Top2a promotes the development of social behavior via PRC2 and H3K27me3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA753112 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15376927_1.fastq.gz | Fastqsanger.gz | |||
| SRR15376927_2.fastq.gz | Fastqsanger.gz | |||
| SRR15376928_1.fastq.gz | Fastqsanger.gz | |||
| SRR15376928_2.fastq.gz | Fastqsanger.gz | |||
| SRR15376929_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description: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 defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the 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.
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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.
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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.
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