MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia

• Published in: Nature communications Vol. 14; no. 1; p. 5208
• Main Authors: Crump, Nicholas T., Smith, Alastair L., Godfrey, Laura, Dopico-Fernandez, Ana M., Denny, Nicholas, Harman, Joe R., Hamley, Joseph C., Jackson, Nicole E., Chahrour, Catherine, Riva, Simone, Rice, Siobhan, Kim, Jaehoon, Basrur, Venkatesha, Fermin, Damian, Elenitoba-Johnson, Kojo, Roeder, Robert G., Allis, C. David, Roberts, Irene, Roy, Anindita, Geng, Huimin, Davies, James O. J., Milne, Thomas A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-08-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/15; 38/23; 38/39; 38/91; 45; 45/15; 49; 49/15; 631/337/100/101; 631/337/176; 631/337/572/2102; 631/67/2332; 692/4028/67/1990/283; Binding; Cell Cycle Proteins; Chromosomes; Elongation; Enhancers; Eukaryotes; Fusion protein; High density; Humanities and Social Sciences; Humans; Leukemia; Leukemia - genetics; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - genetics; Nuclear Proteins - genetics; Oncogene Proteins, Fusion - genetics; Oncogenes; Promoter Regions, Genetic - genetics; Regulatory Sequences, Nucleic Acid; Science; Science (multidisciplinary); Transcription elongation; Transcription factors; Transcription Factors - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40981-9

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.
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.