Journal
GENOME BIOLOGY
Volume 21, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13059-020-02030-2
Keywords
PML-RAR alpha; ChIA-PET; 3D genome architecture; CTCF; RNA polymerase II (RNAPII); Transcription factor (TF); Transcriptional regulation; Super-enhancer (SE)
Funding
- NIH [HG009409, DK107967]
- HFSP [RGP0039/2017]
- Roux family endowment
- NCI [P30CA034196]
- National Natural Science Foundation of China [31100942]
- Polish National Science Centre [2014/15/B/ST6/05082, UMO-2013/09/B/NZ2/00121]
- National Leading Research Centre in Bialystok
- European Union under the European Social Fund
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BackgroundAcute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RAR alpha, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RAR alpha in leukemogenesis remain largely unknown.ResultsUsing an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RAR alpha induction and perform additional analyses in patient-derived APL cells with native PML-RAR alpha. We discover that PML-RAR alpha 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.ConclusionsOur results not only provide novel topological insights for the roles of PML-RAR alpha in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.
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