On the Origin of lncRNAs: Missing Link Found

Abstract

Non-coding (nc)RNAs known as enhancer-derived RNAs (eRNAs) and as long ncRNAs (lncRNAs) have received much attention, but their true functional specialization and evolutionary origins remain obscure. The recent characterization of Bloodlinc, an eRNA derived from a super-enhancer that also functions as a lncRNA, suggests that lncRNAs can evolve from eRNAs.

Keywords: CTCF; chromatin loop; eRNA; lncRNA; noncoding RNA; superenhancer; topological activation domain.

Figure 1. Evolution of lncRNAs

(A) Typical enhancers are transcribed bidirectionally to produce eRNAs, which are short, unspliced, non-polyadenylated RNAs that can work in cis to stabilize enhancer-promoter communication and transcription factor (TF) binding. Insulator elements bound by CTCF and cohesins usually restrain the action of a typical enhancer. Topological activation domains (TADs) are large chromatin domains encompassing many genes and delimited by strong insulator elements. (B) Super-enhancers evolved to ensure robust expression of cell type-specific genes via selection of clusters of TF binding sites. Consequently, transcription over super-enhancers covers a longer distance, which increases the chances of spurious splicing, polyadenyation and stabilization of the RNA. Evolutionary forces can co-opt these stable RNAs to confer them with trans-functions at loci outside of the TAD of origin via fine-tuning of accidental RNA-RNA or RNA-protein interactions. In this scenario, distal regulation by a lncRNA derived from a super-enhancer would further reinforce cell type-specific transcription and cellular identity.