Yang Qi, Jiang Nian, Zou Han, Fan Xuning, Liu Tao, Huang Xi, Wanggou Siyi, Li Xuejun
Department of Neurosurgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan 410008, PR China.
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.
Comput Struct Biotechnol J. 2022 Apr 8;20:1967-1978. doi: 10.1016/j.csbj.2022.04.007. eCollection 2022.
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 -amplified glioblastoma remains unclear.
In this study, we explored alterations in 3D chromatin organization of amplified glioblastoma and its subsequent impact by performing a comparative analysis of Hi-C, RNA-seq, and whole-genome sequencing (WGS) on -amplified glioblastoma-derived A172 and normal astrocytes (HA1800 cell line).
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 amplified glioblastoma-derived tumor cells. Moreover, our results revealed that 7p11.2 duplication activated expression in -amplified glioblastoma via neo-TAD formation and novel enhancer-promoter interaction emergence between and .
The disordered 3D genomic map and multi-omics data of amplified glioblastoma provide a resource for future interrogation of the relationship between chromatin interactions and transcriptome in tumorigenesis.
在超过一半的胶质母细胞瘤病例中发现了扩增和/或突变。然而，染色质相互作用及其对基因表达的调控在扩增型胶质母细胞瘤中的作用仍不清楚。
在本研究中，我们通过对扩增型胶质母细胞瘤来源的A172细胞和正常星形胶质细胞（HA1800细胞系）进行Hi-C、RNA测序（RNA-seq）和全基因组测序（WGS）的比较分析，探索了扩增型胶质母细胞瘤三维染色质组织的改变及其后续影响。
A172细胞显示出染色质松弛增加以及染色体区域意外缠结。HA1800和A172细胞系之间全基因组范围的区室切换和差异表达基因图谱表明，区室激活重塑了染色质可及性并激活了肿瘤发生相关基因。拓扑相关结构域（TAD）分析显示，A172中改变的TAD结构域也有助于癌基因激活和肿瘤抑制因子失活。有趣的是，胶质母细胞瘤来源的A172细胞显示出不同的染色质环接触倾向。肿瘤发生相关信号通路中的基因在改变的染色质环的锚定位点显著富集。癌基因激活和肿瘤抑制因子失活与染色质环改变有关。结构变异（SVs）对扩增型胶质母细胞瘤来源的肿瘤细胞的染色质构象有显著影响。此外，我们的结果显示，7p11.2重复通过新TAD形成以及和之间新的增强子-启动子相互作用的出现，激活了扩增型胶质母细胞瘤中的表达。
扩增型胶质母细胞瘤的三维基因组图谱紊乱和多组学数据为未来研究肿瘤发生过程中染色质相互作用与转录组之间的关系提供了资源。
