|Description||The Cancer eRNA Atlas.|
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Enhancers are a key class of non-coding regulatory DNA regions, and their critical roles in cancer have attracted more and more attention. Recent studies of ours and others have shown that enhancer activities can be inferred from RNA-seq data based on enhancer RNA (eRNA) signals. But quantifying eRNA profiles depend heavily on precise enhancer transcription loci, and currently only a small proportion of eRNA loci has been identified. This knowledge gap significantly limits the investigations of enhancer-mediated cancer mechanisms. Further, ChIP-seq cannot be easily applied to large cohorts of tissue samples such as TCGA, preventing the related clinical investigations and applications.
Here we develop the Cancer eRNA Atlas (TCeA) data portal to utilize ultra-deep RNA-seq data aggregated from TCGA and GTEx (~10,000 samples/runs in each set) for the discovery of eRNA epxression patterns in super-enhancers. We found that super-enhancers usually contain discrete loci featured by sharp eRNA expression peaks (~100bp). The locations of eRNA expression peaks are highly recurrent across different tissues, once activated. The expression of super-enhancer eRNA loci are regulated by well-positioned nucleosomes. These well-positioned nucleosomes are not only conserved across different tissues but also across mammalian evolution. Based on these principles, we systematically identified >300,000 such precise eRNA loci in ~377 Mb of super-enhancer regions (and more in the broad putative regulatory regions), providing the very first high-resolution map of eRNA loci in super-enhancers (see our work-flow in Figure 1). With this map, super-enhancer activities can be easily and accurately measured in patient samples using routine RNA-seq, thereby enabling a broad range of biological investigations and translational applications. TCEA portal has provided the annotation of these eRNA loci and quantified their activity in > 20,000 tumor (TCGA), tissue (GTEx), and cell line (CCLE) samples.