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

Qi Yang; Nian Jiang; Han Zou; Xuning Fan; Tao Liu; Xi Huang; Siyi Wanggou; Xuejun Li

doi:10.1016/j.csbj.2022.04.007

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

Comput Struct Biotechnol J. 2022 Apr 8:20:1967-1978. doi: 10.1016/j.csbj.2022.04.007. eCollection 2022.

Authors

Qi Yang^{1

2}, Nian Jiang^{1

2}, Han Zou^{1

2}, Xuning Fan³, Tao Liu³, Xi Huang^{4

5

6}, Siyi Wanggou^{1

2}, Xuejun Li^{1

2}

Affiliations

¹ Department of Neurosurgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan 410008, PR China.
² Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan 410008, PR China.
³ Annoroad Gene Tech. (Beijing) Co., Ltd, Block 1, Yard 88, Kechuang 6 RD, Beijing Economic-Technological Development Area, Beijing 100176, PR China.
⁴ Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
⁵ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 3E1, Canada.

Abstract

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 whole-genome 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.

Keywords: 3D genomic; Astrocytes; DE, Differentially expressed; FDR, False discovery rate; GBM, Glioblastoma multiform; Glioblastoma; Hi-C; ICE, Iterative correction and eigenvector decomposition; IDE, Distance decay exponent; PCC, Pearson’s correlation coefficient; SV, Structure variation; Structure Variation; TAD, Topological associating domain; Tumorigenesis; WGS, Whole-genome sequencing.