Chromatin topology reorganization and transcription repression by PML-RARα in acute promyeloid leukemia
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
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.
|Journal series||Genome Biology, ISSN 1465-6906, [1474-7596]|
|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||; ;|
|Score||= 200.0, 10-06-2020, ArticleFromJournal|
|Publication indicators||= 0; = 0; : 2018 = 2.536; : 2015 = 11.313 (2) - 2015=13.168 (5)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.