Disruption of TAD hierarchy promotes LTR co-option in cancer

作者：Elissa W.P. Wong, Merve Şahin, Rui Yang, UkJin Lee, Dan Li, Yingqian A. Zhan, Rohan Misra, Fanny Tomas, Nawaf Alomran, Alexander Polyzos, Cindy J. Lee, Tuan Trieu, Alexander Martinez‐Fundichely, Thomas Wiesner, Andrew Rosowicz, Shuyuan Cheng, Christina Liu, Morgan Lallo, Alexander N. Shoushtari, Taha Merghoub, Pierre-Jacques Hamard, Richard P. Koche, Ekta Khurana, Effie Apostolou, Deyou Zheng, Yu Chen, Christina S. Leslie, Ping Chi · 发表于：Nature Genetics · 年份：2025 · DOI：10.1038/s41588-025-02239-6 · 被引用次数：5 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、RNA Research and Splicing

Transposable elements (TEs) are abundant in the human genome, and they provide the source for genetic and functional diversity. Previous studies have suggested that TEs are repressed by DNA methylation and chromatin modifications. Here through integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters (altPs) at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and the recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. Perturbation of hierarchical chromatin topology can lead to co-option of LTRs as functional altPs, driving aberrant transcriptional activation of oncogenes. These data uncovered a new layer of regulatory mechanisms of TE expression and posit TAD hierarchy dysregulation as a new mechanism for altP-mediated oncogene activation and transcriptional diversity in cancer.