The histone variant H2A.Z is an important regulator of enhancer activity.
The histone variant H2A.Z is an important regulator of enhancer activity.
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DOI：
10.1093/nar/gkv825
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发表时间：
2015-11-16
影响因子：
14.9
通讯作者：
Gévry N
中科院分区：
文献类型：
--
作者：
Brunelle M;Nordell Markovits A;Rodrigue S;Lupien M;Jacques PÉ;Gévry N
不同细胞类型中的基因调控程序主要通过细胞特异性增强子活性来定义。组蛋白变体H2A.Z主要通过控制近端启动子在转录中发挥重要作用，但其对增强子功能的影响尚不清楚。在这里，我们通过全基因组方法证明了H2A.Z存在于雌激素受体α（ERα）结合的活性增强子的子集中。我们还确定H2A.Z不会影响ERα增强子周围的局部核小体定位，使用核小体分辨率和无监督模式发现的ChIP测序。我们进一步强调了H2 A. Z富集的增强子与染色质可及性、H3 K122 ac富集和低甲基化DNA相关。此外，在雌激素刺激时，H2A.Z占据的增强子产生增强子RNA（eRNA），并募集RNA聚合酶II以及RAD 21，其是参与增强子和启动子之间的染色质相互作用的粘附素复合物的成员。重要的是，它们的募集和eRNA的产生被H2A.Z耗尽所消除，从而揭示了H2A.Z占据和增强子活性之间的新的功能联系。总之，我们的研究结果表明，H2A.Z作为一个重要的球员增强子功能，建立和维持RNA聚合酶II的招聘，eRNA转录和增强子-启动子相互作用，增强子活性的所有基本属性所需的染色质环境。
Gene regulatory programs in different cell types are largely defined through cell-specific enhancers activity. The histone variant H2A.Z has been shown to play important roles in transcription mainly by controlling proximal promoters, but its effect on enhancer functions remains unclear. Here, we demonstrate by genome-wide approaches that H2A.Z is present at a subset of active enhancers bound by the estrogen receptor alpha (ERα). We also determine that H2A.Z does not influence the local nucleosome positioning around ERα enhancers using ChIP sequencing at nucleosomal resolution and unsupervised pattern discovery. We further highlight that H2A.Z-enriched enhancers are associated with chromatin accessibility, H3K122ac enrichment and hypomethylated DNA. Moreover, upon estrogen stimulation, the enhancers occupied by H2A.Z produce enhancer RNAs (eRNAs), and recruit RNA polymerase II as well as RAD21, a member of the cohesin complex involved in chromatin interactions between enhancers and promoters. Importantly, their recruitment and eRNAs production are abolished by H2A.Z depletion, thereby revealing a novel functional link between H2A.Z occupancy and enhancer activity. Taken together, our findings suggest that H2A.Z acts as an important player for enhancer functions by establishing and maintaining a chromatin environment required for RNA polymerase II recruitment, eRNAs transcription and enhancer-promoters interactions, all essential attributes of enhancer activity.