Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation

Abstract

Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with the ubiquitin-proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 (MMP-2) gene promoter and represses transcription by recruitment of the histone deacetylase 3 (HDAC3), the nuclear receptor corepressor (NCoR), and deacetylation of histones bound to the promoter. Both normal and expanded AT3 physiologically interacted with HDAC3 and NCoR in a SCA3 cell model and human pons tissue; however, normal AT3-containing protein complexes showed increased histone deacetylase activity, whereas expanded AT3-containing complexes had reduced deacetylase activity. Consistently, histone analyses revealed an increased acetylation of total histone H3 in expanded AT3-expressing cells and human SCA3 pons. Expanded AT3 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of HDAC3, NCoR, and deacetylation of the promoter, allowing aberrant MMP-2 transcription via the transcription factor GATA-2. For transcriptional repression normal AT3 cooperates with HDAC3 and requires its intact ubiquitin-interacting motifs (UIMs), whereas aberrant transcriptional activation by expanded AT3 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain. These findings demonstrate that normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function. Expanded AT3 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…The polyQ tract has no effect on the deubiquitinating function of ataxin-3 [95], so it may be concluded that neuropathology in SCA3 is mainly due to a gain of toxic function mediated by the expanded polyQ tract. Normal ataxin-3 binds to target DNA sequences in the promoter of the matrix metalloproteinase-2 gene and represses transcription by recruitment of histone deacetylase 3, the nuclear receptor corepressor, and deacetylation of histones bound to the promoter [96]. In transfected mouse neuroblastoma N2a and human embryonic kidney 293T cells, the aggregation of polyQ-expanded ataxin-3 could be blocked by the suppression of the Ca 2+ -dependent protease calpain [97].…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…Histone deacetylase 3 (HDAC3) plays an important role in transcriptional repression of various genes (Evert et al, 2006;Jayne et al, 2006;Villagra et al, 2007). P300, in cooperation with HDAC3, represses c-myc expression (Sankar et al, 2007).…”

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…Due to the sequestration of ataxin-3 and other factors into nuclear aggregates, a secondary effect of transcriptional deregulation is thought to occur [152,153]. Additionally, Evert et al showed that mutant ataxin-3 had impaired transcriptional repression through its ability to inhibit histone acetylase activity [154].…”

“…Transcriptional dysregulation has been widely implicated in a number of the SCA and polyQ diseases [153,154,192,193]. It stands to reason that a SCA disease in which the causative protein is a wellknown transcription factor would have associated transcriptional dysregulation.…”