An unexpected contribution of lincRNA splicing to enhancer function

2018

Cell Systems

Graphical AbstractHighlights d eRNA-producing centers (EPCs) can be readily annotated from DHS and GRO-seq data d EPCs that serve as lncRNA promoters are associated with more active enhancers d lncRNA splicing is associated with higher enhancer activity d The ability to drive lncRNA production is a conserved feature of some enhancers Authors Noa Gil, Igor Ulitsky Correspondence igor.ulitsky@weizmann.ac.il In BriefTwo structurally distinct species of noncoding RNAs, eRNAs and lncRNAs, are produced from enhancers, but functional implications are unclear. We find that lncRNA-producing enhancers are more active and that this heightened activity is driven by conserved, directional splicing signals, indicating a causal role of lncRNA processing in enhancer activity. SUMMARYActive enhancers in mammals produce enhancer RNAs (eRNAs) that are bidirectionally transcribed, unspliced, and unstable. Enhancer regions are also enriched with long noncoding RNA (lncRNA) transcripts, which are typically spliced and substantially more stable. In order to explore the relationship between these two classes of RNAs, we analyzed DNase hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA-producing centers (EPCs). EPCs found very close to transcription start sites of lncRNAs exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic chromatin landscape. These EPCs are associated with higher enhancer activity, driven at least in part by the presence of conserved, directional splicing signals that promote lncRNA production, pointing at a causal role of lncRNA processing in enhancer activity. Together, our results suggest that the conserved ability of some enhancers to produce lncRNAs augments their activity in a manner likely mediated through lncRNA maturation.

Section: Discussionsupporting

confidence: 67%

Production of Spliced Long Noncoding RNAs Specifies Regions with Increased Enhancer Activity

Gil

2018

Cell Systems

“…These regions are associated with stronger enhancer activity, which is encoded in their sequences (Figure 2D) and appears to be driven in part by the presence of conserved, directional splicing signals that drive lncRNA production. Appearance in evolution of lncRNA transcripts in intergenic regions is associated with modestly higher expression of the flanking PCGs (Kutter et al 2012); consistently, recent studies, based on methods complementary to the ones we used here, reported that splicing of RNA transcripts, both coding and noncoding, could increase the expression of nearby genes (Engreitz et al 2016;Tan et al 2018). Together with our findings, the emerging conclusion is that RNA splicing and/or recruitment of the spliceosome plays a general role in sculpting the local chromatin/activity state of the underlying genomic region, thereby causing enhanced expression of the associated PCGs.…”

Section: Discussionsupporting

confidence: 64%

Production of spliced long noncoding RNAs specifies regions with increased enhancer activity

Gil

2018

Preprint

Active enhancers in mammals produce enhancer RNAs (eRNAs), that are bidirectionally transcribed, unspliced, and unstable noncoding RNAs. Enhancer regions are also enriched with long noncoding RNA (lncRNA) genes, which are typically spliced and are longer and substantially more stable than eRNAs. In order to explore the relationship between these two classes of RNAs and the implications of lncRNA transcription on enhancer functionality, we analyzed DNAse hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA producing centers (EPCs). A subset of EPCs, which are found very close to the transcription start site of lncRNA genes, exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic landscape of bound proteins. These EPCs are associated with a subset of relatively highly active enhancers. This stronger enhancer activity is driven, at least in part, by the presence of evolutionary conserved, directional splicing signals that promote lncRNA production, pointing at a causal role of lncRNA processing in enhancer activity. Together, our results suggest a model whereby the ability of some enhancers to produce lncRNAs, which is conserved in evolution, enhances their activity in a manner likely mediated through maturation of the associated lncRNA.

“…Inefficient splicing may help place lncRNAs at different subnuclear compartments and poise them for specific activities. Conversely, splicing itself is reported to be important for the functions of at least some lncRNAs (Engreitz et al 2016;Gil and Ulitsky 2018;Tan et al 2018). Regulated splicing can further assist in "releasing" the RNA from one compartment to another, allowing precise timing of its functional activity.…”

Section: Discussionmentioning

confidence: 99%

Predictive models of subcellular localization of long RNAs

Zuckerman

2019

RNA

Export to the cytoplasm is a key regulatory junction for both protein-coding mRNAs and long noncoding RNAs (lncRNAs), and cytoplasmic enrichment varies dramatically both within and between those groups. We used a new computational approach and RNA-seq data from human and mouse cells to quantify the genome-wide association between cytoplasmic/ nuclear ratios of both gene groups and various factors, including expression levels, splicing efficiency, gene architecture, chromatin marks, and sequence elements. Splicing efficiency emerged as the main predictive factor, explaining up to a third of the variability in localization. Combination with other features allowed predictive models that could explain up to 45% of the variance for protein-coding genes and up to 34% for lncRNAs. Factors associated with localization were similar between lncRNAs and mRNAs with some important differences. Readily accessible features can thus be used to predict RNA localization.