Journal Article

The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates <i>SCA2</i> gene transcription through direct interaction with its gene product, ataxin-2

Linda Hallen, Holger Klein, Carola Stoschek, Silke Wehrmeyer, Ute Nonhoff, Markus Ralser, Jeannine Wilde, Christina Röhr, Michal R. Schweiger, Kurt Zatloukal, Martin Vingron, Hans Lehrach, Zoltán Konthur and Sylvia Krobitsch

in Human Molecular Genetics

Volume 20, issue 1, pages 104-114
Published in print January 2011 | ISSN: 0964-6906
Published online October 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq436
The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates SCA2 gene transcription through direct interaction with its gene product, ataxin-2

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Gene transcription is controlled by transcriptional regulators acting with specific co-regulators to allow gene activation and repression. Here, we report the identification of the KRAB-containing zinc-finger transcriptional regulator, ZBRK1, as an interaction partner of the SCA2 gene product ataxin-2. Furthermore, we discovered that an elevated ZBRK1 level resulted in increased ataxin-2 levels, whereas interference on transcriptional and protein levels of ZBRK1 yielded reduced ataxin-2 levels, suggesting that a complex comprising ZBRK1 and ataxin-2 regulates SCA2 gene transcription. A bioinformatic analysis utilizing the known ZBRK1 consensus DNA-binding motif revealed ZBRK1-binding sites in the SCA2 promoter. These predicted sites were experimentally validated by chromatin-immunoprecipitation experiments along with luciferase-based promoter analyses corroborating that SCA2 gene transcription is controlled by a ZBRK1/ataxin-2 complex. Finally, we demonstrate that SCA2 gene transcription is significantly reduced in colon tumors possessing low ZBRK1 transcripts. Thus, our results provide first evidence that ataxin-2 acts as a co-regulator of ZBRK1 activating its own transcription, thereby representing the first identified ZBRK1 co-activator.

Journal Article.  6087 words.  Illustrated.

Subjects: Genetics and Genomics

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