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The Journal of Neuroscience, November 1, 2006, 26(44):11474-11486; doi:10.1523/JNEUROSCI.2053-06.2006
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Neurobiology of Disease
Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation
Bernd O. Evert,1 Julieta Araujo,1 Ana M. Vieira-Saecker,1 Rob A. I. de Vos,2 Sigrid Harendza,3 Thomas Klockgether,1 andUllrich Wüllner1 1Department of Neurology, University of Bonn, 53105 Bonn, Germany, 2Laboratorium Pathologie Oost Nederland, 7512 AD Enschede, The Netherlands, and 3Department of Nephrology, University of Hamburg, 20246 Hamburg, Germany
Correspondence should be addressed to Dr. Bernd Evert, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Email: b.evert{at}uni-bonn.de
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.
Key words: ataxin-3; polyglutamine; histone acetylation; HDAC3; NCoR; MMP-2
Received May 13, 2006; revised Aug. 27, 2006; accepted Sept. 21, 2006.
Correspondence should be addressed to Dr. Bernd Evert, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Email: b.evert{at}uni-bonn.de
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