Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease

Dunah, Anthone W.; Jeong, Hyeong-Chai; Griffin, April M.; Kim, Yong Man; Standaert, David G.; Hersch, Steven M.; Mouradian, M. Maral; Young, Anne B.; Tanese, Naoko; Krainc, Dimitri

doi:10.1126/science.1072613

Cited by 638 publications

(514 citation statements)

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“…Consistent with prior research, we have provided direct evidence that mutant Htt-552 in glial cells reduced the expression of GLT-1 but not of GLAST and decreased glutamate uptake in astrocytes, which was mainly caused by decreased expression of GLT-1. Because there are Sp1-binding sites in the promoter of GLT-1 and the transcription of GLT-1 is Sp1-dependent [24,25] , previous reports of mutant Htt binding more Sp1 and reducing Sp1-mediated GLT-1 expression in astrocytes may explain this www.chinaphar.com Chen LL et al Acta Pharmacologica Sinica npg phenomenon [10] .…”

Section: Recovery Of Glt-1 Expression and Function By Rapamycinmentioning

confidence: 99%

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Chen

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the effects of rapamycin on glutamate uptake in cultured rat astrocytes expressing N-terminal 552 residues of mutant huntingtin (Htt-552). Methods: Primary astrocyte cultures were prepared from the cortex of postnatal rat pups. An astrocytes model of Huntington's disease was established using the astrocytes infected with adenovirus carrying coden gene of N-terminal 552 residues of Huntingtin. The protein levels of glutamate transporters GLT-1 and GLAST, the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the autophagy substrate p62 in the astrocytes were examined using Western blotting. The mRNA expression levels of GLT-1 and GLAST in the astrocytes were determined using Real-time PCR. [ 3 H]glutamate uptake by the astrocytes was measured with liquid scintillation counting. Results: The expression of mutant Htt-552 in the astrocytes significantly decreased both the mRNA and protein levels of GLT-1 but not those of GLAST. Furthermore, Htt-552 significantly reduced [ 3 H]glutamate uptake by the astrocytes. Treatment with the autophagy inhibitor 3-MA (10 mmol/L) significantly increased the accumulation of mutant Htt-552, and reduced the expression of GLT-1 and [ 3 H]glutamate uptake in the astrocytes. Treatment with the autophagy stimulator rapamycin (0.2 mg/mL) significantly reduced the accumulation of mutant Htt-552, and reversed the changes in GLT-1 expression and [ 3 H]glutamate uptake in the astrocytes. Conclusion: Rapamcin, an autophagy stimulator, can prevent the suppression of GLT-1 expression and glutamate uptake by mutant Htt-552 in cultured astrocytes.

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Section: Recovery Of Glt-1 Expression and Function By Rapamycinmentioning

confidence: 99%

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Chen

Wang

et al. 2012

Acta Pharmacol Sin

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“…Scanning the putative promoter regions of these 100 genes for other transcription factors revealed the presence of many sites for known transcription factors, including consensus binding sites for the ubiquitous transcription factors, COUP-TF, which has been shown to interact with Bcl11b (Lin et al, 1999), Sp1, TBP and CREB. Transcriptional control by the latter factors is disrupted by the presence of mutant htt protein, with Sp1 and CBP specifically interacting with htt protein (McCampbell et al 2000;Steffan et al, 2000;Dunah et al 2002;Li et al 2002). Nonetheless, binding sites for these and other transcription factors were equally represented in striatal and non-striatal gene groups (p values ranging from 0.16 to 1.0) ( Table 2), suggesting that these transcription factors have less of a contribution to the specific control of striatal gene expression.…”

Section: Bcl11b Binding Sites Are Overrepresented In Proximal Promotementioning

confidence: 99%

“…Studies have shown that mutant htt interacts with ubiquitous transcription factors such as the cAMP response element-binding protein-(CREB)-binding protein (CBP), Specificity protein 1 (Sp1), TATA binding box protein (TBP) and widely expressed components of the basal polymerase II transcriptional machinery such as the transcription initiation factor complexes TFIID and TFIIF, and the TATA box binding protein (TBP)-associated factor (TAF4; a.k.a. TAFII130) (McCampbell et al, 2000;Shimohata et al, 2000;Dunah et al, 2002;Li et al, 2002;van Roon-Mom et al, 2002;Zhai et al, 2005). However, other mechanisms of transcription factor disruption due to mutant htt have been proposed (Chen-Plotkin et al, 2006;Sadri-Vakili et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Desplats

Lambert

Thomas

2008

Neurobiology of Disease

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Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease.

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“…Polyglutamine [poly(Q)] expansions of mutant Htt (mtHtt) protein lead to a number of cellular abnormalities that include altered nucleosome dynamics and subsequent transcriptional dysregulation (1)(2)(3)(4). Consistent with transcriptional repression playing a role in the pathogenesis of HD, decreased acetylation and increased methylation of histones, well established mechanisms of gene activation and silencing, have been found in HD experimental models (5)(6)(7)(8).…”

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confidence: 99%

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Ryu

Lee

Hagerty

et al. 2006

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

284

252

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Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients. H untington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded stretches of CAG repeats coding for glutamine in the Huntingtin (Htt) gene. Polyglutamine [poly(Q)] expansions of mutant Htt (mtHtt) protein lead to a number of cellular abnormalities that include altered nucleosome dynamics and subsequent transcriptional dysregulation (1-4). Consistent with transcriptional repression playing a role in the pathogenesis of HD, decreased acetylation and increased methylation of histones, well established mechanisms of gene activation and silencing, have been found in HD experimental models (5-8). Histone acetylation is involved in the regulation of gene expression and is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) (9). The poly(Q) stretches in mtHtt interact physically with CREB binding protein (CBP), a transcriptional coactivator, and block intrinsic CBP histone acetyltransferase activity (2, 5). These specific interactions have led to a model in which mtHtt, by harboring extra glutamines, becomes a hyperactive glutamine-containing corepressor (10). Transcriptional repression may also be attributable to epigenetic modifications, such as histone methylation and histone deacetylation (11). Thus, transcriptional dysfunction has been proposed to play an important role in the neuronal cell death of HD and has be...

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Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease

Cited by 638 publications

References 35 publications

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

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