1. CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.
- Author
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Sopher BL, Ladd PD, Pineda VV, Libby RT, Sunkin SM, Hurley JB, Thienes CP, Gaasterland T, Filippova GN, and La Spada AR
- Subjects
- Animals, Ataxin-7, CCCTC-Binding Factor, Gene Expression Regulation genetics, Humans, Mice, Mice, Transgenic, Nerve Tissue Proteins genetics, Promoter Regions, Genetic genetics, Promoter Regions, Genetic physiology, RNA, Untranslated metabolism, Repressor Proteins genetics, Tumor Cells, Cultured, Chromosome Mapping, Gene Expression Regulation physiology, Nerve Tissue Proteins metabolism, RNA, Antisense metabolism, Repressor Proteins metabolism
- Abstract
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG/polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription coactivator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multifunctional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense noncoding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 derepressed ataxin-7 sense transcription in a cis-dependent fashion and was accompanied by chromatin remodeling. Discovery of this pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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