MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Nicholas T. Crump, Alastair Smith, Laura Godfrey, Ana M. Dopico-Fernandez, Nicholas Denny, Joe Harman, Joseph C. Hamley, Nicole Jackson, Catherine Chahrour, Simone G. Riva, Siobhan Rice, Jaehoon Kim, Venkatesha Basrur, Damian Fermin, Kojo S.J. Elenitoba‐Johnson, Robert G. Roeder, C. David Allis, Irene Roberts, Anindita Roy, Huimin Geng, James Davies, Thomas A. Milne
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.