From structure to function: Route to understanding lncRNA mechanism

Abstract

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.

Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

“…In the nucleus, lncRNAs can act through chromatin modifications, transcriptional regulations or interaction with enhancers. In the cytoplasm, lncRNAs act as miRNA sponges, influence mRNA stability and level of translation [ 123 ]. LncRNAs also play a role in regulating the expression of genes by acting as signals (participating in transmission of specific signaling pathways as a signal transduction molecule), scaffolds (downstream effectors can bind to the same lncRNA molecule to achieve information exchange and integration between different signaling pathways), guides (lncRNA can recruit chromatin-modifying enzymes to target genes) and decoys (lncRNA binds directly to proteins thus blocking the role of the molecule and signaling pathways) [ 124 ].…”

Long Non-Coding RNA Regulation of Epigenetics in Vascular Cells

“…LncRNAs can be categorised by their origin of transcription and position of neighbouring genes into sense, natural antisense, intronic, intergenic, bidirectional promoter, and enhancer lncRNAs. Their biogenesis is distinct from that of mRNA as they are poorly evolutionarily conserved, often less abundant, more tissue-specific, display distinct spatiotemporal expression and specific subcellular localisation and function, and tend to form secondary structural domains folded into specific scaffolds [10,11]. Indeed, despite significant differences in the primary sequence, lncRNA homology across species can be identified through the analysis of their secondary and tertiary structures key to their specific function [12].…”

“…Further advancements in the field largely depend on a better understanding of the structural organisation of lncRNAs and structure-to-function relations. Due to the poor conservation across species, the currently available tools for functional prediction based on a primary sequence similarity or structural predictions are not of great use [11]. However, the use of CRISPR (clustered regularly interspaced short palindromic repeats)-mediated gene editing to introduce targeted modifications into lncRNAs, together with novel technologies such as genome-wide chromatin interrogation, locked nucleic acids, bridged nucleic acids, and novel approaches to RNA purification in vitro and in vivo, will provide a more comprehensive understanding of the lncRNA structural domains, their folding patterns, and undiscovered mechanisms of action.…”

The role of long noncoding RNAs in livestock adipose tissue deposition

“…In addition, while the process of lncRNA production from specific genomic sites may be conserved, the sequence, structure, and function of the products may not be conserved [29]. Finally, the conservation of lncRNA functions in different species is also a relevant point in the field, and is often associated with sequence and structure [30]. Most importantly, the low sequence conservation of lncRNAs across different species has led some to dismiss lncRNAs as transcriptional noise [31].…”