Local regulation of gene expression by lncRNA promoters, transcription and splicing

Mammalian genomes are pervasively transcribed(1,2) to produce thousands of long non-coding RNAs (lncRNAs)(3,4). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA-protein interactions to influence the expression of nearby genes(5-7), and it has been suggested that many other lncRNAs can also act as local regulators(8,9). Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes(2,10,11). However, these correlations have been challenging to dissect(12) and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers(13-16), and the process of transcription itself may contribute to gene regulation by recruiting activating factors or remodelling nucleosomes(10,17,18). Here we use genetic manipulation in mouse cell lines to dissect 12 genomic loci that produce lncRNAs and find that 5 of these loci influence the expression of a neighbouring gene in cis. Notably, none of these effects requires the specific lncRNA transcripts themselves and instead involves general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Furthermore, such effects are not limited to lncRNA loci: we find that four out of six protein-coding loci also influence the expression of a neighbour. These results demonstrate that cross-talk among neighbouring genes is a prevalent phenomenon that can involve multiple mechanisms and cis-regulatory signals, including a role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and non-coding genes.