MLL-AF4 cooperates with PAF1 and FACT to drive high density enhancer interactions in leukemia [Micro-Capture C]

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 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. Micro-Capture-C

异常增强子激活是驱动多数癌症中癌基因表达的关键机制。尽管学界对真核生物中大型染色体结构域的调控机制已有较为充分的认知，但增强子-启动子相互作用的具体细节仍有待进一步阐明。近期研究表明，BRD4、中介体（Mediator）这类共激活因子对增强子-启动子相互作用的影响甚微。在由MLL-AF4融合蛋白驱动的白血病中，本研究借助超高分辨率技术Micro-Capture-C（MCC）证实：MLL-AF4的结合可在部分关键靶基因位点诱导形成范围广泛、密度较高的增强子-启动子相互作用区域。这类增强子位点富集PAF1C、FACT等转录延伸因子，且敲除这些因子会完全阻断增强子与启动子之间的相互接触。本研究不仅为解析MLL-AF4如何驱动白血病中关键基因的高水平转录提供了新的研究模型，同时也提出了一个连接增强子-启动子互作与转录延伸的通用调控模型。Micro-Capture-C