Alterations in 3D chromatin organization contribute to tumorigenesis of EGFR-amplified glioblastoma

Background: EGFR 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.Methods: In 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 wholegenome sequencing (WGS) on EGFR-amplified glioblastoma-derived A172 and normal astrocytes (HA1800 cell line).Results: A172 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.Conclusions: The 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. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

Automated summary

In this study, the alterations in 3D chromatin organization of EGFR-amplified glioblastoma were explored, and it was found that the chromatin relaxation and unexpected entanglement of chromosome regions were observed in the glioblastoma cells. The activation of compartments reshaped chromatin accessibility and activated tumorigenesis-related genes. The altered topological associating domains (TADs) and chromatin loop alterations were associated with oncogene activation and tumor repressor deactivation.