Mammalian RNA switches: Molecular rheostats in gene regulation, disease, and medicine

Abstract

Alteration of RNA structure by environmental signals is a fundamental mechanism of gene regulation. For example, the riboswitch is a noncoding RNA regulatory element that binds a small molecule and causes a structural change in the RNA, thereby regulating transcription, splicing, or translation of an mRNA. The role of riboswitches in metabolite sensing and gene regulation in bacteria and other lower species was reported almost two decades ago, but riboswitches have not yet been discovered in mammals. An analog of the riboswitch, the protein-directed RNA switch (PDRS), has been identified as an important regulatory mechanism of gene expression in mammalian cells. RNA-binding proteins and microRNAs are two major executors of PDRS via their interaction with target transcripts in mammals. These protein-RNA interactions influence cellular functions by integrating environmental signals and intracellular pathways from disparate stimuli to modulate stability or translation of specific mRNAs. The discovery of a riboswitch in eukaryotes that is composed of a single class of thiamine pyrophosphate (TPP) suggests that additional ligand-sensing RNAs may be present to control eukaryotic or mammalian gene expression. In this review, we focus on protein-directed RNA switch mechanisms in mammals. We offer perspectives on the potential discovery of mammalian protein-directed and compound-dependent RNA switches that are related to human disease and medicine.

Keywords: Disease; Gut microbiota; Medicine; Metabolite; MicroRNA; Mitochondria; Protein-directed RNA switch; RNA binding protein; Riboswitch; Translational control.

Graphical abstract

Fig. 1

Protein-directed RNA switch in the 3′UTR of VEGFA and other transcripts. (A) GAIT- and miR-297-RISC-dependent, hnRNP L-containing HILDA complex-directed VEGFA RNA switch. miR-574 acts as an RNA decoy to negatively regulate the VEGFA RNA switch. (B) The secondary structure of the 125-nt VEGFA hypoxia stability region (HSR) in the translation-permissive conformation (middle). The GAIT element (green) and hnRNP L binding CA-rich element (CARE, red) are highlighted. The GAIT complex binds to the GAIT element and represses VEGFA mRNA translation under IFN-γ stimulus; while the hnRNP L-bearing HILDA complex binds to CARE and prevent GAIT complex binding and restores VEGFA mRNA translation under hypoxic condition (Left). miR-297-RISC binds to CARE of VEGFA mRNA and inhibits its translation in normoxia; while the HILDA complex binds to CARE and blocks the interaction of miR-297-RISC and activates VEGFA mRNA translation in hypoxia (Right). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Schematic model of mammalian protein-directed RNA switches. Four types of human PDRSs are shown. (A) 5′UTR-dependent, hnRNP E2-mediated blockage of 43S pre-initiation complex scanning and miR-328-driven inactivation of hnRNP E2 and translational activation of CEBPA mRNA during myeloid cell differentiation. (B) miRNA-dependent, PTBP-directed RNA switches during fibroblast-to-neuron trans-differentiation. (C) m⁶A-dependent, hnRNP C-directed RNA switches in HEK293T cells. (D) Ded1p/DDX3-mediated structural switch of 5′UTR regulates translation initiation codon selection in yeast.

Fig. 3

Four types of potential mammalian RNA switches. Putative physiological (two types), pathogenic, and pharmacological human RNA switches and their putative ligands are proposed. See text for details. A ribosome is an RNA helicase that unwinds the putative 46-nt stem-loop located in ATP8/ATP6 mRNA coding sequence (CDS). Nicotine: an alkaloid produced in tobacco and an environmental compound from smoking. Chorismic acid: an intermediate compound produced by gut bacteria for aromatic amino acid synthesis. 4EPS: a gut bacteria derived compound that regulates brain function and cause mental disorders.

Fig. 4

A putative RNA switch element located in mammalian mitochondrial ATP8/ATP6 mRNA. A 46-nt overlapping region was uncovered in both ATP8 and ATP6 genes. This RNA fragment may form a putative stem-loop structure, which inhibits ribosome loading and translation initiation for ATP6 until the pioneering ATP8-translating ribosome unwinds it to mediate the coordinated translation of ATP8/ATP6 mRNA and maintain 1:1 stoichiometric ratio of both proteins.