Integrative Identification by Hi-C Revealed Distinct Advanced Structural Variations in Lung Adenocarcinoma Tissue

Tingting Song; Menglin Yao; Ying Yang; Zhiqiang Liu; Li Zhang; Weimin Li

doi:10.1007/s43657-023-00103-3

Integrative Identification by Hi-C Revealed Distinct Advanced Structural Variations in Lung Adenocarcinoma Tissue

Phenomics. 2023 Jun 15;3(4):390-407. doi: 10.1007/s43657-023-00103-3. eCollection 2023 Aug.

Authors

Tingting Song^#¹, Menglin Yao^#¹, Ying Yang¹, Zhiqiang Liu¹, Li Zhang¹, Weimin Li¹

Affiliation

¹ Department of Respiratory and Critical Care Medicine, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan Province China.

^# Contributed equally.

Abstract

Advanced three-dimensional structure variations of chromatin in large genome fragments, such as conversion of A/B compartment, topologically associated domains (TADs) and chromatin loops are related closely to occurrence of malignant tumors. However, the structural characteristics of lung cancer still remain uncovered. In this study, we used high-throughput chromosome (Hi-C) conformation capture technology to detect the advanced structural variations in chromatin of two non-smoking lung adenocarcinoma (LUAD) tumor and paired normal tissues. The results indicate that significant chromatin variations are detected in tumor tissues compared with normal tissues. At compartment scale, the main conversion type of compartment is A → B in tumor tissues, which are concentrated mainly on chromosome 3 (Chr3) (33.6%). A total of 216 tumor-specific TADs are identified in tumor tissues, which are distributed mainly in Chr1 (19), Chr2 (15) and Chr3 (17). Forty-one distinct enhancer-promoter loops are observed in tumor tissue, which are associated closely to tumor-related pathways including mitogen-activated protein kinase (MAPK), Phosphatidylinositol-3-kinase-Protein kinase B (PI3K-AKT), Ras, Wnt and Ras1. The most important observation in this study is that we identify five important genes (SYT16, NCEH1, NXPE3, MB21D2, and DZIP1L), which are detected in both A → B compartment, TADs and chromatin loops in tumor samples, and four of these genes (NCEH1, NXPE3, MB21D2, and DZIP1L) locate on q arm of Chr3. Further gene expression and invasion experiment analysis show that NCEH1, MB21D2 and SYT16 are involved in the tumor development. Thus, we provide a comprehensive overview of advanced structures in LUAD for the first time and provide a basis for further research on the genetic variation of this tumor.

Keywords: Advanced structural variations; Chromosome 3; High-throughput chromosome; Lung cancer; Tumor-related genes.

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