BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.
BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.
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DOI：
10.1016/j.celrep.2016.03.054
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发表时间：
2016-04-19
期刊：
影响因子：
8.8
通讯作者：
Vakoc CR
中科院分区：
文献类型：
--
作者：
Bhagwat AS;Roe JS;Mok BYL;Hohmann AF;Shi J;Vakoc CR
溴结构域和外端（BET）蛋白BRD4可以物理地与中介复合物相互作用，但这种关联与BET抑制剂在癌症中的治疗效果的相关性尚不清楚。本研究表明，BET抑制可导致急性髓性白血病（AML）细胞基因组中顺式调控元件亚群快速释放Mediator。这些中介排斥位点与邻近基因的转录抑制高度相关，这些基因富含转录因子MYB的靶标和与白血病发生相关的功能。AML细胞中Mediator的shRNA筛选发现，MED12、MED13、MED23和MED24亚基在这种情况下与BRD4具有相似的调节功能，包括在维持髓细胞成熟阻断中发挥共同作用。这些发现表明BRD4和Mediator之间的相互作用对于基因特异性转录激活和AML维持具有重要的功能。
The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. An shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance.