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Abstract
Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.
Original language | English |
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Pages (from-to) | 3022-3031.e7 |
Number of pages | 18 |
Journal | Cell Reports |
Volume | 28 |
Issue number | 12 |
DOIs | |
Publication status | Published - 17 Sept 2019 |
Keywords
- acute myeloid leukemia
- RUNX1-ETO
- promoter-enhancer interactions
- Promoter-Capture Hi-C
- transcriptional networks
- chromatin programming
- transcription factors
- epigenetic regulation
- integrated analysis of high-throughput data
- AP-1 signaling in acute myeloid leukemia
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Dive into the research topics of 'RUNX1-ETO depletion in t(8;21) AML leads to C/EBPα- and AP-1-mediated alterations in enhancer-promoter interaction'. Together they form a unique fingerprint.Projects
- 1 Finished
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Mechanistic insights into aberrant transcriptional programming in acute myeloid leukaemia
1/07/15 → 31/12/21
Project: Research
Equipment
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Birmingham Environment for Academic Research (BEAR)
Facility/equipment: Equipment