[Sequence- and Timing- Dependent Manipulation of RNA Methylation]

In recent years, chemical modifications of RNA, known as the epitranscriptome, have been shown to influence not only the regulation of gene expression but also diseases such as neurodegenerative disorders and viral infections. Among them, N⁶-methyladenosine (m⁶A), which is highly abundant in transcripts, has been shown to regulate RNA stability, localization, and translation and has also been implicated in development, differentiation, and cancer. However, there are limitations in understanding the role of individual m⁶As in disease and biological phenomena using enzymatic knockdown methods that alter RNA methylation levels throughout the cell; if RNA methylation states can be selectively regulated by RNA sequences, the function of RNA methylation in a variety of biological phenomena can be elucidated. With this background, systems have been developed to selectively and temporally control the methylation state of specific adenosine. Using RNA-binding proteins that can freely alter the sequence of the RNA to which they bind, we created sequence-specific demethylases and methylases and demonstrated that these artificial proteins can regulate the methylation state of adenosine near the target sequence of the RNA-binding protein. In addition, the switching of methylation and demethylation activities by external stimuli is being developed in combination with external stimulus-dependent heterodimeric systems. In this review, developments in molecular tools for the sequence-selective regulation of epitranscriptomes are presented.