1. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
- Author
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Nicholas T. Crump, Alastair L. Smith, Laura Godfrey, Ana M. Dopico-Fernandez, Nicholas Denny, Joe R. Harman, Joseph C. Hamley, Nicole E. Jackson, Catherine Chahrour, Simone Riva, Siobhan Rice, Jaehoon Kim, Venkatesha Basrur, Damian Fermin, Kojo Elenitoba-Johnson, Robert G. Roeder, C. David Allis, Irene Roberts, Anindita Roy, Huimin Geng, James O. J. Davies, and Thomas A. Milne
- Subjects
Science - Abstract
Abstract Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.
- Published
- 2023
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