RNAs have emerged as a major target for diagnostics and therapeutics approaches. Regulatory nonprotein‐coding RNAs (ncRNAs) in particular display remarkable versatility. They can fold into complex structures and interact with proteins, DNA, and other RNAs, thus modulating activity, localization, or interactome of multi‐protein complexes. Thus, ncRNAs confer regulatory plasticity and represent a new layer of regulatory control. Interestingly, long noncoding RNAs (lncRNAs) tend to acquire complex secondary and tertiary structures and their function—in many cases—is dependent on structural conservation rather than primary sequence conservation.Whereas for many proteins, structure and its associated function are closely connected, for lncRNAs, the structural domains that determine functionality and its interactome are still not well understood. Numerous approaches for analyzing the structural configuration of lncRNAs have been developed recently. Here, will provide an overview of major experimental approaches used in the field, and discuss the potential benefit of using combinatorial strategies to analyze lncRNA modes of action based on structural information.

The human genome encodes several thousand long non-protein coding transcripts > 200 nucleotides in length, a subset of which were shown to play important roles in regulation of gene expression. We recently identified TINCR, a lncRNA required for induction of key differentiation genes in epidermal tissue, including genes mutated in human skin diseases characterized by disrupted epidermal barrier formation. High-throughput analyses of TINCR RNA- and protein-interactomes revealed TINCR interaction with differentiation mRNAs as well as the Staufen1 protein. TINCR, together with Staufen1, seems to stabilize a subset of mRNAs required for epidermal differentiation. Here, we discuss the emerging roles of Staufen1 and TINCR in the regulation of mammalian cell differentiation mediated by interaction with target mRNAs. We consider a role for TINCR as an epithelial-specific guide for targeting the Staufen1 protein to specific mRNAs, reflecting the increasing complexity of gene regulatory processes in mammalian cells and tissue.

The More the Merrier—Complexity in Long Non-Coding RNA Loci