CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA

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. [Display omitted] ► The atx7 repeat region contains an alternative promoter and antisense RNA—SCAANT1 ► CTCF binding promotes SCAANT1; loss of SCAANT1 derepressed atx7 sense transcription ► SCAANT1 antisense ncRNA transcription represses the atx7 alternative promoter in cis ► Regulatory bidirectional transcription may be a feature of many repeat diseases