Common DNA methylation dynamics in endometriod adenocarcinoma and glioblastoma suggest universal epigenomic alterations in tumorigenesis.
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ABSTRACT:
SUBMITTER: Karlow JA
PROVIDER: S-EPMC8140130 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEGFR amplification and/or mutation are found in more than half of the cases with glioblastoma. Yet, the role of chromatin interactions and its regulation of gene expression in EGFR-amplified glioblastoma remains unclear.MethodsIn this study, we explored alterations in 3D chromatin organization of EGFR-amplified glioblastoma and its subsequent impact by performing a comparative analysis of Hi-C, RNA-seq, and whole-genome sequencing (WGS) on EGFR-amplified glioblastoma-derived A172 and normal astrocytes (HA1800 cell line).ResultsA172 cells showed an elevated chromatin relaxation, and unexpected entanglement of chromosome regions. A genome-wide landscape of switched compartments and differentially expressed genes between HA1800 and A172 cell lines demonstrated that compartment activation reshaped chromatin accessibility and activated tumorigenesis-related genes. Topological associating domain (TAD) analysis revealed that altered TAD domains in A172 also contribute to oncogene activation and tumor repressor deactivation. Interestingly, glioblastoma-derived A172 cells showed a different chromatin loop contact propensity. Genes in tumorigenesis-associated signaling pathways were significantly enriched at the anchor loci of altered chromatin loops. Oncogene activation and tumor repressor deactivation were associated with chromatin loop alteration. Structure variations (SVs) had a dramatic impact on the chromatin conformation of EGFR-amplified glioblastoma-derived tumor cells. Moreover, our results revealed that 7p11.2 duplication activated EGFR expression in EGFR-amplified glioblastoma via neo-TAD formation and novel enhancer-promoter interaction emergence between LINC01446 and EGFR.ConclusionsThe disordered 3D genomic map and multi-omics data of EGFR-amplified glioblastoma provide a resource for future interrogation of the relationship between chromatin interactions and transcriptome in tumorigenesis.
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Project description:BACKGROUND: Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10-50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family. METHODS: We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15). RESULTS: We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15). CONCLUSION: The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.
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