RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction.
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.
['Ptasinska|Anetta|A|', 'Pickin|Anna|A|', 'Assi|Salam A|SA|', 'Chin|Paulynn Suyin|PS|', 'Ames|Luke|L|', 'Avellino|Roberto|R|', 'Gröschel|Stefan|S|', 'Delwel|Ruud|R|', 'Cockerill|Peter N|PN|', 'Osborne|Cameron S|CS|', 'Bonifer|Constanze|C|']
D022762:CCAAT-Enhancer-Binding Proteins D002891:Chromosomes, Human, Pair 21 D002898:Chromosomes, Human, Pair 8 D050676:Core Binding Factor Alpha 2 Subunit D004742:Enhancer Elements, Genetic D017353:Gene Deletion D015973:Gene Expression Regulation, Leukemic D006801:Humans D015470:Leukemia, Myeloid, Acute D015514:Oncogene Proteins, Fusion D011401:Promoter Regions, Genetic D000075142:RUNX1 Translocation Partner 1 Protein D018808:Transcription Factor AP-1 D014178:Translocation, Genetic
RUNX1-ETO acute myeloid leukemia epigenetic regulation transcription factors Promoter-Capture Hi-C AP-1 signaling in acute myeloid leukemia chromatin programming integrated analysis of high-throughput data promoter-enhancer interactions transcriptional networks