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Spatial Interplay between Polycomb and Trithorax Complexes Controls Transcriptional Activity in T Lymphocytes.

ABSTRACT: Trithorax group (TrxG) and Polycomb group (PcG) proteins are two mutually antagonistic chromatin modifying complexes, however, how they together mediate transcriptional counter-regulation remains unknown. Genome-wide analysis revealed that binding of Ezh2 and menin, central members of the PcG and TrxG complexes, respectively, were reciprocally correlated. Moreover, we identified a developmental change in the positioning of Ezh2 and menin in differentiated T lymphocytes compared to embryonic stem cells. Ezh2-binding upstream and menin-binding downstream of the transcription start site was frequently found at genes with higher transcriptional levels, and Ezh2-binding downstream and menin-binding upstream was found at genes with lower expression in T lymphocytes. Interestingly, of the Ezh2 and menin cooccupied genes, those exhibiting occupancy at the same position displayed greatly enhanced sensitivity to loss of Ezh2. Finally, we also found that different combinations of Ezh2 and menin occupancy were associated with expression of specific functional gene groups important for T cell development. Therefore, spatial cooperative gene regulation by the PcG and TrxG complexes may represent a novel mechanism regulating the transcriptional identity of differentiated cells.

SUBMITTER: Onodera A

PROVIDER: S-EPMC4609743 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Spatial interplay between Polycomb and Trithorax complexes controls transcriptional activity in T lymphocytes

Project description:Trithorax group (TrxG) and Polycomb group (PcG) proteins are two mutually antagonistic chromatin modifying complexes, however, how they together mediate transcriptional counterregulation remains unknown. Genome-wide analysis revealed that binding of Ezh2 and Menin, central members of the PcG and TrxG complexes, respectively, were reciprocally correlated. Moreover, we identified a developmental change in the positioning of Ezh2 and Menin in differentiated T lymphocytes compared to embryonic stem cells. Ezh2-binding upstream and Menin-binding downstream of the transcription start site (TSS) was frequently found at genes with higher transcriptional levels, and Ezh2-binding downstream and Menin-binding upstream was found at genes with lower expression in T lymphocytes. Interestingly, of the Ezh2 and Menin co-occupied genes, those exhibiting occupancy at the same position displayed greatly enhanced sensitivity to loss of Ezh2. Finally, we also found that different combinations of Ezh2 and Menin occupancy were associated with expression of specific functional gene groups important for T cell development. Therefore, spatial cooperative gene regulation by the PcG and TrxG complexes may represent a novel mechanism regulating the transcriptional identity of differentiated cells. ES cells, B cells and T cells are profiled for mRNA expression

2015-09-08 | E-GEOD-72757 | biostudies-arrayexpress

Spatial interplay between Polycomb and Trithorax complexes controls transcriptional activity in T lymphocytes

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-10-10 | GSE73825 | GEO

Spatial interplay between Polycomb and Trithorax complexes controls transcriptional activity in T lymphocytes [array]

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Spatial interplay between Polycomb and Trithorax complexes controls transcriptional activity in T lymphocytes [ChIP-Seq]

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Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK?a regulation.

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Regulation by polycomb and trithorax group proteins in Arabidopsis.

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Polycomb and Trithorax Group Genes in <i>Drosophila</i>.

Project description:Polycomb group (PcG) and Trithorax group (TrxG) genes encode important regulators of development and differentiation in metazoans. These two groups of genes were discovered in Drosophila by their opposing effects on homeotic gene (Hox) expression. PcG genes collectively behave as genetic repressors of Hox genes, while the TrxG genes are necessary for HOX gene expression or function. Biochemical studies showed that many PcG proteins are present in two protein complexes, Polycomb repressive complexes 1 and 2, which repress transcription via chromatin modifications. TrxG proteins activate transcription via a variety of mechanisms. Here we summarize the large body of genetic and biochemical experiments in Drosophila on these two important groups of genes.

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Evolutionary plasticity of polycomb/trithorax response elements in Drosophila species.

Project description:cis-Regulatory DNA elements contain multiple binding sites for activators and repressors of transcription. Among these elements are enhancers, which establish gene expression states, and Polycomb/Trithorax response elements (PREs), which take over from enhancers and maintain transcription states of several hundred developmentally important genes. PREs are essential to the correct identities of both stem cells and differentiated cells. Evolutionary differences in cis-regulatory elements are a rich source of phenotypic diversity, and functional binding sites within regulatory elements turn over rapidly in evolution. However, more radical evolutionary changes that go beyond motif turnover have been difficult to assess. We used a combination of genome-wide bioinformatic prediction and experimental validation at specific loci, to evaluate PRE evolution across four Drosophila species. Our results show that PRE evolution is extraordinarily dynamic. First, we show that the numbers of PREs differ dramatically between species. Second, we demonstrate that functional binding sites within PREs at conserved positions turn over rapidly in evolution, as has been observed for enhancer elements. Finally, although it is theoretically possible that new elements can arise out of nonfunctional sequence, evidence that they do so is lacking. We show here that functional PREs are found at nonorthologous sites in conserved gene loci. By demonstrating that PRE evolution is not limited to the adaptation of preexisting elements, these findings document a novel dimension of cis-regulatory evolution.

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NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition.

Project description:Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.

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