Liu Zhijie, Merkurjev Daria, Yang Feng, Li Wenbo, Oh Soohwan, Friedman Meyer J, Song Xiaoyuan, Zhang Feng, Ma Qi, Ohgi Kenneth A, Krones Anna, Rosenfeld Michael G
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Graduate Program in Bioinformatics and System Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Cell. 2014 Oct 9;159(2):358-73. doi: 10.1016/j.cell.2014.08.027.
Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by trans-recruitment and in situ assembly of a large 1-2 MDa complex of diverse DNA-binding transcription factors by ERα at ERE-containing enhancers. We refer to enhancers recruiting these factors as mega transcription factor-bound in trans (MegaTrans) enhancers. The MegaTrans complex is a signature of the most potent functional enhancers and is required for activation of enhancer RNA transcription and recruitment of coactivators, including p300 and Med1. The MegaTrans complex functions, in part, by recruiting specific enzymatic machinery, exemplified by DNA-dependent protein kinase. Thus, MegaTrans-containing enhancers represent a cohort of functional enhancers that mediate a broad and important transcriptional program and provide a molecular explanation for transcription factor clustering and hotspots noted in the genome.
增强子提供指导细胞类型特异性转录程序的关键信息，其受信号依赖性转录因子及其相关辅因子结合的调控。在此，我们报道，最强烈激活的雌激素（E2）反应性增强子的特征是，雌激素受体α（ERα）在含雌激素反应元件（ERE）的增强子处通过反式招募和原位组装一个由多种DNA结合转录因子组成的1-2兆道尔顿的大型复合物。我们将招募这些因子的增强子称为反式结合的巨型转录因子（MegaTrans）增强子。MegaTrans复合物是最有效的功能性增强子的标志，是激活增强子RNA转录和招募共激活因子（包括p300和Med1）所必需的。MegaTrans复合物部分通过招募特定的酶机制发挥作用，以DNA依赖性蛋白激酶为例。因此，含有MegaTrans的增强子代表了一组功能性增强子，它们介导广泛而重要的转录程序，并为基因组中观察到的转录因子聚类和热点提供了分子解释。
