YY1 and Lig3 collaboratively regulate ecDNA biogenesis (CUT&Tag)
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ABSTRACT:
PROVIDER: PRJNA1211587 | ENA |
REPOSITORIES: ENA
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Project description:Extrachromosomal DNA (ecDNA) is an important carrier for the amplification of proto-oncogenes. It can not only drive cancer progression by increasing the copy number of oncogenes but also influence the transcriptional regulation of oncogenes by increasing chromatin accessibility and regulating chromatin interactions. Currently, the generation of ecDNA is rather complex and the exact mechanism remains unclear. This study aims to investigate the molecular mechanism underlying the generation of ecDNA in order to identify the targets for ecDNA-targeted drug therapies. We analyzed the chromatin landscape in COLO320-DM and COLO320-HSR cells through CUT&Tag. The results of CUT&Tag for Lig3, the open chromatin marker H3K27ac, and the promoter marker H3K4me3 showed that Lig3 was specifically enriched in the MYC ecDNA amplification regions and bound to a large number of open chromatin regions and promoter regions, indicating that Lig3 may be related to the formation of ecDNA and stably bind to ecDNA, thereby maintaining the integrity of the genes carried by ecDNA. Furthermore, we found that there were a large number of merge peaks between Lig3 and YY1 across the whole genome, which were abundantly occupied at the MYC ecDNA amplification sites. Meanwhile, we observed that in COLO320-DM cells (where oncogenes are amplified in the form of ecDNA), there was a significant enrichment of YY1 in the MYC amplification regions, while in COLO320-HSR cells (where oncogenes are amplified on the homogeneously staining regions, HSR), the peaks of YY1 were significantly decreased. Our data suggest that YY1 is essential for the generation of ecDNA. It forms a complex with Lig3 to jointly regulate the formation of ecDNA, and this complex can be detected as it resides on ecDNA for a relatively long period of time. This may also be related to the stability of ecDNA and its involvement in genomic regulation.
2025-07-25 | GSE287200 | GEO
Project description:YY1 is a widely expressed transcriptional regulatory factor that is overexpressed in various cancer types, promoting the expression of numerous oncogenes and contributing to cancer progression. It has been identified as a significant biomarker of cancer, correlating with poor prognosis in cancer patients. Moreover, YY1 is an essential regulator of DNA looping, preferentially occupying enhancers and promoters. YY1-mediated enhancer-promoter loops participate in various cancer-related biological functions by regulating gene expression. The circular nature of ecDNA suggests that its formation involves a DNA looping process. Notably, in tumor cells, YY1-mediated DNA looping is closely associated with the activation of multiple oncogenes and immunosuppressive genes, resembling the types of genes carried by ecDNA. Therefore, we investigated the link between DNA looping mediated by YY1 and ecDNA generation. We conducted YY1 HiCUT in COLO320-DM/HSR cells. We found that in COLO320-DM cells, a large number of YY1-mediated loops were located in the MYC amplification region, while only 1% of these loops were observed in the same region in COLO320-HSR cells. The result indicates YY1 mediates DNA looping through dimerization in cells has potential correlation with ecDNA biogenesis.
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Project description:YY1-mediated DNA looping promotes the generation of ecDNA (HiCUT)
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Project description:The protein Yin-Yang 1 (YY1) is a ubiquitous multifunctional transcription factor. Interestingly, there are several cellular functions controlled by YY1 that could play a role in Leishmania pathogenesis. Leishmaniasis is a human disease caused by protozoan parasites of the genus Leishmania. This study examined the potential role of macrophage YY1 in promoting Leishmania intracellular survival. Knockdown of YY1 resulted in attenuated survival of Leishmania in infected macrophages, suggesting a role of YY1 in Leishmania persistence. Biochemical fractionation studies revealed Leishmania infection caused redistribution of YY1 to the cytoplasm from the nucleus where it is primarily located. Inhibition of nuclear transport by leptomycin B attenuates infection-mediated YY1 redistribution and reduces Leishmania survival. This suggests that Leishmania induces the translocation of YY1 from the nucleus to the cytoplasm of infected cells, where it may regulate host molecules to favour parasite survival. A label-free quantitative whole proteome approach showed that the expression of a large number of macrophage proteins was dependent on the YY1 level. Interestingly, several of these proteins were modulated in Leishmania-infected cells, revealing YY1-dependent host response and suggesting their potential role in Leishmania pathogenesis. Together, these findings identify YY1 as a novel and essential virulence factor by proxy that promotes Leishmania survival.
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Project description:Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice [CUT&Tag]
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Project description:We systematically analyzed the alterations in mRNA transcriptome evoked by knockdown of YY1 with or without pyridostatin (PDS) treatment. Statistical analysis showed a strong correlation between PDS-regulated and YY1-regulated genes (Pearson r > 0.67), underscoring the role of YY1-G4 structure interaction in YY1-mediated gene regulation. Moreover, the RNA-Seq results revealed that YY1 can positively or negatively regulate the expression of genes through its interaction with G4 structures.
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Project description:In this study, we established ecDNA-containing cell models by either transfecting synthetic circular DNA or excising endogenous chromosomal DNA. We found that ecDNA can be stable maintained in these cell models. By identifying proteins on nascent DNA, we found DNA damage repair pathway was significantly enriched in ecDNA-containing cells. ecDNA can activate DNA damage response. Further evidence show that TOP2B and LIG3. The association of ecDNA replication with cell proliferation and DNA damage response was explored by comprehensive profiling and analysis. Utilizing EdU (5-ethynyl-2’-deoxyuridine)-immunoprecipitation-mass spectrometry (EdU-IP-MS), we identified critical regulators involved in ecDNA replication and examined their functional roles in cancer cell DNA damage response and proliferation.
2025-04-18 | PXD060725 | Pride
Project description:Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for ecDNA induction with extensive characterization of newly formed ecDNA to examine their biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of 800kb, 1 Mb, and 1.8 Mb ecDNAs reaching or exceeding 15%. We show non-homologous end joining and microhomology-mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar can form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.
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