EZH2 Variants Differentially Regulate Polycomb Repressive Complex 2 in Histone Methylation and Cell Differentiation
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ABSTRACT:
PROVIDER: PRJNA507765 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8267520.fastq.gz | Fastqsanger.gz | |||
| SRR8267521.fastq.gz | Fastqsanger.gz | |||
| SRR8267522.fastq.gz | Fastqsanger.gz | |||
| SRR8267523.fastq.gz | Fastqsanger.gz | |||
| SRR8267514.fastq.gz | Fastqsanger.gz |
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Project description:Background: Polycomb repressive complex 2 (PRC2) is responsible for establishing and maintaining histone H3K27 methylation during cell differentiation and proliferation. H3K27 can be mono-, di-, or tri-methylated, resulting in differential gene regulation. However, it remains unknown how PRC2 specifies the degree and biological effects of H3K27 methylation within a given cellular context. One way to determine PRC2 specificity may be through alternative splicing of Ezh2, PRC2’s catalytic subunit, during cell differentiation and tissue maturation. Results: We fully characterized the alternative splicing of Ezh2 in somatic cells and male germ cells and found that Ezh’s exon 14 was differentially regulated during mitosis and meiosis. The Ezh2 isoform containing exon 14 (ex14-Ezh2) is upregulated during cell cycle progression, consistent with a role in maintaining H3K27 methylation during chromatin replication. In contrast, the isoform lacking exon 14 (ex14D-Ezh2) was almost exclusively present in spermatocytes when new H3K27me2 is established during meiotic differentiation. Moreover, Ezh2’s transcript is normally controlled by E2F transcription activators, but in spermatocytes, Ezh2’s transcription is controlled by the meiotic regulator MYBL1. Compared to ex14-EZH2, ex14D-EZH2 has a diminished efficiency for catalyzing H3K27me3 and promotes embryonic stem cell differentiation. Conclusions: Ezh2’s expression is regulated at transcriptional and post-transcriptional levels in a cellular context-dependent manner. EZH2 variants determine functional specificity of PRC2 in histone methylation during cell proliferation and differentiation.
2018-12-01 | GSE123174 | GEO
Project description:BACKGROUND:Polycomb repressive complex 2 (PRC2) is responsible for establishing and maintaining histone H3K27 methylation during cell differentiation and proliferation. H3K27 can be mono-, di-, or trimethylated, resulting in differential gene regulation. However, it remains unknown how PRC2 specifies the degree and biological effects of H3K27 methylation within a given cellular context. One way to determine PRC2 specificity may be through alternative splicing of Ezh2, PRC2's catalytic subunit, during cell differentiation and tissue maturation. RESULTS:We fully characterized the alternative splicing of Ezh2 in somatic cells and male germ cells and found that Ezh's exon 14 was differentially regulated during mitosis and meiosis. The Ezh2 isoform containing exon 14 (ex14-Ezh2) is upregulated during cell cycle progression, consistent with a role in maintaining H3K27 methylation during chromatin replication. In contrast, the isoform lacking exon 14 (ex14D-Ezh2) was almost exclusively present in spermatocytes when new H3K27me2 is established during meiotic differentiation. Moreover, Ezh2's transcript is normally controlled by E2F transcription activators, but in spermatocytes, Ezh2's transcription is controlled by the meiotic regulator MYBL1. Compared to ex14-EZH2, ex14D-EZH2 has a diminished efficiency for catalyzing H3K27me3 and promotes embryonic stem cell differentiation. CONCLUSIONS:Ezh2's expression is regulated at transcriptional and post-transcriptional levels in a cellular context-dependent manner. EZH2 variants determine functional specificity of PRC2 in histone methylation during cell proliferation and differentiation.
| S-EPMC6282306 | biostudies-literature
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:Polycomb proteins assemble to form complexes with important roles in epigenetic regulation. The Polycomb Repressive Complex 2 (PRC2) modulates the di- and tri-methylation of lysine 27 on histone H3, each of which are associated with gene repression. Although three subunits, EZH1/2, SUZ12 and EED, form the catalytic core of PRC2, a wider group of proteins associate with low stoichiometry. This raises the question of whether dynamic variation of the PRC2 interactome results in alternative forms of the complex during differentiation. Here we compared the physical interactions of PRC2 in undifferentiated and differentiated states of NTERA2 pluripotent embryonic carcinoma cells. Label-free quantitative proteomics was used to assess endogenous immunoprecipitation of the EZH2 and SUZ12 subunits of PRC2. A high stringency dataset reflecting the endogenous state of PRC2 was produced that included all previously reported ‘core’ and ‘associated’ PRC2 components, and several novel interacting proteins. Comparison of the interactomes obtained in undifferentiated and differentiated cells revealed candidate proteins that favoured either one or other state. For example, SALL4 and ZNF281 associate with PRC2 in pluripotent cells, while PCL1 and SMAD3 more associate with PRC2 in differentiating cells. Analysis of the mRNA and protein levels of these factors found that their association with PRC2 correlated with their cell state-specific expression. Taken together, we propose that dynamic changes to the PRC2 interactome during differentiation may contribute to directing its activity during cell fate transitions.
2016-09-27 | PXD004462 | Pride
Project description:The project aimed at identifying the cofactors regulating Polycomb complex PRC2 enzymatic activity in gonads. We used a knock-in mouse model where the enzymatic subunit of PRC2 (either EZH2 or EZH1) is tagged (Flag-tag) to purify PRC2 from mouse adult testis. This experiment revealed the existence of a new cofactor for PRC2 that we called GPIF (AU022751).
2019-07-22 | PXD012354 | Pride
Project description:EZH2, the catalytic component of the Polycomb repressive complex 2 (PRC2), silences gene transcription by methylating histone H3 at lysine 27. Recently we identified ZRANB1 as the EZH2 deubiquitinase. ZRANB1 binds, deubiquitinates, and stabilizes EZH2. To determine whether ZRANB1 is a functional regulator of EZH2, we performed RNA-Seq analysis to compare the effect of ZRANB1 knockdown or EZH2 knockdown on global gene expression.
2018-04-18 | GSE104910 | GEO
Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. ChIP-seq has been performed for G9a and Ezh2 in wild type TT2 mES cells or in mES cells lacking both G9a and GLP (G9a-/-GLP-/-). As a control, input DNA was saved before immunoprecipitation. Note that the two inputs (Input_TT2_0 and Input_TT2_1) have been combined and used as control for Ezh2 and G9a ChIP-seq.
2014-01-03 | E-GEOD-46536 | biostudies-arrayexpress
Project description:Polycomb group proteins are important epigenetic regulators for organ development, cell proliferation and differentiation, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including EZH2, promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. The canonical function of EZH2, along with its essential binding partners EED and SUZ12, is to methylate histone H3K27 and repress its downstream targets. In this study, we discover that EZH2 regulates androgen receptor (AR) expression levels and AR signaling in prostate cancer. Targeting EZH2 with the newly identified EZH2 inhibitor, astemizole, could effectively inhibit the progression of castration-resistant prostate cancer.
2018-12-22 | GSE124268 | GEO
Project description:Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of PRC2 and used the resultant data to screen for novel potential targets. The RNA polymerase II (Pol II) transcription factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of many, but not all, PRC2 target genes as measured by both steady state and nascent RNA levels. We propose that PRC2 regulates transcription of a subset of target genes in part via methylation of EloA.
2017-11-16 | GSE104657 | GEO
Project description:Polycomb Repressive Complex 2 methylates Elongin A to regulate transcription
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