Abstract
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.
Highlights
Distal-acting enhancers are key elements in the regulatory processes that establish cell-type-specific patterns of gene expression
Deciphering the relationship between chromatin modifications and enhancer transcription To understand the relationship between chromatin modifications and enhancer RNAs (eRNAs) transcription, we collected ChIP-seq for 24 chromatin modifications in human IMR90 cells [23,24] and global run-on sequencing (GRO-seq) levels at enhancers [25] (Figure 1b, Supplementary Table S1, see ‘Materials and Methods’ section)
Using P300 ChIP-seq data, we identified P300-bound enhancers in IMR90 cells and further used GRO-seq data to classify them into eRNA+ and eRNAÀ enhancers
Summary
Distal-acting enhancers are key elements in the regulatory processes that establish cell-type-specific patterns of gene expression. Genome-wide identification of functionally active enhancers is necessary to understand the expression of genes, as well as developmental, and disease-related, processes. Chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) has allowed the genome-wide mapping enhancers by virtue of their specific chromatin features [1,2]. H3K27ac, in combination with H3K4me, is an important indicator of enhancer activity [13,14]. Other marks, such as H3K4me and H3K36me, are related to enhancer activity [15,16]. Poised enhancers are not functionally active but can be activated during differentiation or in response to external stimuli [13,17]. During the differentiation of embryonic stem cells (ESC), there is lineage-specific replacement of H3K27me with H3K27ac, resulting in the activation of lineage-specific enhancers [16–18]
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