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.
Highlights
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood
This assay was sensitive to depletion of other Non-Specific Lethal (NSL) complex members (Supplementary Fig. 1b), NSL1, NSL3 and MOF served as positive controls for the genome-wide screen
Improving our understanding of transcription of NSL target genes is imperative given that haploinsufficiency of KANSL1 is causative of the debilitating Koolen-de Vries syndrome
Summary
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferasecontaining 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. Misregulation and mutation of epigenetic regulators have a significant pathological potential that can lead to e.g. developmental disorders or cancers[2,3] While diagnosis of such diseases is greatly improving, for example due to the advances of next-generation sequencing[4], the relevant molecular understanding to establish a therapeutic approach is often missing. This remains challenging for broadly expressed regulators, where the co-factors instructing their activity on ubiquitous versus tissue-specific target genes, remain often poorly defined. Our work reveals an unexpected BET protein signature in patients with haploinsufficiency of KANSL1, which underlies the Koolen-de Vries intellectual disability syndrome
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