TAD层级的破坏促进LTR在癌症中的协同选择

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY
Elissa W. P. Wong, Merve Sahin, 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 Koche, Ekta Khurana, Effie Apostolou, Deyou Zheng, Yu Chen, Christina S. Leslie, Ping Chi
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引用次数: 0

摘要

转座因子(te)在人类基因组中含量丰富,是遗传和功能多样性的来源。先前的研究表明,te受到DNA甲基化和染色质修饰的抑制。通过整合转录组和3D基因组结构研究,我们发现单倍缺失的NIPBL选择性激活TE亚类长末端重复序列(lts)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ltr的转录激活。分层染色质拓扑结构的扰动可导致ltr作为功能性altp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altp介导的癌基因激活和转录多样性的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Disruption of TAD hierarchy promotes LTR co-option in cancer

Disruption of TAD hierarchy promotes LTR co-option in cancer

Disruption of TAD hierarchy promotes LTR co-option in cancer
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. NIPBL perturbation activates long terminal repeat (LTR)-derived alternative promoters due to reorganization of chromatin’s hierarchical structure, leading to LTR co-option and oncogene activation in melanoma cell lines.
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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
期刊介绍: Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution
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