LNCing RNA to immunity

Abstract

Despite an ever-increasing appreciation of how protein-coding genes shape immune responses, the molecular underpinnings of immune regulation remain incompletely understood. This incomplete picture impedes the development of more precise therapeutics and diagnostics for immune-mediated diseases. Long noncoding RNAs (lncRNAs) are versatile cell- and context-specific regulators of gene expression and cellular function. The number of lncRNA genes rivals that of protein-coding genes; however, comparatively little is known about their function. Even though the functions of most lncRNA genes are unknown, multiple lncRNAs have recently emerged as important immune regulators. Therefore, further unlocking the role of lncRNAs in the mammalian immune system coupled with their tissue-specific expression might lead to more precise therapeutics and diagnostics for immune disorders in general.

Keywords: alloimmunity; antitumor immunity; autoimmunity; immunity; inflammatory immune disorders; long noncoding RNA.

Figure 1.. Examples of lncRNA molecular mechanisms.

A) LncRNAs in the nucleus often recruit chromatin modifying complexes to gene promoters thereby regulating cis and trans gene expression^,,,,. B) Some lncRNAs sequester chromatin modifying complexes away from their cis or trans target gene promoters. C) LncRNAs may also form R-loops which recruit chromatin modifying complexes that then regulate cis target gene promoters. D) Promoter antisense (PAS) lncRNAs of ligand-induced paused protein-coding genes recruit demethylases that release repressive transcriptional complexes from their paused cis protein-coding genes. E) Enhancer elements within or near lncRNAs recruit transcription factors to promoters of cis and trans target gene promoters. The lncRNA in this situation is dispensable for gene regulation. F) Cytosolic lncRNAs can regulate the translation of mRNAs. G) LncRNAs regulate signal transduction at multiple levels including receptor activation, activity of signaling molecules, and activation and localization of transcription factors^,,. H) Enzyme activity can be regulated by direct lncRNA binding^,. I) LncRNA can serve as “sponges” for miRNAs thereby increasing the expression of mRNAs targeted by the “sponged” miRNAs. J) LncRNAs can also harbor occult small open reading frames (sORF) that produce micro-peptides with potentially distinct functions from their parent lncRNA molecules. This figure was created using BioRender (https://biorender.com/).

Figure 2.. Modulatory LncRNAs in immune cells.

Selected lncRNAs that regulate immune cell development, differentiation, activation, and function are shown. LncRNAs that have been reported to promote (blue typeset), inhibit (red typeset), or both inhibit and promote (pink) the developmental step or function of their indicated cell type are denoted. LncRNAs with an “*” have orthologs in mice and humans. LncRNAs in all capital letters without an asterisk are present in humans but do not have a known mouse ortholog. For further functional details about each lncRNA, please refer to the text. CLP: common lymphoid progenitor, CMP: common myeloid progenitor, ILC: innate lymphoid cell, NK: natural killer cell, Th: CD4⁺ helper T cell. This figure was created using BioRender (https://biorender.com/).