Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

Chen‐Plotkin, Alice S.; Sadri‐Vakili, Ghazaleh; Yohrling, George J.; Braveman, Melissa W.; Benn, Caroline; Glajch, Kelly E.; DiRocco, Derek P.; Farrell, Laurie; Krainc, Dimitri; Ginés, Sílvia; MacDonald, Marcy E.; Jang, Jinhee

doi:10.1016/j.nbd.2005.11.001

Cited by 104 publications

(98 citation statements)

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“…Because only soluble mutant htt binds Sp1, shorter htt fragments may bind Sp1 and prevent Sp1 binding to promoter DNA before they form aggregates. It should be noted that Sp1 mediates the expression of a large number of genes and is reported to be up-regulated in some models of HD (13,41). It is known that Sp1 expression is induced by oxidative stress in neurons (42).…”

Section: Discussionmentioning

confidence: 99%

“…Mutant htt probably causes oxidative stress to increase Sp1 levels, which may also activate some genes that can trigger cellular pathological pathways under certain conditions. However, growing evidence has shown that mutant htt inhibits the binding of Sp1 to DNA promoters and suppresses the transcription of certain Sp1-mediated genes (12)(13)(14)(15). Our data further demonstrate that this inhibitory effect is context-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, mRNA levels are altered for specific genes in HD mouse and cell models as well as in post-mortem human HD brain (7-11). Mutant htt has a higher affinity than normal htt for certain transcription factors, such as Sp1 (12-15), and these aberrant interactions can functionally deactivate transcription factors by titrating them away from their normal DNA binding sites (12)(13)(14)(15)(16).Biochemical analysis of HD knock-in mice that express a 150-glutamine repeat in the endogenous mouse htt (17) revealed the presence of multiple N-terminal htt fragments smaller than the first 508 amino acids in the nucleus (18), consistent with the notion that cleavage of mutant htt is a key event in HD pathology (19,20). Because htt protein length can influence its cellular toxicity and ability to cause neurodegeneration in HD cellular models and transgenic mice (21, 22), it is important to know whether nuclear N-terminal htt fragments of different length can differentially affect gene transcription.…”

mentioning

confidence: 99%

“…In fact, mRNA levels are altered for specific genes in HD mouse and cell models as well as in post-mortem human HD brain (7)(8)(9)(10)(11). Mutant htt has a higher affinity than normal htt for certain transcription factors, such as Sp1 (12)(13)(14)(15), and these aberrant interactions can functionally deactivate transcription factors by titrating them away from their normal DNA binding sites (12)(13)(14)(15)(16).…”

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confidence: 99%

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Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Cornett

Smith

Friedman

et al. 2006

Journal of Biological Chemistry

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Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments. Huntington disease (HD)3 is an autosomal dominant neurodegenerative disorder resulting from expansion (Ͼ37 repeats) of a polyglutamine (poly(Q)) repeat in the N-terminal region of huntingtin (htt), a 350-kDa protein of unknown function. Proteolytic cleavage of full-length htt, which is predominantly cytoplasmic, generates N-terminal htt fragments that accumulate abnormally and form inclusions over time in neuronal nuclei (1). The nucleus is thought to be a primary site of poly(Q) toxicity, as blocking the nuclear entry of htt suppresses its ability to cause cell death (2), whereas targeting htt to the nucleus by the addition of a nuclear localization signal (NLS) causes a more severe phenotype (3-5).In the nucleus, mutant htt abnormally interacts with a number of transcription factors (6). Accordingly, the nuclear pathology observed in HD is thought to be largely due to transcriptional dysregulation (7,8). In fact, mRNA levels are altered for specific genes in HD mouse and cell models as well as in post-mortem human HD brain (7-11). Mutant htt has a higher affinity than normal htt for certain transcription factors, such as Sp1 (12-15), and these aberrant interactions can functionally deactivate transcription factors by titrating them away from their normal DNA binding sites (12)(13)(14)(15)(16).Biochemical analysis of HD knock-in mice that express a 150-glutamine repeat in the endogenous mouse htt (17) revealed the presence of multiple N-terminal htt fragments smaller than the first 508 amino acids in the nucleus (18), consistent with the notion that cleavage of mutant htt is a key event in HD pathology (19,20). Because htt protein length can influence its cellular toxicity and ability to cause neurodegeneration in HD cellular models and transgenic mice (21, 22), it is important to know whether nuclear N-terminal htt fragments of different length can differentially affect gene transcription. Und...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Cornett

Smith

Friedman

et al. 2006

Journal of Biological Chemistry

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“…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). Overall, there is much evidence that mutant htt disrupts transcriptional regulation; consequential of this concept are gene profiling studies that have revealed dramatic expression alterations of genes, especially those exhibiting enriched expression in the striatum, in the brains of HD mouse models and human subjects with HD (Luthi-Carter et al, 2000;Zucker et al, 2005;Desplats et al, 2006;Hodges et al, 2006;Thomas 2006).…”

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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Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

Rangel‐Barajas

Rebec

2018

CP Neuroscience

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Transgenic mouse models of Huntington's disease (HD), a neurodegenerative condition caused by a single gene mutation, have been transformative in their ability to reveal the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Three model categories have been generated depending on the genetic context in which the mutation is expressed: truncated, full-length, and knock-in. No single model, however, broadly replicates the behavioral symptoms and massive neuronal loss that occur in human patients. The disparity between model and patient requires careful consideration of what each model has to offer when testing potential treatments. Although the translation of animal data to the clinic has been limited, each model can make unique contributions toward an improved understanding of the neurobehavioral underpinnings of HD. Thus, conclusions based on data obtained from more than one model are likely to have the most success in the search for new treatment targets. © 2018 by John Wiley & Sons, Inc.

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Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

Cited by 104 publications

References 31 publications

Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Context-dependent Dysregulation of Transcription by Mutant Huntingtin

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

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

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