Christopher J Brandon, Sarah Robinson-Thiewes, Mangesh Kaulage, Wojciech Rosikiewicz, Matthew J Cuneo, Joseph Brett, Jindpreet Kandola, Walter H Lang, Jonathan Low, Ashraf Mohammed, Adithi Danda, Sam Rider, Marcus Valentine, Jason Ochoada, Brandon Young, Theresa Nguyen, Sandra J Kietlinska, Aaron B Taylor, Burkhard Hoeckendorf, Patrick Rodrigues, Wenwei Lin, Khaled Khairy, Beisi Xu, Anang A Shelat, Taosheng Chen, Tanja Mittag, Aseem Z Ansari
How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich's ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression.