Department of Chemistry and Biochemistry, UCSD, La Jolla 92093, CA, USA and Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA 92093-0359, USA.
Nucleic Acids Res. 2013 Dec;41(22):10032-43. doi: 10.1093/nar/gkt826. Epub 2013 Sep 12.
Enhancers play a pivotal role in regulating the transcription of distal genes. Although certain chromatin features, such as the histone acetyltransferase P300 and the histone modification H3K4me1, indicate the presence of enhancers, only a fraction of enhancers are functionally active. Individual chromatin marks, such as H3K27ac and H3K27me3, have been identified to distinguish active from inactive enhancers. However, the systematic identification of the most informative single modification, or combination thereof, is still lacking. Furthermore, the discovery of enhancer RNAs (eRNAs) provides an alternative approach to directly predicting enhancer activity. However, it remains challenging to link chromatin modifications to eRNA transcription. Herein, we develop a logistic regression model to unravel the relationship between chromatin modifications and eRNA synthesis. We perform a systematic assessment of 24 chromatin modifications in fetal lung fibroblast and demonstrate that a combination of four modifications is sufficient to accurately predict eRNA transcription. Furthermore, we compare the ability of eRNAs and H3K27ac to discriminate enhancer activity. We demonstrate that eRNA is more indicative of enhancer activity. Finally, we apply our fibroblast trained model to six other cell-types and successfully predict eRNA synthesis. Thus, we demonstrate the learned relationships are general and independent of cell-type. We provided a powerful tool to identify active enhancers and reveal the relationship between chromatin modifications, eRNA production and enhancer activity.
增强子在调节远端基因的转录中起着关键作用。虽然某些染色质特征，如组蛋白乙酰转移酶 P300 和组蛋白修饰 H3K4me1，表明存在增强子，但只有一部分增强子具有功能活性。个别染色质标记，如 H3K27ac 和 H3K27me3，已被确定可区分活性和非活性增强子。然而，系统地确定最具信息量的单一修饰或其组合仍然缺乏。此外，增强子 RNA（eRNA）的发现提供了一种直接预测增强子活性的替代方法。然而，将染色质修饰与 eRNA 转录联系起来仍然具有挑战性。在此，我们开发了一种逻辑回归模型来揭示染色质修饰与 eRNA 合成之间的关系。我们对胎儿肺成纤维细胞中的 24 种染色质修饰进行了系统评估，并证明四种修饰的组合足以准确预测 eRNA 转录。此外，我们比较了 eRNAs 和 H3K27ac 区分增强子活性的能力。我们证明 eRNA 更能指示增强子活性。最后，我们将我们在成纤维细胞中训练的模型应用于另外六种细胞类型，并成功预测了 eRNA 的合成。因此，我们证明所学到的关系是通用的，不依赖于细胞类型。我们提供了一种强大的工具来识别活性增强子，并揭示染色质修饰、eRNA 产生和增强子活性之间的关系。
