YY1-mediated DNA looping promotes the generation of ecDNA (HiCUT)
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ABSTRACT:
PROVIDER: PRJNA1211673 | ENA |
REPOSITORIES: ENA
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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.
2025-07-25 | GSE287239 | GEO
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 and Lig3 collaboratively regulate ecDNA biogenesis (CUT&Tag)
| PRJNA1211587 | ENA
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.
2025-03-14 | PXD059968 | Pride
Project description:CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3-D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely pre-existing in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3-D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of YY1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a pre-existing topological framework created by constitutive CTCF-mediated interactions.
2017-05-22 | GSE85185 | GEO
Project description:MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC
| PRJNA1183381 | ENA
Project description:MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC
| PRJNA1036260 | ENA
Project description:MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC
| PRJNA1183380 | ENA
Project description:Tumor-associated macrophages are mainly polarized into the M2 phenotype, which remodels the tumor microenvironment and promotes tumor progression by secreting various cytokines. Herein, we reported that Yin Yang 1 (YY1) was highly expressed on tumor-infiltrated M2 macrophages in prostate cancer and was associated with poorer clinical outcomes. Using transgenic mice overexpressing YY1, we found that the tumor-promoting effects of oe-YY1 mice could be suppressed by macrophage depletion. Further in-vitro and in-vivo experiments using YY1 overexpressing and knocked down M2 macrophages demonstrated that YY1 induced M2 polarization and increased macrophages-induced prostate cancer progression by the IL-6/STAT3 pathway. Furthermore, YY1 promoted phase-separated condensates and upregulated IL-6 by modulating p300, NF-κB and CEBPB as a transcription complex. By conducting chromatin immunoprecipitation sequencing of M2 macrophages and monocytes, an M2-specific IL-6 enhancer associated with the YY1 complex was shown to upregulate IL-6 expression in M2 macrophages, and H3K27ac and YY1 signals significantly increased around this enhancer. In conclusion, YY1 complex promotes the M2 macrophages polarization and upregulates IL-6 in macrophages by inducing phase separation and a M2-specific enhancer, thereby increasing prostate cancer progression. These findings might lead to novel therapies targeting YY1 in prostate tumor-associated macrophages.
2023-04-01 | GSE200947 | GEO