Long ncRNA expression associates with tissue-specific enhancers

Abstract

Long non-coding RNAs (ncRNA) have recently been demonstrated to be expressed from a subset of enhancers and to be required for the distant regulation of gene expression. Several approaches to predict enhancers have been developed based on various chromatin marks and occupancy of enhancer-binding proteins. Despite the rapid advances in the field, no consensus how to define tissue specific enhancers yet exists. Here, we identify 2,695 long ncRNAs annotated by ENCODE (corresponding to 28% of all ENCODE annotated long ncRNAs) that overlap tissue-specific enhancers. We use a recently developed algorithm to predict tissue-specific enhancers, PreSTIGE, that is based on the H3K4me1 mark and tissue specific expression of mRNAs. The expression of the long ncRNAs overlapping enhancers is significantly higher when the enhancer is predicted as active in a specific cell line, suggesting a general interdependency of active enhancers and expression of long ncRNAs. This dependency is not identified using previous enhancer prediction algorithms that do not account for expression of their downstream targets. The predicted enhancers that overlap annotated long ncRNAs generally have a lower ratio of H3K4me1 to H3K4me3, suggesting that enhancers expressing long ncRNAs might be associated with specific epigenetic marks. In conclusion, we demonstrate the tissue-specific predictive power of PreSTIGE and provide evidence for thousands of long ncRNAs that are expressed from active tissue-specific enhancers, suggesting a particularly important functional relationship between long ncRNAs and enhancer activity in determining tissue-specific gene expression.

Identification of novel long non-coding RNAs deregulated in hepatocellular carcinoma using RNA-sequencing

“…In our study we also highlighted that more than 20% of the differentially expressed lncRNAs overlap with genomic loci described as enhancers [32]. In particular, we observed that 6 out of 11 eRNAs showed significant alterations in the tumour-adjacent cirrhotic tissues, with either gain or loss of co-expressed genes compared with control livers or paired matched HCCs.…”

“…Importantly, we observed a better clustering using only differentially expressed lncRNAs than when using differentially expressed protein-coding RNAs or all differentially expressed genes. Interestingly, 4 upregulated and 9 downderegulated lncRNAs in HCC (22.8% of all deregulated lncRNAs) have been recently described as lncRNAs associated with predicted enhancer activity [32]. A pathway analysis of upregulated protein-coding genes using Enrichr [33] showed an enrichment in genes mainly involved in cell cycle (p-value=0.0008) and angiogenesis (Supplementary Document 2).…”

Architectural and Functional Commonalities between Enhancers and Promoters

“…Transgenic overexpression of NeST was shown to induce IFN- γ synthesis in activated CD8+ T cells, suggesting a possible trans -mechanism to regulate its neighboring gene. Interestingly, a recent study found the previously described lncRNA, ncRNA-a3 mapping to a bi-directionally transcribed enhancer of the TAL1 gene (Orom et al, 2010; Vucicevic et al, 2015). Therefore, it is likely that as eRNAs in different human cells are fully catalogued, many of the currently annotated lncRNAs with enhancer-like function will fall under the classification of eRNAs (Vucicevic et al, 2015).…”

Diverse regulatory interactions of long noncoding RNAs

“…Stringent analysis of a set of intergenic lncRNAs by examining enhancer and promoter-characteristic histone marks (high K4me1/me3 and low K4me1/me3, respectively) for accurately determined transcription initiation sites revealed that intergenic lncRNAs are almost evenly divided between those arising from enhancer-associated (elncRNA) or promoter-associated (plncRNA) elements [14]. For example, a functionally characterized lncRNA, ncRNA-a3 , displayed similar characteristics to eRNAs as it was shown to originate from a bi-directionally transcribed enhancer of the TAL1 gene [13,16]. Therefore, some previously annotated lncRNAs appear to originate from functionally active enhancers, resulting in their new classification as eRNAs.…”