Gaub, A., Sheikh, B.N., Basilicata, M.F., Vincent, M., Nizon, M., Colson, C., Bird, M.J., Bradner, J.E., Thevenon, J., Boutros, M., Akhtar, A. (2020). Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation.  Nat. Commun. 11(1): 2243.

FBrf0245611

Research paper

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states.

PMC7206058 (PMC) (EuropePMC)