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.
Authors
- Thomas Wiesner (ORCID: https://orcid.org/0000-0001-5877-2992)
- Taha Merghoub (ORCID: https://orcid.org/0000-0002-1518-5111)
- Christina Liu (ORCID: https://orcid.org/0000-0002-5723-177X)
- Alexander Polyzos (ORCID: https://orcid.org/0000-0002-2509-9698)
- UkJin Lee (ORCID: https://orcid.org/0000-0001-6644-4286)
- Ping Chi
- Effie Apostolou (ORCID: https://orcid.org/0000-0002-8111-0863)
- Cindy J. Lee (ORCID: https://orcid.org/0000-0002-2613-4387)
- Pierre-Jacques Hamard (ORCID: https://orcid.org/0000-0002-2484-6161)
- Alexander Noor Shoushtari (ORCID: https://orcid.org/0000-0002-8065-4412)
- Rohan Misra (ORCID: https://orcid.org/0000-0002-6355-2764)
- Ekta Khurana (ORCID: https://orcid.org/0000-0002-4351-7566)
- Deyou Zheng (ORCID: https://orcid.org/0000-0003-4354-5337)
- Merve Şahin (ORCID: https://orcid.org/0000-0003-3858-8332)
- Elissa W.P. Wong (ORCID: https://orcid.org/0000-0003-4843-9816)
- Alexander Martinez‐Fundichely (ORCID: https://orcid.org/0000-0002-7660-5511)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Tuan Trieu
- Yingqian A. Zhan (ORCID: https://orcid.org/0000-0002-3548-9227)
- Christina S. Leslie (ORCID: https://orcid.org/0000-0002-4571-5910)
- Rui Yang (ORCID: https://orcid.org/0000-0001-9358-9907)
- Morgan Lallo
- Andrew Rosowicz
- Fanny Tomas
- Nawaf Alomran
- Dan Li (ORCID: https://orcid.org/0000-0002-8777-4580)
- Yu Chen (ORCID: https://orcid.org/0000-0002-0171-3884)
- Shuyuan Cheng (ORCID: https://orcid.org/0000-0003-0746-509X)
Institutions
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Swim Across America (US)
- Lander Institute (IL)
- Yale University (US)
- Kettering University (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- College Medical Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Weill Cornell Medicine (US)
- Medical University of Vienna (AT)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-06-30
- DOI
- https://doi.org/10.1038/s41588-025-02239-6
- Citations
- 4
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22