One obvious question, based upon our Venetoclax in vitro results is: Why does the cell need such a complicated pathway for adjusting ataxin-7 expression? Ataxin-7 is a core, and likely essential, component of different ubiquitously expressed transcription coactivator complexes (Helmlinger et al., 2004, Palhan et al., 2005 and Zhao et al., 2008). As deletion of the ataxin-7 ortholog Sgf73 eliminates Ubp8-mediated histone deubiquitination in yeast (Köhler et al., 2008), and knockdown of ataxin-7 results in disassembly of the STAGA complex in mammals (Palhan et al.,

2005), tight regulation of ataxin-7 expression could be a mechanism for controlling the activity of these coactivators. CTCF is a master regulator of transcription, and its expression Pictilisib ic50 cannot be significantly adjusted without killing the cell. However, minor changes in CTCF levels, or binding activity, could have a dramatic impact upon the transcriptional activity of the

cell through its regulation of ataxin-7 expression, since ataxin-7 expression alterations would be amplified by affecting the stability and function of entire co-activator complexes. Thus, CTCF control of ataxin-7 levels could serve as a rheostat for setting global transcription activity status for the cell. Another important implication of our work is its relevance to SCA7 disease pathogenesis and repeat disease biology. As we have shown, expansion of the ataxin-7 CAG repeat tract reduces SCAANT1 promoter activity, resulting in minimally detectable levels of SCAANT1 from the expanded allele in SCA7 patient fibroblasts. This reduction in SCAANT1 expression derepresses the ataxin-7 alternative promoter, and significantly boosts the level

of ataxin-7, creating a feed forward effect that agonizes the SCA7 disease pathway by favoring increased production of mutant ataxin-7 protein (Figure 8). Although we cannot exclude a role for altered transcript stability in this process, a survey of histone posttranslational modifications in our SCA7 transgenic mice revealed repressive chromatin modifications in the alternative promoter when Oxymatrine SCAANT1 transcription is robust, indicating that transcriptional activity is likely more important than transcript stability in controlling ataxin-7 sense expression. As bidirectional transcription in association with CTCF binding is emerging as a common feature of repeat disease loci, our findings could be applicable at other repeat disease loci, including loci that have not been carefully screened for antisense transcripts. Furthermore, the existence of regulatory bidirectional transcription may offer an entry point for therapeutically modulating ataxin-7 expression at the RNA level.