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

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.

Author P. Wang - [Jackson Laboratory]
P. Wang,,
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, Zhonghui Tang - [Jackson Laboratory]
Zhonghui Tang,,
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, Byoungkoo Lee - [Jackson Laboratory]
Byoungkoo Lee,,
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, Jiang Zhu - Cisco (Cisco) [Jackson Laboratory]
Jiang Zhu,,
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, Liuyang Cai - [Jackson Laboratory]
Liuyang Cai,,
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, Przemyslaw Szalaj - [University of Warsaw, Centre of New Technologies]
Przemyslaw Szalaj,,
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, Simon Zhongyuan Tian - [Jackson Laboratory]
Simon Zhongyuan Tian,,
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, Meizhen Zheng - [Jackson Laboratory]
Meizhen Zheng,,
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, Dariusz Plewczyński (FMIS / DIPS) - [Centrum Nowych Technologii, Uniwersytet Warszawski]
Dariusz Plewczyński,,
- Department of Information Processing Systems
- Centrum Nowych Technologii, Uniwersytet Warszawski
, Xiaoan Ruan - [Jackson Laboratory]
Xiaoan Ruan,,
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et al.`
Journal seriesGenome Biology, ISSN 1465-6906, [1474-7596]
Issue year2020
Vol21
Keywords in EnglishPML-RARα, ChIA-PET, 3D genome architecture, CTCF, RNA polymerase II(RNAPII), Transcription factor (TF), Transcriptional regulation, Super-enhancer (SE)
ASJC Classification1105 Ecology, Evolution, Behavior and Systematics; 1307 Cell Biology; 1311 Genetics
DOIDOI:10.1186/s13059-020-02030-2
URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212609/pdf/13059_2020_Article_2030.pdf
Languageen angielski
Score (nominal)200
Score sourcejournalList
ScoreMinisterial score = 200.0, 10-06-2020, ArticleFromJournal
Publication indicators Scopus Citations = 0; WoS Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 2.536; WoS Impact Factor: 2015 = 11.313 (2) - 2015=13.168 (5)
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