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CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA

Bryce L Sopher1, Paula D Ladd, Victor V Pineda

  • 1Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.

Neuron
|June 22, 2011
PubMed

Insights

Spinocerebellar ataxia type 7 (SCA7) involves altered ataxin-7 gene expression. CTCF regulates a noncoding RNA (SCAANT1) that represses ataxin-7 transcription, with its loss causing disease-associated epigenetic changes.

Area of Science:

  • Neurogenetics
  • Molecular Biology
  • Epigenetics

Background:

  • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder linked to CAG/polyglutamine expansions in the ataxin-7 gene.
  • Ataxin-7 protein is crucial for transcription coactivator complexes, and its function is impaired in polyglutamine diseases.

Purpose of the Study:

  • To investigate the regulatory mechanisms of ataxin-7 gene expression.
  • To understand the role of CTCF and a novel noncoding RNA in SCA7 pathogenesis.

Main Methods:

  • Analysis of the ataxin-7 gene locus, including flanking CTCF binding sites and an alternative promoter.
  • Introduction of ataxin-7 mini-genes into mouse models.
  • Assessment of CTCF's role in SCAANT1 expression and its impact on ataxin-7 transcription and chromatin structure.

Main Results:

  • Discovery of a convergently transcribed antisense noncoding RNA, SCAANT1, adjacent to the ataxin-7 gene.
  • CTCF is essential for SCAANT1 expression.
  • Loss of SCAANT1 leads to derepression of ataxin-7 sense transcription and associated chromatin remodeling in cis.

Conclusions:

  • CTCF-mediated regulation of SCAANT1 is a critical pathway influencing ataxin-7 gene expression.
  • Altered epigenetic regulation at bidirectional repeat loci contributes to SCA7 pathology.
  • This finding highlights the importance of noncoding RNAs in neurodegenerative disease mechanisms.

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