Conformation and structural dynamics of the Xist lncRNA A-repeats

Abstract

Long noncoding RNAs (lncRNAs) are non‐protein‐encoding transcripts with lengths of 500 or more nucleotides (nt), with some spanning up to several thousands of nucleotides 1. LncRNAs have emerged as important regulators of gene expression and cellular functions, as transcriptional regulators at the level of chromatin, as scaffolding platforms, and as guides for RNP localization 2–9. Recent advancements in chemical probing experiments and their coupling with next generation sequencing analysis have enabled us to determine the secondary structures of nearly 50 of the known 200,000 lncRNAs 10–13. Critically, the molecular functions of lncRNAs depend on local and global structures, which are modulated by RNA binding proteins 14–22. RNAs are often conformationally flexible and may utilize structural variability to regulate biological function 23–28. For the lncRNA COOLAIR, it was recently demonstrated that changes in temperature promote the interconversion of structural states, with specific conformations being linked to specific biological processes 29. The lncRNA Braveheart is dynamic and interactions with its cognate protein binding partner, the cellular nucleic acid binding protein (CNBP), alter the conformation of the lncRNA 17. The structures of lncRNAs are also modulated by post‐transcriptional modifications, such as N‐6 methyladenosine (m6A), as has been shown for Xist and MALAT1 20,30. In these instances, the m6A modification leads to conformational changes to increase the accessibility of protein binding sites. Thus, lncRNA conformational dynamics are critical for function.