1. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
- Author
-
Crump NT, Smith AL, Godfrey L, Dopico-Fernandez AM, Denny N, Harman JR, Hamley JC, Jackson NE, Chahrour C, Riva S, Rice S, Kim J, Basrur V, Fermin D, Elenitoba-Johnson K, Roeder RG, Allis CD, Roberts I, Roy A, Geng H, Davies JOJ, and Milne TA
- Subjects
- Humans, Transcription Factors genetics, Regulatory Sequences, Nucleic Acid, Promoter Regions, Genetic genetics, Cell Cycle Proteins, Oncogene Proteins, Fusion genetics, Myeloid-Lymphoid Leukemia Protein genetics, Nuclear Proteins genetics, Leukemia genetics
- 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., (© 2023. Springer Nature Limited.)
- Published
- 2023
- Full Text
- View/download PDF