Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction

Dominique Helmlinger,Huda Y Zoghbi,Yvon Trottier,Aaron B Bowman,Didier Devys,Serge Picaud,Adrien Eberlin,Anne Gansmüller,Sara Hardy,Làszlò Tora,Gretta Abou-Sleymane

doi:10.1371/journal.pbio.0040067

Abstract

Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.

Highlights

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by expansion of an unstable CAG trinucleotide repeat encoding a polyglutamine stretch [1,2]
We recently demonstrated that ataxin-7 (ATXN7), the protein mutated in SCA7, is a bona fide subunit of TFTC, the TATA-binding protein (TBP)-free TBP-associated factor (TAF)-containing complex, and STAGA, the SPT3/TAF9/ GCN5 acetyltransferase complex [5]
Taking advantage of the mosaic progression of the R7E retinal phenotype, we showed that Rho down-regulation and rod dysfunction were completely correlated with chromatin decondensation

Summary

Introduction

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by expansion of an unstable CAG trinucleotide repeat encoding a polyglutamine (polyQ) stretch [1,2]. The expansion of a translated CAG repeat causes eight other progressive neurodegenerative diseases, including Huntington disease [3]. Aggregation of expanded polyQ-containing proteins in the nucleus is a hallmark of these diseases. Despite these common properties, polyQ diseases show distinctive features, which may reflect the unique protein context of the polyQ expansion in each disease. SCA7 can be distinguished from other polyQ diseases, as it is the only one affecting the retina leading to visual impairment and eventually to blindness [4]

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Results

Conclusion