scholarly journals Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex

2018 ◽  
Vol 475 (24) ◽  
pp. 3921-3932 ◽  
Author(s):  
Grace E. Adams ◽  
Aditya Chandru ◽  
Shaun M. Cowley
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Histone Deacetylation ◽  
Mammalian Development ◽  
Cellular Processes ◽  
General Transcription Factor ◽  
Repressor Proteins ◽  
Active Transcription ◽  
The Many

At face value, the Sin3 histone deacetylase (HDAC) complex appears to be a prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression. While this is almost certainly part of its role, Sin3 stubbornly refuses to be pigeon-holed in quite this way. Genome-wide mapping studies have found that Sin3 localises predominantly to the promoters of actively transcribed genes. While Sin3 knockout studies in various species result in a combination of both up- and down-regulated genes. Furthermore, genes such as the stem cell factor, Nanog, are dependent on the direct association of Sin3 for active transcription to occur. Sin3 appears to have properties of a co-repressor, co-activator and general transcription factor, and has thus been termed a co-regulator complex. Through a series of unique domains, Sin3 is able to assemble HDAC1/2, chromatin adaptors and transcription factors in a series of functionally and compositionally distinct complexes to modify chromatin at both gene-specific and global levels. Unsurprisingly, therefore, Sin3/HDAC1 have been implicated in the regulation of numerous cellular processes, including mammalian development, maintenance of pluripotency, cell cycle regulation and diseases such as cancer.

scholarly journals The Rpd3-Sin3 Histone Deacetylase Regulates Replication Timing and Enables Intra-S Origin Control in Saccharomyces cerevisiae

2004 ◽  
Vol 24 (11) ◽  
pp. 4769-4780 ◽  
Author(s):  
Jennifer G. Aparicio ◽  
Christopher J. Viggiani ◽  
Daniel G. Gibson ◽  
Oscar M. Aparicio
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Replication Timing ◽  
Histone Deacetylation ◽  
Origin Firing ◽  
Replication Checkpoint ◽  
Genome Transcription ◽  
Late Origin

ABSTRACT The replication of eukaryotic genomes follows a temporally staged program, in which late origin firing often occurs within domains of altered chromatin structure(s) and silenced genes. Histone deacetylation functions in gene silencing in some late-replicating regions, prompting an investigation of the role of histone deacetylation in replication timing control in Saccharomyces cerevisiae. Deletion of the histone deacetylase Rpd3 or its interacting partner Sin3 caused early activation of late origins at internal chromosomal loci but did not alter the initiation timing of early origins or a late-firing, telomere-proximal origin. By delaying initiation relative to the earliest origins, Rpd3 enables regulation of late origins by the intra-S replication checkpoint. RPD3 deletion suppresses the slow S phase of clb5Δ cells by enabling late origins to fire earlier, suggesting that Rpd3 modulates the initiation timing of many origins throughout the genome. Examination of factors such as Ume6 that function together with Rpd3 in transcriptional repression indicates that Rpd3 regulates origin initiation timing independently of its role in transcriptional repression. This supports growing evidence that for much of the S. cerevisiae genome transcription and replication timing are not linked.

scholarly journals The PRH/Hex repressor protein causes nuclear retention of Groucho/TLE co-repressors

2008 ◽  
Vol 417 (1) ◽  
pp. 121-132 ◽  
Author(s):  
Cecile Desjobert ◽  
Peter Noy ◽  
Tracey Swingler ◽  
Hannah  Williams ◽  
Kevin Gaston ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Dominant Negative ◽  
Vertebrate Development ◽  
Nuclear Retention ◽  
Subnuclear Localization ◽  
Cellular Processes ◽  
Haematopoietic Cells ◽  
Repressor Proteins ◽  
Homeobox Protein ◽  
Important Regulator

The PRH (proline-rich homeodomain) [also known as Hex (haematopoietically expressed homeobox)] protein is a transcription factor that functions as an important regulator of vertebrate development and many other processes in the adult including haematopoiesis. The Groucho/TLE (transducin-like enhancer) family of co-repressor proteins also regulate development and modulate the activity of many DNA-binding transcription factors during a range of diverse cellular processes including haematopoiesis. We have shown previously that PRH is a repressor of transcription in haematopoietic cells and that an Eh-1 (Engrailed homology) motif present within the N-terminal transcription repression domain of PRH mediates binding to Groucho/TLE proteins and enables co-repression. In the present study we demonstrate that PRH regulates the nuclear retention of TLE proteins during cellular fractionation. We show that transcriptional repression and the nuclear retention of TLE proteins requires PRH to bind to both TLE and DNA. In addition, we characterize a trans-dominant-negative PRH protein that inhibits wild-type PRH activity by sequestering TLE proteins to specific subnuclear domains. These results demonstrate that transcriptional repression by PRH is dependent on TLE availability and suggest that subnuclear localization of TLE plays an important role in transcriptional repression by PRH.

scholarly journals Transcriptional Repression by the SMRT-mSin3 Corepressor: Multiple Interactions, Multiple Mechanisms, and a Potential Role for TFIIB

1998 ◽  
Vol 18 (9) ◽  
pp. 5500-5510 ◽  
Author(s):  
Chi-Wai Wong ◽  
Martin L. Privalsky
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Alternative Pathway ◽  
Eukaryotic Transcription ◽  
Histone Deacetylase 1 ◽  
General Transcription Factor ◽  
Corepressor Complex ◽  
Chromatin Template ◽  
Physical Interactions

ABSTRACT A variety of eukaryotic transcription factors, including the nuclear hormone receptors, Max-Mad, BCL-6, and PLZF, appear to mediate transcriptional repression through the ability to recruit a multiprotein corepressor complex to the target promoter. This corepressor complex includes the SMRT/N-CoR polypeptides, mSin3A or -B, and histone deacetylase 1 or 2. The presence of a histone-modifying activity in the corepressor complex has led to the suggestion that gene silencing is mediated by modification of the chromatin template, perhaps rendering it less accessible to the transcriptional machinery. We report here, however, that the corepressor complex actually appears to exhibit multiple mechanisms of transcriptional repression, only one of which corresponds with detectable recruitment of the histone deacetylase. We provide evidence instead of an alternative pathway of repression that may be mediated by direct physical interactions between components of the corepressor complex and the general transcription factor TFIIB.

scholarly journals Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications

2005 ◽  
Vol 25 (19) ◽  
pp. 8456-8464 ◽  
Author(s):  
Xuan Zhao ◽  
Thomas Sternsdorf ◽  
Timothy A. Bolger ◽  
Ronald M. Evans ◽  
Tso-Pang Yao
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Activity ◽  
Histone Deacetylation ◽  
Muscle Cell Differentiation ◽  
Histone Deacetylase 4 ◽  
Reconstituted System ◽  
Sumo E3 Ligase

ABSTRACT The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

scholarly journals Histone Deacetylase 1 Can Repress Transcription by Binding to Sp1

1999 ◽  
Vol 19 (8) ◽  
pp. 5504-5511 ◽  
Author(s):  
Angelika Doetzlhofer ◽  
Hans Rotheneder ◽  
Gerda Lagger ◽  
Manfred Koranda ◽  
Vladislav Kurtev ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Trichostatin A ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
3T3 Fibroblasts ◽  
C Terminus ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Carboxy Terminal

ABSTRACT The members of the Sp1 transcription factor family can act as both negative and positive regulators of gene expression. Here we show that Sp1 can be a target for histone deacetylase 1 (HDAC1)-mediated transcriptional repression. The histone deacetylase inhibitor trichostatin A activates the chromosomally integrated murine thymidine kinase promoter in an Sp1-dependent manner. Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and 293 cells demonstrate that Sp1 and HDAC1 can be part of the same complex. The interaction between Sp1 and HDAC1 is direct and requires the carboxy-terminal domain of Sp1. Previously we have shown that the C terminus of Sp1 is necessary for the interaction with the transcription factor E2F1 (J. Karlseder, H. Rotheneder, and E. Wintersberger, Mol. Cell. Biol. 16:1659–1667, 1996). Coexpression of E2F1 interferes with HDAC1 binding to Sp1 and abolishes Sp1-mediated transcriptional repression. Our results indicate that one component of Sp1-dependent gene regulation involves competition between the transcriptional repressor HDAC1 and the transactivating factor E2F1.

scholarly journals Targeted Recruitment of the Sin3-Rpd3 Histone Deacetylase Complex Generates a Highly Localized Domain of Repressed Chromatin In Vivo

1998 ◽  
Vol 18 (9) ◽  
pp. 5121-5127 ◽  
Author(s):  
David Kadosh ◽  
Kevin Struhl
Keyword(s):  
Dna Binding ◽  
Histone Deacetylase ◽  
Chromatin Structure ◽  
Transcriptional Repression ◽  
Dna Binding Proteins ◽  
Histone Deacetylation ◽  
Yeast Cells ◽  
Multiprotein Complex ◽  
Eukaryotic Organisms

ABSTRACT Eukaryotic organisms contain a multiprotein complex that includes Rpd3 histone deacetylase and the Sin3 corepressor. The Sin3-Rpd3 complex is recruited to promoters by specific DNA-binding proteins, whereupon it represses transcription. By directly analyzing the chromatin structure of a repressed promoter in yeast cells, we demonstrate that transcriptional repression is associated with localized histone deacetylation. Specifically, we observe decreased acetylation of histones H3 and H4 (preferentially lysines 5 and 12) that depends on the DNA-binding repressor (Ume6), Sin3, and Rpd3. Mapping experiments indicate that the domain of histone deacetylation is highly localized, occurring over a range of one to two nucleosomes. Taken together with previous observations, these results define a novel mechanism of transcriptional repression which involves targeted recruitment of a histone-modifying activity and localized perturbation of chromatin structure.

scholarly journals Targeted Recruitment of Rpd3 Histone Deacetylase Represses Transcription by Inhibiting Recruitment of Swi/Snf, SAGA, and TATA Binding Protein

2002 ◽  
Vol 22 (18) ◽  
pp. 6458-6470 ◽  
Author(s):  
Jutta Deckert ◽  
Kevin Struhl
Keyword(s):  
Dna Binding ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Associated Factors ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Histone Deacetylation ◽  
Nucleosome Remodeling ◽  
Activation Domains

ABSTRACT Certain DNA-binding repressors inhibit transcription by recruiting Rpd3 histone deacetylase complexes to promoters and generating domains of histone deacetylation that extend over a limited number of nucleosomes. Here, we show that the degree of Rpd3-dependent repression depends on the activator and the level of activation, not the extent of histone deacetylation. In all cases tested, activator binding is unaffected by histone deacetylation. In contrast, Rpd3-dependent repression is associated with decreased occupancy by TATA binding protein (TBP), the Swi/Snf nucleosome-remodeling complex, and the SAGA histone acetylase complex. Transcriptional repression is bypassed by direct recruitment of TBP and several TBP-associated factors, but not by natural activation domains or direct recruitment of polymerase II holoenzyme components. These results suggest that the domain of localized histone deacetylation generated by recruitment of Rpd3 mediates repression by inhibiting recruitment of chromatin-modifying activities and TBP.

scholarly journals The N-CoR/Histone Deacetylase 3 Complex Is Required for Repression by Thyroid Hormone Receptor

2003 ◽  
Vol 23 (15) ◽  
pp. 5122-5131 ◽  
Author(s):  
Takahiro Ishizuka ◽  
Mitchell A. Lazar
Keyword(s):  
Thyroid Hormone ◽  
Histone Deacetylase ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Thyroid Hormone Receptor ◽  
Histone Deacetylation ◽  
Orphan Receptor ◽  
Small Interfering Rnas ◽  
Histone Deacetylase 3 ◽  
Nonspecific Effects

ABSTRACT Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is associated with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is critical for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.

scholarly journals Dynamic Analysis of Proviral Induction and De Novo Methylation: Implications for a Histone Deacetylase-Independent, Methylation Density-Dependent Mechanism of Transcriptional Repression

2000 ◽  
Vol 20 (3) ◽  
pp. 842-850 ◽  
Author(s):  
Matthew C. Lorincz ◽  
Dirk Schübeler ◽  
Scott C. Goeke ◽  
Mark Walters ◽  
Mark Groudine ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Mammalian Cells ◽  
Fluorescent Protein ◽  
De Novo ◽  
Trichostatin A ◽  
Histone Deacetylation ◽  
Over Time

ABSTRACT Methylation of cytosines in the CpG dinucleotide is generally associated with transcriptional repression in mammalian cells, and recent findings implicate histone deacetylation in methylation-mediated repression. Analyses of histone acetylation in in vitro-methylated transfected plasmids support this model; however, little is known about the relationships among de novo DNA methylation, transcriptional repression, and histone acetylation state. To examine these relationships in vivo, we have developed a novel approach that permits the isolation and expansion of cells harboring expressing or silent retroviruses. MEL cells were infected with a Moloney murine leukemia virus encoding the green fluorescent protein (GFP), and single-copy, silent proviral clones were treated weekly with the histone deacetylase inhibitor trichostatin A or the DNA methylation inhibitor 5-azacytidine. Expression was monitored concurrently by flow cytometry, allowing for repeated phenotypic analysis over time, and proviral methylation was determined by Southern blotting and bisulfite methylation mapping. Shortly after infection, proviral expression was inducible and the reporter gene and proviral enhancer showed a low density of methylation. Over time, the efficacy of drug induction diminished, coincident with the accumulation of methyl-CpGs across the provirus. Bisulfite analysis of cells in which 5-azacytidine treatment induced GFP expression revealed measurable but incomplete demethylation of the provirus. Repression could be overcome in late-passage clones only by pretreatment with 5-azacytidine followed by trichostatin A, suggesting that partial demethylation reestablishes the trichostatin-inducible state. These experiments reveal the presence of a silencing mechanism which acts on densely methylated DNA and appears to function independently of histone deacetylase activity.

Biological roles and mechanistic actions of co-repressor complexes

2002 ◽  
Vol 115 (4) ◽  
pp. 689-698 ◽  
Author(s):  
Kristen Jepsen ◽  
Michael G. Rosenfeld
Keyword(s):  
Dna Binding ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Protein Complexes ◽  
Genetically Engineered ◽  
Repressor Proteins ◽  
Multiple Protein ◽  
Genetically Engineered Mice ◽  
Cell Signaling Pathways

Transcriptional repression, which plays a crucial role in diverse biological processes, is mediated in part by non-DNA-binding co-repressors. The closely related co-repressor proteins N-CoR and SMRT, although originally identified on the basis of their ability to associate with and confer transcriptional repression through nuclear receptors, have been shown to be recruited to many classes of transcription factor and are in fact components of multiple protein complexes containing histone deacetylase proteins. This association with histone deacetylase activity provides an important component of the mechanism that allows DNA-binding proteins interacting with N-CoR or SMRT to repress transcription of specific target genes. Both N-CoR and SMRT are important targets for cell signaling pathways, which influence their expression levels, subcellular localization and association with other proteins. Recently, the biological importance of these proteins has been revealed by studies of genetically engineered mice and human diseases such as acute promyelocytic leukemia (APL) and resistance to thyroid hormone(RTH).

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