Bhagwat Anand S, Roe Jae-Seok, Mok Beverly Y L, Hohmann Anja F, Shi Junwei, Vakoc Christopher R
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell Rep. 2016 Apr 19;15(3):519-530. doi: 10.1016/j.celrep.2016.03.054. Epub 2016 Apr 7.
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. A 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.
含溴结构域和额外末端（BET）蛋白BRD4可与中介体复合物发生物理相互作用，但这种关联与BET抑制剂在癌症治疗中的效果之间的相关性尚不清楚。在此，我们表明BET抑制导致中介体从急性髓系白血病（AML）细胞基因组中的一部分顺式调控元件上快速释放。这些中介体被驱逐的位点与邻近基因的转录抑制高度相关，这些邻近基因富含转录因子MYB的靶标以及与白血病发生相关的功能。在AML细胞中对中介体进行的短发夹RNA（shRNA）筛选确定，MED12、MED13、MED23和MED24亚基在这种情况下发挥与BRD4相似的调控功能，包括在维持髓系成熟阻滞中具有共同作用。这些发现表明，BRD4与中介体之间的相互作用对于基因特异性转录激活和AML维持具有功能重要性。
