Three-dimensional genome architecture in intrahepatic cholangiocarcinoma.

Abstract

Purpose: Intrahepatic cholangiocarcinoma (ICC) is a common primary hepatic tumors with a 5-year survival rate of less than 20%. Therefore, it is crucial to elucidate the molecular mechanisms of ICC. Recently, the advance of high-throughput chromosome conformation capture (Hi-C) technology help us look insight into the three-dimensional (3D) genome structure variation during tumorigenesis. However, its function in ICC pathogenesis remained unclear.

Methods: Hi-C and RNA-sequencing were applied to analyze 3D genome structures and gene expression in ICC and adjacent noncancerous hepatic tissue (ANHT). Furthermore, the dysregulated genes due to 3D genome changes were validated via quantitative real-time PCR and immunohistochemistry.

Results: Primarily, the intrachromosomal interactions of chr1, chr2, chr3, and chr11 and the interchromosomal interactions of chr1-chr10, chr13-chr21, chr16-chr19, and chr19-chr22 were also significantly distinct between ANHT and ICC, which may potentially contribute to the activation of cell migration and invasion via the upregulation of WNT10A, EpCAM, S100A3/A6, and MAPK12. Interestingly, 56 compartment regions from 23 chromosomes underwent A to B or B to A transitions during ICC oncogenesis, which attenuated the complement pathway through the downregulation of C8A/C8B, F7, F10, and F13B. Notably, topologically associated domain (TAD) rearrangements were identified in the region containing HOPX (chr4: 57,514,154-57,522,688) and ACVR1 (chr2:158,592,958-158,732,374) in ICC, which may contribute to the hijacking of remote enhancers that were previously outside the TAD and increased expression of HOPX and ACVR1.

Conclusions: This study reveals relationship between 3D genome structural variations and gene dysregulation during ICC tumorigenesis, indicating the molecular mechanisms and potential biomarkers.