Top2a Differentially Modulates Promoter Activity in Embryonic Stem Cells via Trim28 Recruitment and PRC2 Displacement [ATAC-Seq]
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ABSTRACT:
PROVIDER: PRJNA1080199 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28085824_1.fastq.gz | Fastqsanger.gz | |||
| SRR28085824_2.fastq.gz | Fastqsanger.gz | |||
| SRR28085825_1.fastq.gz | Fastqsanger.gz | |||
| SRR28085825_2.fastq.gz | Fastqsanger.gz | |||
| SRR28085826_1.fastq.gz | Fastqsanger.gz |
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Project description:High levels of the type II topoisomerase α (Top2a) play a crucial role in maintaining the stemness of embryonic stem cells (ESCs). However, the mechanisms governing Top2a's ESC-specific function remain largely unknown. Here, using an unbiased proteomic approach, we discovered Trim28, along with subunits of various chromatin remodeling complexes and modifiers, among the top interactors of Top2a on ESC chromatin. We demonstrate that Top2a directly interacts with Trim28 in an ESC-specific manner. Functionally, Trim28 can promote Top2a expression, and synergize with Top2a in maintaining stemness of ESCs as well as promoting induced pluripotent stem cells (iPSCs) generation. Genome-wide approaches reveal that Top2a-Trim28 co-regulated genes contribute to glycolysis and self-renewal, and Top2a fine-tunes promoter activity by recruiting Trim28 to co-activated genes and displacing PRC2 to co-repressed genes. Remarkably, targeting Top2a in combination with Trim28 in breast cancer stem cells shows an extremely synergistic anti-tumorigenic effect. Therefore, Top2a collaborates with Trim28 in ESCs to fulfill its cell type-specific functions, which may highlight the therapeutic strategy of combinational targeting of Top2a and Trim28 to combat cancer stem cells.
2025-03-01 | GSE259215 | GEO
Project description:High levels of the type II topoisomerase α (Top2a) play a crucial role in maintaining the stemness of embryonic stem cells (ESCs). However, the mechanisms governing Top2a's ESC-specific function remain largely unknown. Here, using an unbiased proteomic approach, we discovered Trim28, along with subunits of various chromatin remodeling complexes and modifiers, among the top interactors of Top2a on ESC chromatin. We demonstrate that Top2a directly interacts with Trim28 in an ESC-specific manner. Functionally, Trim28 can promote Top2a expression, and synergize with Top2a in maintaining stemness of ESCs as well as promoting induced pluripotent stem cells (iPSCs) generation. Genome-wide approaches reveal that Top2a-Trim28 co-regulated genes contribute to glycolysis and self-renewal, and Top2a fine-tunes promoter activity by recruiting Trim28 to co-activated genes and displacing PRC2 to co-repressed genes. Remarkably, targeting Top2a in combination with Trim28 in breast cancer stem cells shows an extremely synergistic anti-tumorigenic effect. Therefore, Top2a collaborates with Trim28 in ESCs to fulfill its cell type-specific functions, which may highlight the therapeutic strategy of combinational targeting of Top2a and Trim28 to combat cancer stem cells.
2025-03-01 | GSE257545 | GEO
Project description:High levels of the type II topoisomerase α (Top2a) play a crucial role in maintaining the stemness of embryonic stem cells (ESCs). However, the mechanisms governing Top2a's ESC-specific function remain largely unknown. Here, using an unbiased proteomic approach, we discovered Trim28, along with subunits of various chromatin remodeling complexes and modifiers, among the top interactors of Top2a on ESC chromatin. We demonstrate that Top2a directly interacts with Trim28 in an ESC-specific manner. Functionally, Trim28 can promote Top2a expression, and synergize with Top2a in maintaining stemness of ESCs as well as promoting induced pluripotent stem cells (iPSCs) generation. Genome-wide approaches reveal that Top2a-Trim28 co-regulated genes contribute to glycolysis and self-renewal, and Top2a fine-tunes promoter activity by recruiting Trim28 to co-activated genes and displacing PRC2 to co-repressed genes. Remarkably, targeting Top2a in combination with Trim28 in breast cancer stem cells shows an extremely synergistic anti-tumorigenic effect. Therefore, Top2a collaborates with Trim28 in ESCs to fulfill its cell type-specific functions, which may highlight the therapeutic strategy of combinational targeting of Top2a and Trim28 to combat cancer stem cells.
2025-03-01 | GSE257544 | GEO
Project description:Top2a Differentially Modulates Promoter Activity in Embryonic Stem Cells via Trim28 Recruitment and PRC2 Displacement [RNA-Seq]
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Project description:Top2a Differentially Modulates Promoter Activity in Embryonic Stem Cells via Trim28 Recruitment and PRC2 Displacement [ChIP-Seq]
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Project description:Human infants exhibit innate social behaviors at birth, yet little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused behavioral defects related to core symptoms of autism, including impairments in social interaction and communication. Mutation of Top2a in zebrafish caused downregulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets possess binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation. Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.
2021-09-20 | GSE181730 | GEO
Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.
2020-08-07 | PXD014290 | Pride
Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.
2021-09-22 | PXD020684 | Pride
Project description:EZH2 is generally associated with H3K27 methylation and gene silencing. Mass spectrometry of the EZH2-interactome in MCF7 cells revealed EZH2-interactions with SWI/SNF subunits and TRIM28, which formed a complex with EZH2 distinct from PRC2. Transcriptome profiling showed that EZH2 primarily activates transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment and expression of this gene set, in parallel with decreased CD44hi/CD24lo mammosphere formation. These results support PRC2-independent functions of EZH2 and TRIM28 in mammary stem cell enrichment and maintenance.
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Project description:Top2a promotes the development of social behavior via PRC2 and H3K27me3
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