Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

• DOI: 10.1038/s41467-020-16103-0
• Publication Date: 2020-05-07T10:03:08Z
• Authors: Aline Gaub; Bilal N. Sheikh; M. Felicia Basili...; Marie Vincent; Mathilde Nizon; Cindy Colson; Matthew J. Bird; James E. Bradner; Julien Thevenon; Michael Boutros; Asifa Akhtar
• Keywords: [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry; Epigenomics; Male; Transcriptional Activation; 570; Science; Article; Histones; Mice; 03 medical and health sciences; Pregnancy; Animals; Drosophila Proteins; Promoter Regions, Genetic; Cells, Cultured; 0303 health sciences; Molecular Biology/Molecular Networks [q-bio.MN]; Gene Expression Profiling; Q; Nuclear Proteins; [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN]; Acetylation; Chromatin; [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN]; Drosophila; Female; RNA Interference

AbstractCells 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.