TP63 mediates the generation of tumour-specific chromatin loops that underlie MYC activation in radiation-induced tumorigenesis

作者：Qiaowei Liu, Shuai Jiang, Xiang Xu, Kang Xu, Yawen Luo, Yu Zhou, Meida Xiang, Zhouyang Xu, Lijie Wang, Sujie Zhang, Haitao Tao, Xuhui Yang, Chongbo Jiang, Xiaoguang Qi, Hao Li, Yiming Gao, Yao Li, Shihui Fu, Ping‐Kun Zhou, Xiaochen Bo, Hebing Chen, Xiaohua Chen, Yi Hu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63754-y · 被引用次数：2 · 研究领域：Genomics and Chromatin Dynamics、DNA Repair Mechanisms、Cancer Genomics and Diagnostics

Alterations in 3D chromatin conformation may disrupt the interplay between promoters and distal enhancers. How gene regulatory circuits are reshaped during ionizing radiation-induced tumorigenesis remains unclear, and little is known about the mediators that drive these processes. To decipher the chromatin alterations in radiation-induced lung cancer, we performed ATAC-seq, RNA-seq and Hi-C analyses of human bronchial epithelial cells and corresponding radiation-induced malignantly transformed cell lines. We found that this malignant transformation is accompanied by chromatin switching from the inactive B compartment to the active A compartment, an increased number of TADs and gained ATAC-seq peaks that mediate new distal chromatin contacts. We identified tumour protein 63 (TP63) as a mediator of new chromatin-accessible sites that anchor tumour-specific chromatin contacts in radiation-induced tumour cells. A TP63-mediated accessible chromatin site anchors a tumour-specific TAD boundary and multiple tumour-specific chromatin loops, which might underlie MYC oncogene activation during malignant transformation. Radiation-induced malignantly transformed cells undergo multi-scale 3D genome reorganization. TP63 acts as a key mediator, creating accessible chromatin sites that form tumour-specific loops activating the MYC oncogene during malignant transformation.