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

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 loss of these factors abolishes enhancer-promoter contact. This work not only provides a new 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.

INSTRUMENT(S): LTQ

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Medulla Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Thomas Milne  

LAB HEAD: Thomas A Milne

PROVIDER: PXD043920 | Pride | 2023-08-18

REPOSITORIES: pride