1. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
- Author
-
Crump, Nicholas, Smith, Alastair, Godfrey, Laura, Dopico-Fernandez, Ana, Denny, Nicholas, Harman, Joe, Hamley, Joseph, Jackson, Nicole, Chahrour, Catherine, Riva, Simone, Rice, Siobhan, Kim, Jaehoon, Basrur, Venkatesha, Fermin, Damian, Elenitoba-Johnson, Kojo, Roeder, Robert, Allis, C, Roberts, Irene, Roy, Anindita, Geng, Huimin, Davies, James, and Milne, Thomas
- Subjects
Humans ,Nuclear Proteins ,Transcription Factors ,Regulatory Sequences ,Nucleic Acid ,Leukemia ,Promoter Regions ,Genetic ,Cell Cycle Proteins ,Oncogene Proteins ,Fusion ,Myeloid-Lymphoid Leukemia Protein - 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