Discovery of active enhancers through bidirectional expression of short transcripts

Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Genome biology (Impact Factor: 10.81). 11/2011; 12(11):R113. DOI: 10.1186/gb-2011-12-11-r113
Source: PubMed


Long-range regulatory elements, such as enhancers, exert substantial control over tissue-specific gene expression patterns. Genome-wide discovery of functional enhancers in different cell types is important for our understanding of genome function as well as human disease etiology.
In this study, we developed an in silico approach to model the previously reported phenomenon of transcriptional pausing, accompanied by divergent transcription, at active promoters. We then used this model for large-scale prediction of non-promoter-associated bidirectional expression of short transcripts. Our predictions were significantly enriched for DNase hypersensitive sites, histone H3 lysine 27 acetylation (H3K27ac), and other chromatin marks associated with active rather than poised or repressed enhancers. We also detected modest bidirectional expression at binding sites of the CCCTC-factor (CTCF) genome-wide, particularly those that overlap H3K27ac.
Our findings indicate that the signature of bidirectional expression of short transcripts, learned from promoter-proximal transcriptional pausing, can be used to predict active long-range regulatory elements genome-wide, likely due in part to specific association of RNA polymerase with enhancer regions.

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    • "signature of active REs (Core et al., 2008, 2014; Melgar et al., 2011). We used discriminative regulatory element detection from GRO-seq (dREG), which recognizes the pattern of divergent transcription at active REs, to characterize the regulatory state of both nascent transcription and RE activation (Figure 2A, green; Danko et al., 2014). "
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    Cell Reports 10/2015; 13(2). DOI:10.1016/j.celrep.2015.08.075 · 8.36 Impact Factor
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    • "Pol II occupies enhancers of stimulated macrophages, neurons, keratinocytes, and breast cancer cells, resulting in localized transcription of eRNAs (De Santa et al., 2010; Hah et al., 2013; Kim et al., 2010; Lam et al., 2013; Li et al., 2013; Melo et al., 2013; Ørom et al., 2010; Ostuni et al., 2013). Currently, eRNAs are described as a rare population of $0.5–5 kb transcripts, some of which undergo polyadenylation (based on poly[A]+ sequencing) (De Santa et al., 2010; Djebali et al., 2012; Hah et al., 2013; Kim et al., 2010; Melgar et al., 2011; Ørom et al., 2010). The significance and molecular mechanisms by which eRNAs exert their function are currently under investigation. "
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    • "Wang et al. (147) found that eRNA expression was better at indicating enhancer activation than TF binding and histone modification data. In addition to chromatin state and evolutionary conservation, the detection of eRNAs has been used to identify putative enhancers (148). It remains an open question whether these eRNAs are simply transcriptional noise or are functionally important. "
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