Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples – including Xist, which orchestrates X chromosome inactivation – has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here researchers from MIT discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. The researchers explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus.
Long non-coding RNAs can form spatial compartments in the nucleus
a | Interactions with proteins and DNA enable long non-coding RNAs (lncRNAs) to form dynamic spatial compartments in the nucleus. Assembly may be controlled by passive diffusion and interactions that are characterized by specific association and dissociation constants (Kon and Koff). The lncRNA Firre forms high-affinity interactions with specific DNA loci on different mouse chromosomes, resulting in the colocalization of these loci in three-dimensional (3D) space to facilitate the co-regulation of genes involved in energy metabolism and/or adipogenesis. b | The upregulation of the lncRNA NEAT1 (nuclear enriched abundant transcript 1), which initially localizes in close 3D proximity to its transcribed locus, nucleates the formation of paraspeckles. These are characterized by high local concentration of NEAT1 and of paraspeckle proteins. c | High affinity to both protein and DNA enables lncRNAs to recruit genomic loci to functional nuclear bodies to influence gene expression. For example, interactions between MALAT1 and protein components of pre-organized nuclear speckles could assist in promoting transcription or regulating mRNA splicing. Pol II, RNA polymerase II.