Methyl-lysine readers PHF20 and PHF20L1 define two distinct NSL complexes
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ABSTRACT:
PROVIDER: PRJNA779539 | ENA |
REPOSITORIES: ENA
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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.
2022-03-02 | GSE188601 | GEO
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.
2022-04-04 | PXD029258 | Pride
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.
| S-EPMC8867114 | biostudies-literature
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.
2017-05-22 | GSE82115 | GEO
Project description:Glioblastoma (GBM) is the most common tumor of the central nervous system with poor prognosis. PHF20 was highly expressed in primary human glioma specimens. However, the molecular mechanism of by which PHF20 regulated glioblastoma remains poorly understood. In the study, we investigate the gene expression profile of that regulated by PHF20 in U87 cells.
2017-10-31 | GSE93680 | GEO
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
Project description:Although reprogramming of somatic cells to generate inducible pluripotent stem cells (iPSCs) is associated with remarkable epigenetic changes, the role and mechanisms of epigenetic factors in this process remains poorly understood. Here we describe identification of Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, while ectopic expression of Jmjd3 markedly inhibited reprogramming. We further show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways acting in concert. The latter pathway is entirely novel and involved Jmjd3 targeting of PHF20 for ubiquitination and degradation by recruiting an E3 ligase Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a or p21, indicating dominant effects of this protein on reprogramming. Our findings identify a previously unrecognized role of Jmjd3 in reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls the reprogramming process. This study was an examination of phf20 and wdr5 binding patterns in embryonic stem cells, using a ChIP-Sequencing methodology with antibodies for each of these factors in the cell lines indicated.
2013-12-06 | E-GEOD-43247 | biostudies-arrayexpress
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.
2012-02-27 | E-GEOD-29306 | biostudies-arrayexpress
Project description:Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including nutrient-deprived conditions. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Here, using combination of RNA-seq, ATAC-seq and ChIP-seq, we demonstrated found that plant homeodomain finger protein 20 (Phf20PHF20), which is an epigenetic reader possessing methyl binding activity, plays a key role in controlling the expression of autophagy genes. PHF20 activates autophagy genes through enhancer activation via H3K36me2 binding activity as an epigenetic reader and that our findings emphasize the importance of nuclear regulation of autophagy.
2022-06-23 | GSE193392 | GEO
Project description:Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including nutrient-deprived conditions. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Here, using combination of RNA-seq, ATAC-seq and ChIP-seq, we demonstrated found that plant homeodomain finger protein 20 (Phf20PHF20), which is an epigenetic reader possessing methyl binding activity, plays a key role in controlling the expression of autophagy genes. PHF20 activates autophagy genes through enhancer activation via H3K36me2 binding activity as an epigenetic reader and that our findings emphasize the importance of nuclear regulation of autophagy.
2022-06-23 | GSE193217 | GEO