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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188601 | GEO | 2022/03/02

REPOSITORIES: GEO

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PHF20 and PHF20L1 in NSL complex

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. By performing an in-depth biochemical and functional characterization, we define the association and contributions of the two methyl lysine reader homologs PHF20 and PHF20L1 to the NSL complex.

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PHF20 readers link methylation of histone H3K4 and p53 with H4K16 acetylation

Project description:PHF20 is a core component of the lysine acetyltransferase complex MOF-NSL that produces the major epigenetic mark, H4K16ac, and is necessary for transcriptional regulation and DNA repair, however the role of PHF20 in the complex remains elusive. Here, we report on functional crosstalk between epigenetic readers of PHF20. We show that the PHF20 PHD finger recognizes dimethylated lysine 4 of histone H3 (H3K4me2) and represents first example of a native PHD reader selective for this modification. Biochemical and structural analyses illuminate the molecular mechanism underlying this function and explain the preference of Tudor2, another reader in PHF20, for dimethylated p53. Binding of the PHD finger to H3K4me2 is required for histone acetylation, accumulation of PHF20 at target genes, and transcriptional activation. Together, our findings establish a novel PHF20-mediated link between MOF HAT, p53 and H3K4me2-dependent cellular events and suggest a model for rapid spreading of H4K16ac-encriched open chromatin.

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

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

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Methyl-lysine readers PHF20 and PHF20L1 define two distinct gene expression-regulating NSL complexes.

Project description:The methyl-lysine readers plant homeodomain finger protein 20 (PHF20) and its homolog PHF20-like protein 1 (PHF20L1) are known components of the nonspecific lethal (NSL) 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. Using mass spectrometry, genome-wide chromatin analysis, and protein-domain mapping, we identify the existence of two distinct NSL complexes that exclusively contain either PHF20 or PHF20L1. We show that the C-terminal domains of PHF20 and PHF20L1 are essential for complex formation with NSL, and the Tudor 2 domains are required for chromatin binding. The genome-wide chromatin landscape of PHF20-PHF20L1 shows that these proteins 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 or impact the recruitment of the NSL complex to those target gene promoters, suggesting the existence of an alternative mechanism that compensates for the transcription of genes whose sustained expression is important for critical cellular functions. This work shifts the current paradigm and lays the foundation for studies on the differential roles of PHF20 and PHF20L1 in regulating NSL complex activity in physiological and diseases states.

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Analysis of NSL knockout brains

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.

2020-03-31 | GSE138981 | GEO

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

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Loss of PHF20 does not negatively affect deposition of H4K16 acetylation, but does impact the expression of MOF targets

Project description:Protein post-translational modifications transmit signals in part by creating binding sites for effector molecules. This is especially true in epigenetic pathways where histone tails are heavily modified, resulting in the recruitment of molecules that can affect transcription. One such molecule, plant homeodomain finger protein 20 (PHF20), uses a Tudor domain to read dimethyl-lysine residues and is a known component of the MOF histone acetyltransferase protein complex, suggesting it plays a role in the crosstalk between lysine methylation and histone acetylation. We sought to investigate the biological role of PHF20 by generating a knockout mouse. Without PHF20, mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Mechanistically, PHF20 is not required for maintaining the global H4K16 acetylation levels, but instead works downstream in transcriptional regulation of MOF target genes. ChIP sequencing of H4K16ace ChIP DNA from PHF20 knockout and wild type cells using Illumina Solexa Genome Analyzer II single end sequencing protocol.

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Identification of genes and pathways that regulated by PHF20 via gene expression profile analysis in U87 cell with PHF20 silencing

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2022-03-18 | GSE198646 | GEO

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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.

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