美国纽约州纽约市纪念斯隆-凯特琳癌症中心医学部研究小组报道了TAD层级的破坏促进LTR在癌症中的协同选择。相关论文于2025年6月30日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

通过整合转录组和3D基因组结构研究，该研究组发现单倍缺失的NIPBL选择性激活TE亚类长末端重复序列（LTRs）上的替代启动子（altPs）。这种激活通过拓扑关联域（TAD）层次结构的重组和近端增强子的招募发生。这些观察结果表明，TAD层次结构限制了已经具有开放染色质特征的LTRs的转录激活。分层染色质拓扑结构的扰动可导致LTRs作为功能性altPs的共同选择，从而驱动癌基因的异常转录激活。这些数据揭示了TE表达和TAD层次失调的新调控机制，作为altPs介导的癌基因激活和转录多样性的新机制。

研究人员表示，转座因子（TEs）在人类基因组中含量丰富，为遗传和功能多样性提供了基础。先前的研究表明，TEs受到DNA甲基化和染色质修饰的抑制。

附：英文原文

Title: Disruption of TAD hierarchy promotes LTR co-option in cancer

Author: Wong, Elissa W. P., Sahin, Merve, Yang, Rui, Lee, UkJin, Li, Dan, Zhan, Yingqian A., Misra, Rohan, Tomas, Fanny, Alomran, Nawaf, Polyzos, Alexander, Lee, Cindy J., Trieu, Tuan, Martinez-Fundichely, Alexander, Wiesner, Thomas, Rosowicz, Andrew, Cheng, Shuyuan, Liu, Christina, Lallo, Morgan, Shoushtari, Alexander N., Merghoub, Taha, Hamard, Pierre-Jacques, Koche, Richard, Khurana, Ekta, Apostolou, Effie, Zheng, Deyou, Chen, Yu, Leslie, Christina S., Chi, Ping

Issue&Volume: 2025-06-30

Abstract: 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.

DOI: 10.1038/s41588-025-02239-6

Source: https://www.nature.com/articles/s41588-025-02239-6