Macro LncRNAs: a New Layer of Cis-regulatory Information in the Mammalian Genome

In the past ten years, long non-protein-coding RNAs (lncRNAs) have been shown to comprise a major part of the mammalian transcriptome and are predicted from their highly specific expression patterns, to play a role in regulating protein-coding gene expression in development and disease. Many lncRNAs particularly those lying in imprinted clusters, are predominantly unspliced "macro" transcripts that can also show a low level of splicing, and both the unspliced and spliced transcript have the potential to be functional. Three known imprinted macro lncRNAs have been shown to silence from three to ten genes in cis in imprinted gene clusters. We review here the potential for functional macro lncRNAs, defined here as "inefficiently-spliced lncRNAs" to play a wider cis-regulatory role in the mammalian genome. This potential has been underestimated by the inability of current RNA-seq technology to annotate unspliced macro lncRNAs.