BRD4 recruitment desilences transcription without erasure or depletion of repressive chromatin

BRD4 recruitment desilences transcription without erasure or depletion of repressive chromatin. 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 bioRxiv 2026.04.10.717856; doi:10.64898/2026.04.10.717856

We find that BRD4 readily partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus presenting a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. Epigenetic drugs that gate sequential steps in transcription, synergistically stimulate FXN expression while concomitantly increasing, rather than eliminating, repressive H3K9me3 and HP1 levels. More broadly, this study highlights the dynamic nature of repressive chromatin and the context-dependence of epigenetic marks in regulating gene expression.

BRD4 recruitment desilences transcription without erasure or depletion of repressive chromatin