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

Abstract : 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.
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Aline Gaub, Bilal Sheikh, M Felicia Basilicata, Marie Vincent, Mathilde Nizon, et al.. Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.2243. ⟨10.1038/s41467-020-16103-0⟩. ⟨inserm-02634812⟩

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