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

Aline Gaub, Bilal N. Sheikh, M. Felicia Basilicata, Marie Vincent, Mathilde Nizon, Cindy Colson, Matthew J. Bird, James E. Bradner, Julien Thevenon, Michael Boutros and Asifa Akhtar ()
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Aline Gaub: Max Planck Institute of Immunobiology and Epigenetics
Bilal N. Sheikh: Max Planck Institute of Immunobiology and Epigenetics
M. Felicia Basilicata: Max Planck Institute of Immunobiology and Epigenetics
Marie Vincent: Service de Génétique Médicale
Mathilde Nizon: Service de Génétique Médicale
Cindy Colson: Génétique Clinique, CHU
Matthew J. Bird: Katholieke Universiteit Leuven
James E. Bradner: Novartis Institutes for Biomedical Research
Julien Thevenon: Université Grenoble-Alpes CHU Grenoble
Michael Boutros: German Cancer Research Center (DKFZ)
Asifa Akhtar: Max Planck Institute of Immunobiology and Epigenetics

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16103-0

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