Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases

Sharma, Saurabh; Taliyan, Rajeev

doi:10.1016/j.phrs.2015.08.002

Cited by 44 publications

(29 citation statements)

References 140 publications

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“…It is reasonable to deduce that impaired Tra1‐regulated transcription has an important role in the toxic phenotype observed in HD models. Indeed, reduced histone acetylation is closely associated with HD and histone deacetylase inhibitors improve the HD phenotype in animal models . Thus, further analysis of the role of the major regulators of chromatin remodeling, gene expression and their specific targets may provide avenues for modulating the toxicity of polyQ expansion in HD.…”

Section: Discussionmentioning

confidence: 99%

“…It is now clear that multiple signaling pathways act in parallel to regulate gene expression during misfolded protein stress. Acetyltransferase complexes regulate chromatin remodeling, a process affected in HD . The SAGA (Spt‐Ada‐Gcn5‐Acetyltransferase) and NuA4 (Nucleosome Acetyltransferase of H4) complexes were first identified in yeast as containing the lysine acetyltransferases Gcn5 and Esa1, respectively .…”

Section: Introductionmentioning

confidence: 99%

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Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Jiang

Berg

Genereaux

et al. 2019

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Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington's disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co‐activator complexes and is linked to multiple cellular processes, including protein trafficking and signaling pathways associated with misfolded protein stress. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1 and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of TRA1 expression, linking TORC1 and cell growth regulation to the SAGA acetyltransferase complex during misfolded protein stress.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Jiang

Berg

Genereaux

et al. 2019

Traffic

View full text Add to dashboard Cite

show abstract

“…It is reasonable to think that impaired Tra1-regulated transcription has an important role in the toxic phenotype observed in HD models. Indeed, reduced histone acetylation is closely associated with HD and histone deacetylase inhibitors improve the HD phenotype in animal models 23,24,26,27,91,92 . Thus, better characterization of the role of the major regulators of chromatin remodeling and gene expression and their targets provides insight into how modulating acetylation in HD can be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

Jiang

Berg

Genereaux

et al. 2018

Preprint

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Proteotoxic stress triggers transcriptional responses that allow cells to compensate for the accumulation of toxic misfolded proteins. Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington’s disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes associated with misfolded protein stress, including the heat shock response. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model of HD to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins, mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins also upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 specifically abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of Tra1, linking TORC1 and cell growth regulation to functions of the SAGA acetyltransferase complex during misfolded protein stress.

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“…Mutant mRNA is partially or temporarily retained in the nucleus within splicing speckles, as shown in multiple types of cellular models of polyQ diseases (De Mezer et al, 2011; Urbanek et al, 2016). Increased retention of mutant RNA in the nucleus is associated with compromised functions of proteins that bind to mutant RNA (Jazurek et al, 2016); examples of such malfunctions are alternative splicing abnormalities (Mykowska et al, 2011; Sathasivam et al, 2013; Cabrera and Lucas, 2016) and other gene expression alterations (Sharma and Taliyan, 2015). For that reason, RNA foci are increasingly considered undesired toxic structures, rather than a protective cellular self-defense mechanism.…”

Section: Introductionmentioning

confidence: 99%

Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

Urbanek

Fiszer

Krzyżosiak

2017

Front. Cell. Neurosci.

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In several human polyglutamine diseases caused by expansions of CAG repeats in the coding sequence of single genes, mutant transcripts are detained in nuclear RNA foci. In polyglutamine disorders, unlike other repeat-associated diseases, both RNA and proteins exert pathogenic effects; therefore, decreases of both RNA and protein toxicity need to be addressed in proposed treatments. A variety of oligonucleotide-based therapeutic approaches have been developed for polyglutamine diseases, but concomitant assays for RNA foci reduction are lacking. Here, we show that various types of oligonucleotide-based reagents affect RNA foci number in Huntington’s disease cells. We analyzed the effects of reagents targeting either CAG repeat tracts or specific HTT sequences in fibroblasts derived from patients. We tested reagents that either acted as translation blockers or triggered mRNA degradation via the RNA interference pathway or RNase H activation. We also analyzed the effect of chemical modifications of CAG repeat-targeting siRNAs on their efficiency in the foci decline. Our results suggest that the decrease of RNA foci number may be considered as a readout of treatment outcomes for oligonucleotide reagents.

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Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases

Cited by 44 publications

References 140 publications

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

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