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

Author

Listed:
  • 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
    Normandy University, UNICAEN, BIOTARGEN)

  • 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)
    Medical Faculty Mannheim, Heidelberg University)

  • Asifa Akhtar

    (Max Planck Institute of Immunobiology and Epigenetics)

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.

Suggested Citation

  • Aline Gaub & Bilal N. Sheikh & M. Felicia Basilicata & Marie Vincent & Mathilde Nizon & Cindy Colson & Matthew J. Bird & James E. Bradner & Julien Thevenon & Michael Boutros & Asifa Akhtar, 2020. "Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16103-0
    DOI: 10.1038/s41467-020-16103-0
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    Cited by:

    1. Ting Li & Dingyi Lu & Chengcheng Yao & Tingting Li & Hua Dong & Zhan Li & Guang Xu & Jiayi Chen & Hao Zhang & Xiaoyu Yi & Haizhen Zhu & Guangqin Liu & Kaiqing Wen & Haixin Zhao & Jun Gao & Yakun Zhang, 2022. "Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Chun-Yi Cho & Patrick H. O’Farrell, 2023. "Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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