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

Nat Commun. 2020 May 7;11(1):2243. doi: 10.1038/s41467-020-16103-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cells, Cultured
  • Chromatin / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Epigenomics
  • Female
  • Gene Expression Profiling
  • Histones / metabolism*
  • Male
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pregnancy
  • Promoter Regions, Genetic / genetics
  • RNA Interference / physiology
  • Transcriptional Activation / genetics
  • Transcriptional Activation / physiology*

Substances

  • Chromatin
  • Drosophila Proteins
  • Histones
  • Nuclear Proteins