title: CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.
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.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ladd
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pineda
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sunkin
authors.forename: James B
authors.initials: JB
authors.lastname: Hurley
authors.forename: Cortlandt P
authors.initials: CP
authors.lastname: Thienes
authors.forename: Terry
authors.initials: T
authors.lastname: Gaasterland
authors.forename: Galina N
authors.initials: GN
authors.lastname: Filippova
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D000076246:CCCTC-Binding Factor; D002874:Chromosome Mapping; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D016372:RNA, Antisense / Q000378:metabolism*; D022661:RNA, Untranslated / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D009419:Nerve Tissue Proteins; D016372:RNA, Antisense; D022661:RNA, Untranslated; D012097:Repressor Proteins