BAZ2A-RNA dependent association with TOP2A and KDM1A represses gene expression in prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744891 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15070624.fastq.gz | Fastqsanger.gz | |||
| SRR15070625.fastq.gz | Fastqsanger.gz | |||
| SRR15070626.fastq.gz | Fastqsanger.gz | |||
| SRR15070627.fastq.gz | Fastqsanger.gz | |||
| SRR15070628.fastq.gz | Fastqsanger.gz |
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Project description:BAZ2A represses rRNA genes (rDNA) that are transcribed by RNA polymerase I. In prostate cancer (PCa), BAZ2A function goes beyond this role because it represses genes frequently silenced in metastatic disease. However, the mechanisms of this BAZ2A-mediated repression remain elusive. Here, we show that BAZ2A represses genes through its RNA-binding TAM domain using mechanisms differing from rDNA silencing. Although the TAM domain mediates BAZ2A recruitment to rDNA, in PCa, this is not required for BAZ2A association with target genes. Instead, the BAZ2A-TAM domain in association with RNA mediates the interaction with topoisomerase 2A (TOP2A) and histone demethylase KDM1A, whose expression positively correlates with BAZ2A levels in localized and metastatic PCa. TOP2A and KDM1A pharmacological inhibition up-regulate BAZ2A-repressed genes that are regulated by inactive enhancers bound by BAZ2A, whereas rRNA genes are not affected. Our findings showed a novel RNA-based mechanism of gene regulation in PCa. Furthermore, we determined that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A repress genes critical to PCa and may prove to be useful to stratify prostate cancer risk and treatment in patients.
2023-04-14 | GSE179743 | GEO
Project description:BAZ2A represses rRNA genes (rDNA) that are transcribed by RNA polymerase I. In prostate cancer (PCa), BAZ2A function goes beyond this role because it represses genes frequently silenced in metastatic disease. However, the mechanisms of this BAZ2A-mediated repression remain elusive. Here, we show that BAZ2A represses genes through its RNA-binding TAM domain using mechanisms differing from rDNA silencing. Although the TAM domain mediates BAZ2A recruitment to rDNA, in PCa, this is not required for BAZ2A association with target genes. Instead, the BAZ2A-TAM domain in association with RNA mediates the interaction with topoisomerase 2A (TOP2A) and histone demethylase KDM1A, whose expression positively correlates with BAZ2A levels in localized and metastatic PCa. TOP2A and KDM1A pharmacological inhibition up-regulate BAZ2A-repressed genes that are regulated by inactive enhancers bound by BAZ2A, whereas rRNA genes are not affected. Our findings showed a novel RNA-based mechanism of gene regulation in PCa. Furthermore, we determined that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A repress genes critical to PCa and may prove to be useful to stratify prostate cancer risk and treatment in patients.
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Project description:Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. How genome compartmentalization is regulated remains elusive. Here, comparison of mouse ground-state embryonic stem cells (ESCs) characterized by open and active chromatin, and advanced serum ESCs with a more closed and repressed genome, reveals distinct regulation of their genome organization due to differential dependency on BAZ2A/TIP5, a component of the chromatin remodeling complex NoRC. On ESC chromatin, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. BAZ2A associates with chromatin subdomains within the active A compartment, which intersect through long-range contacts. We found that ground-state chromatin selectively requires BAZ2A to limit the invasion of active domains into repressive compartments. BAZ2A depletion increases chromatin accessibility at B compartments. Furthermore, BAZ2A regulates H3K27me3 genome occupancy in a TOP2A-dependent manner. Finally, ground-state ESCs require BAZ2A for growth, differentiation, and correct expression of developmental genes. Our results uncover the propensity of open chromatin domains to invade repressive domains, which is counteracted by chromatin remodeling to establish genome partitioning and preserve cell identity.
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Project description:Topoisomerases II (TOP2) play role in relief of torsional stress during DNA replication and gene transcription, and TOP2 is also a target of anticancer agents which cause secondary leukemia. To address cell lineage-specific TOP2A cleavage relative to leukemia, here we profile genome-wide TOP2A cleavage in human acute lymphoblastic leukemia (ALL) cell line CEM, and compare to TOP2A cleavage landscape of chronic myelogenous leukemia (CML) cell line K562. We find that TOP2A cleavage activity are correlated with chromosome length, suggesting that TOP2A cleavage is critical for segregation or supercoil relaxation of long chromosomes. Meanwhile, we find that evolutionally conserved TOP2A cleavage cluster regions (CCRs) are depleted in gene promoter and enriched in introns and 3’ UTR, and TOP2A cleavage genes tend to be highly expressed, indicating the conserved function of TOP2A cleavage in promoting transcription elongation and activation. In addition, we found that the oncogenic transcription factor complex TAL1, GATA3 and RUNX1 can further promote the activation of TOP2A cleavage genes by binding to their promoters. Further analysis reveal that native TOP2A cleavage are lineage-specific, which play role in cell commitment and leukemia development , while drug-enhanced TOP2A cleavage promote apoptosis of cancer cells in both ALL and CML.Taken together, our findings suggest that native TOP2A cleavage function in long chromosome segregation and transcription activation, and together with the transcriptional regulatory factors shape the commitment of leukemia cell.
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Project description:Type II topoisomerases orchestrate proper DNA topology and they also are the targets of anticancer drugs that cause leukemias with balanced translocations as secondary cancers. Here, we develop a novel high-throughput sequencing technology to define TOP2 cleavage sites at single base precision in human cells and use the technology to characterize TOP2A cleavage genome-wide in the K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence predilections, occurs in cleavage cluster regions (CCRs) and is enriched in introns and lincRNA loci. In coding genes we discover a bias of TOP2A CCRs towards the distal regions of gene bodies and proximal shifts in TOP2A CCRs with TOP2 poisons. We find high TOP2A cleavage levels in the genes involved in translocations associated with TOP2 poisons in leukemia. In addition, we find that large a proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. By making comparisons to ENCODE data, we uncover distinct TOP2A CCR clusters that overlap with marks of gene transcription, open chromatin and enhancers. Our findings implicate TOP2A as the DNA damage mediator in oncogenic translocations more broadly than was previously appreciated. They also identify TOP2A as a functional DNA element that contributes to the regulation of transcription elongation and gene activation.
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Project description:KDM1A requires an adaptor protein with specific DNA-binding activity to recognize chromatin sequence. We constructed HepG2 cells stably overexpressing KDM1A-Flag tag using lentivirus. We performed Co-IP with Flag-gel and we used LC-MS to determine the immunoprecipitates of KDM1A.
2023-05-19 | PXD043284 |
Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.
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