p53 is not necessary for DUX4 pathology

Darko Bosnakovski; Erik A. Toso; Olivia O. Recht; Anja Cucak; Abhinav K Jain; Michelle C. Barton; Michael Kyba

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/118315 doi: bioRxiv preprint doxycycline (Dandapat et al. 2016 ). Other animal model work includes a mouse carrying human D4Z4 repeats (Krom et al. 2013) which showed some evidence of sporadic DUX4 expression, but no myopathy; and adeno-associated viral (AAV) vector-mediated delivery of DUX4 to skeletal muscle, which showed profound myopathy (Wallace et al. 2011 ). This latter work implicated the p53 pathway in DUX4 pathology, as the p53 knockout background suppressed AAV-DUX4 toxicity. The linkage to p53 is compelling, as this pathway has the potential to push cells into apoptosis, however precisely how DUX4 would activate p53 is not clear. The immediate targets of the DUX4 transcription factor include genes with regulatory elements containing the sequence TAATCTAATCA (Geng et al. 2012; Zhang et al. 2015) , or variants thereof. ChIP-seq has identified many genomic targets (Choi et al. 2016; Geng et al. 2012 ) and at the majority of these, DUX4 displaces nucleosomes, recruits p300 and/or CBP through its C-terminus which promotes acetylation of histone H3 and activation of transcription (Choi et al. 2016 ).