The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries.
The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries.
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DOI：
10.1016/j.molcel.2017.02.027
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发表时间：
2017-04-06
期刊：
影响因子：
16
通讯作者：
Blobel GA
中科院分区：
文献类型：
--
作者：
Hsu SC;Gilgenast TG;Bartman CR;Edwards CR;Stonestrom AJ;Huang P;Emerson DJ;Evans P;Werner MT;Keller CA;Giardine B;Hardison RC;Raj A;Phillips-Cremins JE;Blobel GA
BET（布罗莫结构域和末端外基序）蛋白是用于治疗多种疾病的药理学靶点，但单个BET家族成员的作用仍不清楚。我们发现，BRD 2，而不是BRD 4共定位与建筑/绝缘蛋白CCCTC结合因子（CTCF）全基因组。CTCF将BRD 2招募到共同绑定的站点，而BRD 2对于CTCF占用来说是可有可无的。位于两个不相关基因之间的CTCF/BRD 2占据元件的破坏使得调控影响从一个基因传播到另一个基因，这表明CTCF和BRD 2形成了转录边界。因此，单分子mRNA FISH揭示，在位点特异性CTCF破坏或BRD 2耗尽后，两种基因的表达变得越来越相关。HiC显示BRD 2耗尽削弱了CTCF和BRD 2共同占据的边界，但不是那些缺乏BRD 2的边界。这些发现表明BRD 2支持边界活性，并提高了药理学BET抑制剂可以通过干扰域边界功能部分影响基因表达的可能性。
BET (bromodomain and extraterminal motif) proteins are pharmacologic targets for the treatment of diverse diseases, yet the roles of individual BET family members remain unclear. We find that BRD2 but not BRD4 colocalizes with the architectural/insulator protein CCCTC-binding factor (CTCF) genome-wide. CTCF recruits BRD2 to co-bound sites, whereas BRD2 is dispensable for CTCF occupancy. Disruption of a CTCF/BRD2-occupied element positioned between two unrelated genes enables regulatory influence to spread from one gene to another, suggesting that CTCF and BRD2 form a transcriptional boundary. Accordingly, single molecule mRNA FISH reveals that upon site-specific CTCF disruption or BRD2 depletion, expression of the two genes becomes increasingly correlated. HiC shows that BRD2 depletion weakens boundaries co-occupied by CTCF and BRD2, but not those that lack BRD2. These findings indicate that BRD2 supports boundary activity and raise the possibility that pharmacologic BET inhibitors can influence gene expression in part by perturbing domain boundary function.