Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model

Chen, Yi Chun; Gatchel, Jennifer R.; Lewis, Rebecca Williamson; Mao, Chai An; Grant, Patrick A.; Zoghbi, Huda Y.; Dent, Sharon Y.R.

doi:10.1093/hmg/ddr474

Cited by 53 publications

(51 citation statements)

References 52 publications

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“…The net effect in polyQ ATXN7-expressing cells is the persistence of H2B monoubiquitination at target promoters, which impedes transcriptional elongation and therefore gene expression. Our findings are consistent with recently published work by Chen et al (37) in which the authors were able to demonstrate that heterozygous KO of Gcn5 in SCA7 knock-in mice accelerated cerebellar degeneration and reduced lifespan. The significance of their report in the context of our findings is that studies provide evidence suggesting that SCA7 pathology does not appear to result solely from alterations to GCN5 HAT activity.…”

Section: Discussionsupporting

confidence: 94%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

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

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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.chromatin | SAGA complex | histone modification A s a member of the polyglutamine expansion disorder family, Spinocerebellar ataxia type 7 (SCA7) is an autosomaldominant hereditary disease characterized by cerebellar and retinal degeneration eventually leading to death (1). Although the ataxin-7 (ATXN7) protein is expressed throughout the body, pathology is localized primarily within the cerebellum and retina. Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2, 6, 7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2, 4). Of these, the model used by Custer et al. (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms. Astrocytes play a crucial role in the regulation of synaptic formation and function by ensheathing axon-dendrite connections to form a structure known as the tripartite synapse (9). This intimate interaction allows astrocytes to modulate synaptic function through the release of chemical messengers and the regulation of neurotransmitter and ion concentration within the synapse (9-11). The identification of tissue specificity factors and characterization of associated molecular mechanisms involved in their deregulation will facilitate a more comprehensive understanding of disease-associated events and advance efforts to develop effective treatments.The ATXN7 protein is an integral subunit of GCN5 (general control of amino acid synthesis-5; KAT2A)...

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Section: Discussionsupporting

confidence: 94%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

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

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“…Interestingly, loss of the Drosophila Ataxin-7 in the eye and adult brain results in neural degeneration (Mohan et al 2014). Similarly, mammalian Ataxin-7 plays a primary role in the neurodegenerative disease spinocerebellar ataxia type 7 (David et al 1997(David et al , 1998Del-Favero et al 1998;Johansson et al 1998), and some genes that are regulated by Ataxin-7 contribute to the pathology (Chen et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Seidel

Szerszen

et al. 2017

Genes Dev.

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The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex is a transcriptional coactivator that contains four different modules of subunits. The intact SAGA complex has been well characterized for its function in transcription regulation and development. However, little is known about the roles of individual modules within SAGA and whether they have any SAGA-independent functions. Here we demonstrate that the two enzymatic modules of Drosophila SAGA are differently required in oogenesis. Loss of the histone acetyltransferase (HAT) activity blocks oogenesis, while loss of the H2B deubiquitinase (DUB) activity does not. However, the DUB module regulates a subset of genes in early embryogenesis, and loss of the DUB subunits causes defects in embryogenesis. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that both the DUB and HAT modules bind most SAGA target genes even though many of these targets do not require the DUB module for expression. Furthermore, we found that the DUB module can bind to chromatin and regulate transcription independently of the HAT module. Our results suggest that the DUB module has functions within SAGA and independent functions.

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“…Gcn5 also plays HATindependent roles during development, and the complete loss of this protein leads to early embryonic lethality after gastrulation [57,58]. Gcn5, as a member of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, accelerates neural dysfunction characteristic of polyQ-Atxn7, which causes spinocerebellar ataxia type 7 [59]. At the transcriptional level, knocking out Gcn5 in NSCs leads to changes in gene expression in a pattern similar to the Myc knockout (KO).…”

Section: Hats During Neural Developmentmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model

Cited by 53 publications

References 52 publications

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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