Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma
Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma
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DOI：
10.1016/j.celrep.2018.12.016
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发表时间：
2018-12-26
期刊：
影响因子：
8.8
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Fulciniti, Mariateresa;Lin, Charles Y.;Munshi, Nikhil C.
启动子近端转录因子相关基因表达和超级增强子驱动的转录程序之间的关系还没有很好的定义。然而，它们独特的基因组占有率表明存在一种特定且可分离的基因控制机制。我们探讨了多发性骨髓瘤中E2 F转录因子和BET转录辅激活因子之间的转录和功能相互关系。我们发现，转录因子E2 F1和它的异源二聚体伙伴DP 1代表了在多发性骨髓瘤细胞的依赖性。全局染色质分析揭示了E2 F和BET的不同调控轴，E2 F主要定位于生长和/或增殖基因的活性基因启动子，而BET不成比例地定位于增强子调控的组织特异性基因。这两个独立的基因调控轴可以同时靶向破坏骨髓瘤增殖程序，为联合治疗提供了重要的分子机制。因此，这项研究表明，一个隔离的细胞功能控制，可能会受到干扰，在癌症与发展的一个有前途的治疗策略的潜力。
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.