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

Qiaowei Liu, Shuai Jiang, Xiang Xu, Kang Xu, Yawen Luo, Zongyuan Yu, Meida Xiang, Zhouyang Xu, Lijie Wang, Sujie Zhang, Haitao Tao, Xuhui Yang, Chongbo Jiang, Xiaoguang Qi, Hao Li, Yiming Gao, Yao Li, Shihui Fu, Pingkun Zhou, Xiaochen Bo, Hebing Chen (), Xiaohua Chen () and Yi Hu ()
Additional contact information
Qiaowei Liu: Chinese PLA General Hospital
Shuai Jiang: State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis, NCBA)
Xiang Xu: Academy of Military Medical Sciences
Kang Xu: Academy of Military Medical Sciences
Yawen Luo: Academy of Military Medical Sciences
Zongyuan Yu: Academy of Military Medical Sciences
Meida Xiang: Academy of Military Medical Sciences
Zhouyang Xu: Beijing Institute of Radiation Medicine
Lijie Wang: Chinese PLA General Hospital
Sujie Zhang: Chinese PLA General Hospital
Haitao Tao: Chinese PLA General Hospital
Xuhui Yang: Chinese PLA General Hospital
Chongbo Jiang: Chinese PLA General Hospital
Xiaoguang Qi: Chinese PLA General Hospital
Hao Li: Beijing Institute of Radiation Medicine
Yiming Gao: Chinese PLA General Hospital
Yao Li: Chinese PLA General Hospital
Shihui Fu: Hainan Hospital of Chinese People’s Liberation Army General Hospital
Pingkun Zhou: Beijing Institute of Radiation Medicine
Xiaochen Bo: Academy of Military Medical Sciences
Hebing Chen: Academy of Military Medical Sciences
Xiaohua Chen: Beijing Institute of Radiation Medicine
Yi Hu: Chinese PLA General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63754-y

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