Radiation-Induced 3D Genome Structure Reorganization Regulates Gene Transcription

Abstract

Radiation can induce cellular three-dimensional (3D) genome reorganization. However, the exact functional relevance of spatial rearrangements to gene transcription remains unknown. First, we screened and profiled the global picture of the 3D genome structure reorganization in human hepatocellular carcinoma cells MHCC-LM3 that were irradiated with 4Gy X-ray at a concentration of 100 cGy/min for 4 min using the high-throughput chromosome conformation capture (Hi-C) technique. They were maped and analyzed at three levels: compartment, topologically associating domain (TAD) and TAD boundary, and loop. The regulatory relationships within gene transcription exerted by the related dynamic spatial structure were confirmed by ribonucleic acid sequencing (RNA-seq) and further experimentally confirmed by quantitative real-time polymerase chain reaction in the same treated cell samples. A significant increase in interchromosomal interactions was observed in the irradiated cells. The extent of the effect of dynamic compartment switches and disrupted and gained TAD boundaries on gene transcription was significantly greater than that of small differential chromatin loops. Genes in human leukocyte antigen (HLA) and C‑C motif chemokine ligand (CCL) gene clusters associated with TAD boundary alterations were considerably upregulated, and this effect was maintained 24 h post-radiation. We characterized the radiation-induced landscape map of the 3D genome in cells and elucidated the mechanism by which 3D genome reorganization spatially regulates gene transcription. This study provides a basis for further research directed toward understanding the role of structural alterations in gene expression.