression of a subset of Tup1-repressed genes 23 .…”

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confidence: 99%

A chromatin-mediated mechanism for specification of conditional transcription factor targets

Buck

Lieb

2006

Nat Genet

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Organisms respond to changes in their environment, and many such responses are initiated at the level of gene transcription. Here, we provide evidence for a previously undiscovered mechanism for directing transcriptional regulators to new binding targets in response to an environmental change. We show that Rap1, a master regulator of yeast metabolism, binds to an expanded target set upon nutrient depletion despite decreasing protein levels and no evidence of posttranslational modification. Computational analysis predicted that proteins capable of recruiting the chromatin regulator Tup1 acted to restrict the binding distribution of Rap1 in the presence of nutrients. Deletions of TUP1, genes that encode recruiters of Tup1, or chromatin regulators recruited by Tup1, cause Rap1 to bind specifically and inappropriately to low-nutrient targets. These data, combined with whole-genome measurements of nucleosome occupancy and Tup1 distribution, provide evidence for a mechanism of dynamic target specification that coordinates the genome-wide distribution of intermediate-affinity DNA sequence motifs with chromatin-mediated regulation of accessibility to those sites. Main TextTo survive in fluctuating environments, organisms must respond to changes in their surroundings. One of the primary means of response at the cellular level is the adjustment of levels of gene transcription 1 . In some cases, new transcriptional programs are established by the binding of regulatory proteins to new gene targets under a given environmental condition 2 . These regulatory factors then act to either activate or repress transcription. Four straightforward mechanisms for the regulation of transcription-factor targeting have been demonstrated. These include altering the regulatory factor's concentration in the nucleus 3 , altering binding affinity by post-translational modification 4 or through an allosteric cofactor 5 , and altering binding properties by expression of a protein cofactor 6 . Here, we present experiments that provide evidence for a new mechanism of dynamic transcription factor target specification. In the proposed mechanism, the genome-wide distribution of DNA sequence motifs for which a factor has intermediate affinity is carefully coordinated with chromatinmediated regulation of accessibility to those sites. In this way, rather than through use of a specific cofactor or post-translational modification, the genome itself is remodeled to change the targeting and biological outcome of an unaltered transcription factor. Rap1 (Repressor-Activator Protein 1) directs a transcriptional program that is central to yeast metabolism, activating the transcription of genes encoding the ribosomal protein subunits and glycolytic enzymes [7][8][9] . Nearly 40% of the mRNA initiation events in mitotically growing yeast are activated by Rap1, yet Rap1 is also required for the repression of these same genes in

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confidence: 99%

A chromatin-mediated mechanism for specification of conditional transcription factor targets

Buck

Lieb

2006

Nat Genet

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“…Previous experiments have suggested that Tup1-mediated repression might also involve formation of silencing heterochromatin (18)(19)(20). These include reports that Tup1 binds histone tails along the entire length of the promoter and occludes the transcriptional machinery (18) and that Tup1 recruits a histone deacetylase activity (21). However, although the Tup1-histone tail interactions have been suggested to play a role in repression of certain promoters, others have reported that Tup1 represses significantly even where the relevant histone tails are presumably rendered nonfunctional by mutations (22,23).…”

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confidence: 99%

Interaction of a transcriptional repressor with the RNA polymerase II holoenzyme plays a crucial role in repression

Zaman

Ansari

Koh

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The yeast transcriptional repressor Tup1, tethered to DNA, represses to strikingly different degrees transcription elicited by members of two classes of activators. Repression in both cases is virtually eliminated by mutation of either member of the cyclinkinase pair Srb10͞11. In contrast, telomeric chromatin affects both classes of activators equally, and in neither case is that repression affected by mutation of Srb10͞11. In vitro, Tup1 interacts with RNA polymerase II holoenzyme bearing Srb10 as well as with the separated Srb10. These and other findings indicate that at least one aspect of Tup1's action involves interaction with the RNA polymerase II holoenzyme.

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“…The reason the corepressor targets multiple proteins is not known, nor is it clear whether Tup1 targets all of these polymerase II-associated proteins at every promoter or whether it interacts with different targets at different promoters. Different tetratricopeptide repeats in Ssn6 are required for repression of different genes, and differential changes in H3 and H4 acetylation associated with Tup1-regulated genes have been observed (27,33). Thus, different repressive architectures may exist at different genes regulated by this corepressor.…”

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confidence: 99%

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“…Ssn6-Tup1 interacts physically with class I histone deacetylases (HDACs), 1 and simultaneous mutation of the three HDAC genes, RPD3, HOS1, and HOS2, abolishes repression by Ssn6-Tup1 (27). The Ssn6-Tup1 complex interacts with at least two of these HDACs, Rpd3 and Hos2 (27). Hda1 has also been reported to interact with Tup1 in vitro and is required for deacetylation of histones H3 and H2B at the stress-responsive ENA1 promoter, whereas Rpd3 deacetylates the coding region of this gene (28).…”

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Physical and Functional Interaction of the Yeast Corepressor Tup1 with mRNA 5′-Triphosphatase

Mukai

Davie

Dent

2003

Journal of Biological Chemistry

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The Tup1-Ssn6 complex is an important corepressor in Saccharomyces cerevisiae that inhibits transcription through interactions with the basal transcription machinery and by remodeling chromatin. In a two-hybrid screen for factors that interact with the Schizosaccharomyces pombe Tup1 ortholog, Tup11, we isolated the pct1 ؉ cDNA. The pct1 ؉ gene encodes an mRNA 5 -triphosphatase, which catalyzes the first step of mRNA capping reactions. Pct1 did not interact with the S. pombe Ssn6 ortholog. In vitro glutathione S-transferase pull-down experiments revealed that Pct1 binds to the WD repeat regions of Tup11 and the functionally redundant Tup12 protein. Similarly, the S. cerevisiae Tup1 protein associates with the mRNA 5 -triphosphatase encoded by the CET1 gene. The highly conserved C-terminal domain of Cet1 interacts with Tup1 in vitro, and Tup1-Ssn6 complexes co-purify with the Cet1 protein, indicating that in vivo interactions also occur between these proteins. Over-expression of CET1 compromised repression of an MFA2-lacZ reporter gene that is subject to Tup1-Ssn6 repression. These genetic and biochemical interactions between Tup1-Ssn6 and Cet1 indicate that the capping enzyme associated with RNA polymerase II is a target of the corepressor complex.

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Ssn6–Tup1 interacts with class I histone deacetylases required for repression

Cited by 154 publications

References 39 publications

A chromatin-mediated mechanism for specification of conditional transcription factor targets

A chromatin-mediated mechanism for specification of conditional transcription factor targets

Interaction of a transcriptional repressor with the RNA polymerase II holoenzyme plays a crucial role in repression

Physical and Functional Interaction of the Yeast Corepressor Tup1 with mRNA 5′-Triphosphatase

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