DOT1L 抑制揭示了依赖于 H3K79 甲基化的独特增强子亚群。

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation.

机构信息

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.

MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.

出版信息

Nat Commun. 2019 Jun 26;10(1):2803. doi: 10.1038/s41467-019-10844-3.

Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.

增强子元件是许多重要基因的关键调控特征。一些通用特征，包括存在特定的组蛋白修饰，用于划定潜在的活性增强子。在这里，我们揭示了具有 H3 赖氨酸 79 二甲基或三甲基化（me2/3）（我们称之为 H3K79me2/3 增强子元件或 KEEs）的假定增强子可以在多种细胞类型中找到。混合谱系白血病基因（MLL）重排（MLL-r），如 MLL-AF4，是不可治愈的急性淋巴细胞白血病（ALL）的主要原因。我们使用 DOT1L 抑制剂 EPZ-5676 在 MLL-AF4 白血病细胞中进行研究，结果表明 H3K79me2/3 对于维持染色质可及性、组蛋白乙酰化和转录因子结合是必需的，这种结合特异性地发生在 KEEs 上，而不是非 KEE 增强子上。我们接着证明 H3K79me2/3 对于维持 KEEs 子集上的增强子-启动子相互作用是必需的。总的来说，这些数据表明 H3K79me2/3 在 MLL-AF4 白血病细胞中的一组活性增强子中具有功能作用。