Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20226 (TATA-binding protein)
 1,297 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear thyroid hormone receptors (TRs) act as ligand-dependent activators, but paradoxically unliganded TRs can increase transcription of promoters containing negative response elements (nTRE), and hormone binding represses this activation. The rat growth hormone (GH) promoter contains a positive TRE and a nTRE. Ligand-dependent negative regulation mediated by the nTRE could play an important physiological role in restricting GH gene expression in non-pituitary cells that express TRs. With chromatin immunoprecipitation assays, we show here that the nTRE is responsible for binding of TR to the promoter in non-pituitary HeLa cells and that this element also governs transactivation by the unoccupied receptor and repression by triiodothyronine. Occupancy of the promoter by TR is concomitant with appearance of acetylated histone H3, and triiodothyronine causes release of the receptor as well as disappearance of the acetylated histone from the promoter. Although the nTRE overlaps the TATA box, the receptor does not exclude binding of TATA-binding protein, but could rather facilitate formation of the preinitiation complex. Furthermore, the proximal GH promoter is synergistically stimulated by unliganded TR and TATA-binding protein, whereas the ligand represses this cooperation. Constitutive receptor activity and synergism with TATA-binding protein require binding of corepressors. Furthermore, inhibitors of histone deacetylases enhance promoter activation by the unliganded receptor and reduce triiodothyronine-dependent repression, whereas expression of HDAC1 reverses promoter stimulation. This suggests that partitioning of histone acetylases and deacetylases between the receptors and basal transcription factors could be involved in regulation of the basal GH promoter by TRs.
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PMID:Binding of the thyroid hormone receptor to a negative element in the basal growth hormone promoter is associated with histone acetylation. 1287 87

We performed chromatin immunoprecipitation (ChIP) analyses of developmentally staged solid tissues isolated from wild-type and p53-null mice to determine specific histone N-terminal modifications, histone-modifying proteins, and transcription factor interactions at the developmental repressor region (-850) and core promoter of the hepatic tumor marker alpha-fetoprotein (AFP) gene. Both repression of AFP during liver development and silencing in the brain, where AFP is never expressed, are associated with dimethylation of histone H3 lysine 9 (DiMetH3K9) and the presence of heterochromatin protein 1 (HP1). These heterochromatic markers remain localized to AFP during developmental repression but spread to the upstream albumin gene during silencing. Developmentally regulated decreases in levels of acetylated H3 (AcH3K9) and H4 (AcH4) and of di- and trimethylated H3K4 (DiMetH3K4 and TriMetH3K4) occur at both the core promoter and distal repressor regions of AFP. Hepatic expression of AFP correlates with FoxA interaction at the repressor region and the binding of RNA polymerase II and TATA-binding protein to the core promoter. p53 acts as a developmental repressor of AFP in the liver by binding to chromatin, excluding FoxA interaction and targeting mSin3A/HDAC1 to the distal repressor region. p53-null mice exhibit developmentally delayed AFP repression, concomitant with acetylation of H3K9, methylation of H3K4, and loss of DiMetH3K9, mSin3A/HDAC1, and HP1 interactions.
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PMID:Transcription factor interactions and chromatin modifications associated with p53-mediated, developmental repression of the alpha-fetoprotein gene. 1574 13

We previously showed that ZNF76 is a general transcription repressor targeting TATA-binding protein (TBP), through a process regulated by sumoylation [G. Zheng, Y.C. Yang, ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation, J. Biol. Chem. 279 (2004) 42410-42421]. In this study, two additional regulatory mechanisms for ZNF76 were identified. ZNF76 is acetylated by p300 and deacetylated by HDAC1, and acetylation of ZNF76 leads to its loss of sumoylation and attenuation of TBP interaction. Consistent with their physical antagonism, acetylation, and sumoylation play opposite roles in regulating the transactivation of ZNF76. Besides acetylation and sumoylation, ZNF76 is also regulated through mRNA splicing: two isoforms of ZNF76 have different abilities of interacting with TBP. Our study shows that ZNF76, a TBP-interacting transcriptional modulator, is regulated by both lysine modifications and alternative splicing.
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PMID:Acetylation and alternative splicing regulate ZNF76-mediated transcription. 1633 45

Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase (HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immunoprecipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.
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PMID:Transcriptional repression of human immunodeficiency virus type 1 by AP-4. 1654 Apr 71

The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) and hexamethylene bisacetamide (HMBA), which lacks HDAC inhibitory activity, both possess the capacity to induce leukemia cell differentiation and to enhance the expression of a wide range of transiently transfected reporter genes in 3T3 Swiss cells. In addition, known inducers of leukemia cell differentiation, including hypoxanthine, diazepam, 6-thioguanine and phorbol 12-myristate 13-acetate, also exhibited the ability to enhance reporter gene expression, while randomly chosen compounds that did not induce leukemia cell differentiation did not enhance reporter gene expression. The activity of TSA in the transfection system was modified by co-expression of histone acetyltransferase p300 and HDAC1; whereas, that of HMBA was enhanced by co-expression of the TATA-binding protein TBP. The stimulatory effects of diverse chemical inducers on transiently transfected genes suggest the existence of multiple exploitable targets for the selection of novel inducers of differentiation that function as modulators of gene activity.
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PMID:Relationship between the induction of leukemia cell differentiation and the enhancement of reporter gene expression in 3T3 Swiss cells. 1762 56

Histone acetyltransferases and histone deacetylases (HDACs) are important epigenetic coregulators. It has been thought that HDACs associate with corepressor complexes and repress gene transcription; however, in this study, we have found that PU.1-a key master regulator for hematopoietic self-renewal and lineage specification-requires HDAC activity for gene activation. Deregulated PU.1 gene expression is linked to dysregulated hematopoiesis and the development of leukemia. In this study, we used erythroid differentiation as a model to analyze how the PU.1 gene is regulated. We found that active HDAC1 is directly recruited to active PU.1 promoter in progenitor cells, whereas acetylated HDAC1, which is inactive, is on the silenced PU.1 promoter in differentiated erythroid cells. We then studied the mechanism of HDAC1-mediated activation. We discovered that HDAC1 activates PU.1 gene transcription via deacetylation of TATA-binding protein-associated factor 9 (TAF9), a component in the transcription factor IID (TFIID) complex. Treatment with HDAC inhibitor results in an increase in TAF9 acetylation. Acetylated TAF9 does not bind to the PU.1 gene promoter and subsequently leads to the disassociation of the TFIID complex and transcription repression. Thus, these results demonstrate a key role for HDAC1 in PU.1 gene transcription and, more importantly, uncover a novel mechanism of TFIID recruitment and gene activation.-Jian, W., Yan, B., Huang, S., Qiu, Y. Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly.
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PMID:Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. 2857 46