Optical control of UGGAA repeat RNA foci by photoswitchable RNA-binding ligand

The expansion of specific repeat sequences causes dozens of heritable neuromuscular diseases, where expanded repeat RNAs play key roles in the pathogenic mechanism. Although the formation of RNA foci has been identified as a common hallmark of repeat diseases, their properties, dynamics, and mechanisms underlying toxicity differ for each disease and remain elusive. Here, we demonstrate a novel strategy for the optical control of UGGAA repeat RNA foci, a pathological hallmark of spinocerebellar ataxia type 31 (SCA31), based on the modulation of RNA-RNA interactions by a photoswitchable RNA-binding ligand, NCTA. In the presence of NCTA, UV irradiation induced the growth of UGGAA repeat RNA foci in cells. Subsequent visible light irradiation dissolved the structure into the original smaller RNA foci. Reversible photoisomerization between E- and Z-NCTA is responsible for the photocontrol of RNA foci, where Z-NCTA, produced upon UV light exposure, is the active species that stabilizes the association between UGGAAs. These changes were accompanied by alterations in the composition of RNA-binding proteins within the RNA foci, suggesting that NCTA modulates their properties and functions by remodeling RNA foci. Our photocontrol system enables the spatiotemporal manipulation of dynamic structures containing RNA scaffolds, including other disease-related repeat RNA foci and membraneless ribonucleoprotein organelles, and will be a valuable technique for investigating and regulating their dynamic behavior.