Chromatin topology reorganization and transcription repression by PML-RARα in acute promyeloid leukemia
Authors:
- P. Wang,
- Zhonghui Tang,
- Byoungkoo Lee,
- Jiang Zhu,
- Liuyang Cai,
- Przemyslaw Szalaj,
- Simon Zhongyuan Tian,
- Meizhen Zheng,
- Dariusz Plewczyński,
- Xiaoan Ruan,
- Edison T. Liu,
- Chia-Lin Wei,
- Yijun Ruan
Abstract
Background: Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RARα in leukemogenesis remain largely unknown. Results: Using an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RARα induction and perform additional analyses in patient-derived APL cells with native PML-RARα. We discover that PML-RARα mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation. Conclusions: Our results not only provide novel topological insights for the roles of PML-RARα in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.
- Record ID
- WUT401bfc2536a44470bcdc15efc909d0d7
- Author
- Journal series
- Genome Biology, ISSN 1465-6906, [1474-7596]
- Issue year
- 2020
- Vol
- 21
- Keywords in English
- PML-RARα, ChIA-PET, 3D genome architecture, CTCF, RNA polymerase II(RNAPII), Transcription factor (TF), Transcriptional regulation, Super-enhancer (SE)
- ASJC Classification
- ; ;
- DOI
- DOI:10.1186/s13059-020-02030-2 Opening in a new tab
- URL
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212609/pdf/13059_2020_Article_2030.pdf Opening in a new tab
- Language
- (en) English
- Score (nominal)
- 200
- Score source
- journalList
- Score
- = 200.0, 03-05-2022, ArticleFromJournal
- Publication indicators
- = 3; = 0; : 2018 = 2.536; : 2020 (2 years) = 13.583 - 2020 (5 years) =17.433
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- Uniform Resource Identifier
- https://repo.pw.edu.pl/info/article/WUT401bfc2536a44470bcdc15efc909d0d7/
- URN
urn:pw-repo:WUT401bfc2536a44470bcdc15efc909d0d7
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or PerishOpening in a new tab system.