RNA plays a central role in the regulation of gene expression. RNA degradation is an active and critical process that dictates RNA levels and in part controls the relative levels of gene expression. However, despite many years of research in this area, important and perplexing questions remain about RNA stability. Even when comparable RNA degradation processes are involved individual RNAs can have distinct decay rates and the mechanisms that control such distinctive rates are unknown. RNA structure is likely to be intrinsic to our understanding of the RNA features that govern stability, and until very recently, our ability to measure the true in vivo RNA structure has been incredibly limited. We are addressing the role of RNA structure in the regulation of RNA degradation to determine the RNA structural features that regulate degradation pathways. This research is a multidisciplinary project that integrates molecular biology, nucleic acid chemistry and bioinformatics.
In summary, we have successfully developed five novel chemical profiling methods: SHAPE-Structure-seq (Yang et al., Genome Biology, 2021), CAP-Structure-seq (Yang et al., Nucleic acids Research, 2020), Nuc-Structure-seq (Liu et al., Genome Biology, 2021), SHALiPE-seq (Yang et al., Genome Biology, 2020) and smStructure-seq (Yang et al., Under 2nd review in Nature.). These methods revealed the RNA structural landscapes, facilitating the identification of the RNA structure-mediated RNA degradation elements. Apart from the RNA secondary structure involved in RNA degradation (Yang et al., Nucleic acids Research, 2020; Liu et al., Genome Biology, 2021, Yu et al., Frontiers in Molecular Bioscience, 2022 and Zhang et al., in preparation), we determined the existence of RNA tertiary structure motif, RNA G-quadruplex (Yang et al., Genome Biology, 2021) and revealed that the novel function of RNA G-quadruplex in regulating RNA stability (Yang et al., bioRxiv, 2022). Additionally, we have successfully discovered the novel functional role of GQS in No Go Decay and found that the GQS-mediated NGD is important in regulating plant root cell identity (Zhang et al., Nucleic Acids Research, 2019 and Duncan et al., In preparation). Notably, we have applied deep learning methods in identify RNA structure elements associated with RNA degradation (Yu et al., Frontiers in Molecular Bioscience, 2022 and Zhang et al., in preparation). We have comprehensively determined the mecahnisms of RNA structure-dependent miRNA-mediated RNA degradation. Building on the outputs from this objective, we obtained our ERC Proof of Concept proposal (ref. 966855 “ultraRNAs”), in which we propose to use our “Structure” rules to design and test the translational potential for using artificial miRNAs in cleaving plant viral RNAs, in particular, the beet yellows virus (BYV) in sugar beet, which is harmful virus causing up to 50% crop loss in recent years. Notably, our fundamental work on RNA structure-dependent regulation of RNA degradation derived from this project has been successfully applied in RNA structure-guided antisense oligonucleotide antiviral therapy for SARS-CoV-2 virus (Lulla, V et al., Journal of Virology, 2021).
