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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 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 induces 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE135772 | GEO | 2020/03/13

REPOSITORIES: GEO

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

Project description: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 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 induces 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.

2020-03-13 | GSE135771 | GEO

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ChIP-seq profiling of RNA Polymerase II in Drosophila melanogaster S2 cells depleted of the non-specific lethal (NSL) complex

Project description:We show that the non-specific lethal (NSL) complex in Drosophila binds to housekeeping genes. Individual ChIP-qPCR experiments of NSL target genes indicated a role of the NSL complex in RNA Polymerase II (Pol II) recruitment to promoters. Consequently, we obtained ChIP-Seq profiles of the Pol-II-subunit Rbp3 in S2 cells that were depleted of either NSL1 or NSL3. Rbp3-ChIP from S2 cells treated with siRNA targeted against GFP were used as a control. This experiment is related to experiment E-MTAB-214 and E-MTAB-1085.

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The NSL complex–mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise

Project description:We report that the Drosophila Non-Specific Lethal (NSL) complex is necessary to maintain this stereotypical nucleosomal organization at promoters. Upon NSL1 depletion, nucleosomes invade the NDRs at TSSs of NSL-bound genes. NSL complex member NSL3 binds to TATA-less promoters in a sequence-dependent manner. We showed that the NSL complex is necessary and sufficient to recruit NURF chromatin remodeling complex to target promoters. The NSL complex is not only essential for transcription but is required for accurate TSS selection for genes with multiple TSSs. Further, loss of NSL complex leads to an increase in transcriptional noise. Thus, the NSL complex establishes a canonical nucleosomal organization that enables transcription and determines TSS fidelity.

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Methyl-lysine readers PHF20 and PHF20L1 define two distinct NSL complexes

Project description:The methyl lysine readers PHF (plant homeodomain finger) 20 (PHF20) and its homolog PHF20 Like 1 (PHF20L1) are known components of the NSL (non-specific lethal) complex that regulates gene expression through its histone acetyltransferase activity. In the current model, both PHF homologs coexist in the same NSL complex although this was not formally tested; nor have the functions of PHF20 and PHF20L1 regarding NSL complex integrity and transcriptional regulation been investigated. Here we perform an in-depth biochemical and functional characterization of PHF20 and PHF20L1 in the context of the NSL complex. We identify the existence of two distinct NSL complexes that exclusively contain either PHF20 or PHF20L1; the two PHF homologs do not complex together in the same NSL species. Our data show that the C-terminal domains are essential for PHF20 and PHF20L1 to complex with NSL and the Tudor 2 domains of PHF20 and PHF20L1 are required for chromatin binding. The genome-wide landscape of PHF20/PHF20L1 binding to chromatin shows that they bind mostly to the same genomic regions, at promoters of highly expressed/housekeeping genes. Yet, deletion of PHF20 and PHF20L1 does not abrogate gene expression of the identified targets or impact the recruitment of NSL to the promoters of those genes, suggesting the existence of an alternative mechanism that compensates for the transcription of genes whose sustained expression is important for critical cellular functions.

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Project description:In the current study, we analyse the function of MOF-NSL complex in neural cells. We find that the NSL complex regulates metabolic networks in the brain.

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Analysis of histone modification with the deletion of components of the NSL complex

Project description:The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase complex consists of 9 subunits can acetylate histone H4K16, H4K5 and H4K8. It has been known that this complex shares WDR5 subunit with the MLL/SET histone methyltransferases, suggesting that NSL complex is essential for the multiple transcriptional regulation mechanisms. However, there are few reports on the function of NSL HAT in genome, It is necessary to clarify the details and specificity of histone H4 acetylation cooperates with H3K4 methylation to regulate gene transcription. In this work, Our results show that The NSL complex plays a critical role in regulating multiple histone modifications by using the CRISPR/Cas9 NSL3-KO 293T cell line and ChIP-Seq approach. The global levels of highly enriched H4K16ac, H4K5ac, H3K4me2 and H3K4me3 at TSSs (TSS ± 3 kb region) are inhibited by NSL3-KO. NSL3-KO seemed to have little effect on the enhancer mark H3K27ac and repressor mark H3K27me3, but H3K4me1 was greatly affected by NSL3-KO. Moreover, the NSL complex govern gene transcription and identified genes by a coordinative mode of H4K16ac and H3K4me2/me3. What’s more, De novo motif analysis of MOF and NSL3 targets indicated that the NSL complex forms a gene regulatory network with multiple transcription factors by regulating their genes expression or cooperating with some factors through binding to specific motif.

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