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).

scholarly journals Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells

2005 ◽  
Vol 393 (1) ◽  
pp. 397-409 ◽  
Author(s):  
Steven O. Simmons ◽  
Jonathan M. Horowitz
Keyword(s):  
Dna Binding ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Protein Complexes ◽  
Trichostatin A ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Family Members ◽  
Early Event ◽  
Prostate Tumorigenesis

Nkx3.1 is a homeodomain-containing transcription factor that is expressed early in the development of the prostate gland and is believed to play an important role in the differentiation of prostatic epithelia. Loss of Nkx3.1 protein expression is often an early event in prostate tumorigenesis, and the abundance of Nkx3.1-negative epithelial cells increases with disease progression. In a number of systems, homeodomain proteins collaborate with zinc-finger-containing transcription factors to bind and regulate target genes. In the present paper, we report that Nkx3.1 collaborates with Sp-family members in the regulation of PSA (prostate-specific antigen) in prostate-derived cells. Nkx3.1 forms protein complexes with Sp proteins that are dependent on their respective DNA-binding domains and an N-terminal segment of Nkx3.1, and Nkx3.1 negatively regulates Sp-mediated transcription via Trichostatin A-sensitive and -insensitive mechanisms. A distal 1000 bp portion of the PSA promoter is required for transrepression by Nkx3.1, although Nkx3.1 DNA-binding activity is itself not required. We conclude that Nkx3.1 negatively regulates Sp-mediated transcription via the tethering of histone deacetylases and/or by inhibiting the association of Sp proteins with co-activators.

scholarly journals Differential Contributions of DNA-Binding Proteins to Polycomb Response Element Activity at the Drosophila giant Gene

Genetics ◽  
2020 ◽  
Vol 214 (3) ◽  
pp. 623-634
Author(s):  
Elnaz Ghotbi ◽  
Kristina Lackey ◽  
Vicki Wong ◽  
Katie T. Thompson ◽  
Evan G. Caston ◽  
...  
Keyword(s):  
Dna Binding ◽  
Dna Sequences ◽  
Transcriptional Repression ◽  
Binding Proteins ◽  
Target Genes ◽  
Dna Binding Proteins ◽  
Polycomb Group ◽  
Link Type ◽  
Element Activity

Polycomb-group (PcG) proteins are evolutionarily conserved epigenetic regulators whose primary function is to maintain the transcriptional repression of target genes. Recruitment of Drosophila melanogaster PcG proteins to target genes requires the presence of one or more Polycomb Response Elements (PREs). The functions or necessity for more than one PRE at a gene are not clear and individual PREs at some loci may have distinct regulatory roles. Various combinations of sequence-specific DNA-binding proteins are present at a given PRE, but only Pleiohomeotic (Pho) is present at all strong PREs. The giant (gt) locus has two PREs, a proximal PRE1 and a distal PRE2. During early embryonic development, Pho binds to PRE1 ∼30-min prior to stable binding to PRE2. This observation indicated a possible dependence of PRE2 on PRE1 for PcG recruitment; however, we find here that PRE2 recruits PcG proteins and maintains transcriptional repression independently of Pho binding to PRE1. Pho-like (Phol) is partially redundant with Pho during larval development and binds to the same DNA sequences in vitro. Although binding of Pho to PRE1 is dependent on the presence of consensus Pho-Phol-binding sites, Phol binding is less so and appears to play a minimal role in recruiting other PcG proteins to gt. Another PRE-binding protein, Sp1/Kruppel-like factor, is dependent on the presence of Pho for PRE1 binding. Further, we show that, in addition to silencing gene expression, PcG proteins dampen transcription of an active gene.

Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 359-359
Author(s):  
Fabien Guidez ◽  
Louise Howell ◽  
Mark Isalan ◽  
Marek Cebrat ◽  
Rhoda M. Alani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Binding ◽  
Histone Deacetylase ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Hematopoietic Stem

Abstract The Promyelocytic Leukemia Zinc Finger (PLZF) gene was identified in a rare case of acute promyelocytic leukemia (APL) with translocation t(11;17)(q23;q21) and resistance to therapy with all-trans-retinoic acid. Recent studies have indicated a critical role of PLZF in maintenance of spermatogonial stem cells. Prominent expression of PLZF in hematopoietic stem cells, suggest that it may also play a similar role in this compartment. The wild type PLZF protein is a DNA sequence-specific transcription repressor containing nine Krüppel-like C2-H2 zinc fingers and an N-terminal BTB/POZ repression domain. Transcriptional repression by PLZF is mediated through recruitment of the nuclear receptor co-repressor (N-CoR/SMRT)/histone deacetylase (HDAC) complexes to its target genes, such as c-MYC and HOX genes. We now show that transcriptional repression by PLZF is surprisingly also dependent on the histone acetyl transferase (HAT) activity of the p300 protein. PLZF associates with p300 in vivo and its ability to repress transcription is specifically dependent on acetylation of PLZF on lysines in its C-terminal C2-H2 zinc-finger motifs. Acetylation of PLZF enhances its ability to bind its cognate DNA binding site in vitro as determined by EMSA and in vivo as measured by chromatin immunoprecipitation. An acetylation site mutant of PLZF fails to repress transcription despite retaining its abilities to interact with co-repressor/HDAC complexes, due to inefficient DNA binding. Inhibitors of p300 abolish transcriptional repression by PLZF and mutants of PLZF that mimic acetylation were insensitive to these inhibitory effects. Acetylation of PLZF by p300 was specific since over-expression of another HAT, p/CAF or the selective inhibition of p/CAF had no effect on PLZF activity despite the ability of the proteins to associate with each other. Taken together, our results indicate that a histone deacetylase dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a co-activator protein in transcriptional repression.

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 mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

2003 ◽  
Vol 23 (21) ◽  
pp. 7475-7487 ◽  
Author(s):  
Sharmistha Pal ◽  
Romy Yun ◽  
Antara Datta ◽  
Lynne Lacomis ◽  
Hediye Erdjument-Bromage ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Carbamoyl Phosphate ◽  
Histone Deacetylase 2 ◽  
Protein Protein Interaction ◽  
Corepressor Complex ◽  
Expression Of Genes ◽  
In Cells

ABSTRACT The role of hSWI/SNF complexes in transcriptional activation is well characterized; however, little is known about their function in transcriptional repression. We have previously shown that subunits of the mSin3A/histone deacetylase 2 (HDAC2) corepressor complex copurify with hSWI/SNF complexes. Here we show that the type II arginine-specific methyltransferase PRMT5, which is involved in cyclin E repression, can be found in association with Brg1 and hBrm-based hSWI/SNF complexes. We also show that hSWI/SNF-associated PRMT5 can methylate hypoacetylated histones H3 and H4 more efficiently than hyperacetylated histones H3 and H4. Protein-protein interaction studies indicate that PRMT5 and mSin3A interact with the same hSWI/SNF subunits as those targeted by c-Myc. These observations prompted us to examine the expression profile of the c-Myc target genes, carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) and nucleolin (nuc). We found that cad repression is altered in cells that express inactive Brg1 and in cells treated with the HDAC inhibitor depsipeptide. Using chromatin immunoprecipitation assays, we found that Brg1, mSin3A, HDAC2, and PRMT5 are directly recruited to the cad promoter. These results suggest that hSWI/SNF complexes, through their ability to interact with activator and repressor proteins, control expression of genes involved in cell growth and proliferation.

scholarly journals An Engineered PAX3-KRAB Transcriptional Repressor Inhibits the Malignant Phenotype of Alveolar Rhabdomyosarcoma Cells Harboring the Endogenous PAX3-FKHR Oncogene

2000 ◽  
Vol 20 (14) ◽  
pp. 5019-5031 ◽  
Author(s):  
William J. Fredericks ◽  
Kasirajan Ayyanathan ◽  
Meenhard Herlyn ◽  
Josh R. Friedman ◽  
Frank J. Rauscher
Keyword(s):  
Dna Binding ◽  
Dna Sequences ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Binding Domain ◽  
Stable Expression ◽  
Alveolar Rhabdomyosarcoma ◽  
Dna Binding Domain ◽  
Malignant Phenotype ◽  
Activation Domain

ABSTRACT The t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma tumors (ARMS) creates an oncogenic transcriptional activator by fusion of PAX3 DNA binding motifs to a COOH-terminal activation domain derived from the FKHR gene. The dominant oncogenic potential of the PAX3-FKHR fusion protein is dependent on the FKHR activation domain. We have fused the KRAB repression module to the PAX3 DNA binding domain as a strategy to suppress the activity of the PAX3-FKHR oncogene. The PAX3-KRAB protein bound PAX3 target DNA sequences and repressed PAX3-dependent reporter plasmids. Stable expression of the PAX3-KRAB protein in ARMS cell lines resulted in loss of the ability of the cells to grow in low-serum or soft agar and to form tumors in SCID mice. Stable expression of a PAX3-KRAB mutant, which lacks repression function, or a KRAB protein alone, lacking a PAX3 DNA binding domain, failed to suppress the ARMS malignant phenotype. These data suggest that the PAX3-KRAB repressor functions as a DNA-binding-dependent suppressor of the transformed phenotype of ARMS cells, probably via competition with the endogenous PAX3-FKHR oncogene and repression of target genes required for ARMS tumorigenesis. The engineered repressor approach that directs a transcriptional repression domain to target genes deregulated by the PAX3-FKHR oncogene may be a useful strategy to identify the target genes critical for ARMS tumorigenesis.

scholarly journals Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein

2005 ◽  
Vol 25 (13) ◽  
pp. 5552-5566 ◽  
Author(s):  
Fabien Guidez ◽  
Louise Howell ◽  
Mark Isalan ◽  
Marek Cebrat ◽  
Rhoda M. Alani ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Dna Binding ◽  
Histone Deacetylase ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Acetyltransferase ◽  
Transcriptional Repressor ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger

ABSTRACT Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-containing corepressor complexes to specific DNA binding sites. PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.

scholarly journals Association of the mSin3A-Histone Deacetylase 1/2 Corepressor Complex with the Mouse Steroidogenic Acute Regulatory Protein Gene

2006 ◽  
Vol 20 (1) ◽  
pp. 100-113 ◽  
Author(s):  
Brian F. Clem ◽  
Barbara J. Clark
Keyword(s):  
Dna Binding ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Binding Proteins ◽  
Regulatory Protein ◽  
Regulatory Region ◽  
Steroidogenic Acute Regulatory Protein ◽  
Corepressor Complex ◽  
Promoter Deletion Analysis ◽  
Steroidogenic Acute Regulatory

Abstract Several factors have been identified in the transcriptional repression of the steroidogenic acute regulatory protein (StAR) gene promoter; yet, no associating corepressor complexes have been characterized for the mouse promoter in MA-10 mouse Leydig tumor cells. We now report that Sp3, CAGA element binding proteins, and a corepressor complex consisting of mSin3A, histone deacetylase (HDAC)1, and HDAC2 associates with a transcriptional repressor region within the mouse StAR promoter. 5′-Promoter deletion analysis localized the negative regulatory region between −180 and −150 bp upstream of the transcription start site, and mutations in both the CAGA and Sp binding elements were required to relieve the repression of basal StAR promoter activity. Protein-DNA binding analysis revealed Sp3 and specific CAGA element-binding protein(s) associated with the repressor region. Coimmunoprecipitation analysis identified the presence of the mSin3A, HDAC1, and HDAC2 corepressor complex in MA-10 cells. Furthermore, chromatin immunoprecipitation assays revealed Sp3, mSin3A, and HDAC1/2 association with the proximal region of the StAR promoter in situ. In addition, HDAC inhibition resulted in a dose-dependent activation of a mouse StAR reporter construct, whereas mutations within the repressor region diminished this effect by 44%. In sum, these data support a novel regulatory mechanism for transcriptional repression of the mouse StAR promoter by DNA binding of Sp3 and CAGA element-binding proteins, and association of the Sin3 corepressor complex exhibiting HDAC activity.

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