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Discovery of active enhancers through bidirectional expression of short transcripts

Michael F Melgar12, Francis S Collins1* and Praveen Sethupathy345*

Author affiliations

1 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA

2 Current address: School of Medicine, The University of California at San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA

3 Department of Genetics, The University of North Carolina at Chapel Hill, 130 South Building, Chapel Hill, NC 27599, USA

4 Carolina Center for Genome Sciences, The University of North Carolina at Chapel Hill, 130 South Building, Chapel Hill, NC 27599, USA

5 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 130 South Building, Chapel Hill, NC 27599, USA

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Citation and License

Genome Biology 2011, 12:R113  doi:10.1186/gb-2011-12-11-r113

Published: 14 November 2011

Abstract

Background

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.

Results

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.

Conclusions

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.