In Jan 2022, Dr Yongfeng Jin, Professor at the College of Life Sciences, Zhejiang University, Adjunct Professor at the Shanghai Institute for Advanced Study of Zhejiang University, published a research paper on Hidden RNA pairings counteract the first-come, first-served splicing principle to drive stochastic choice in Drosophila melanogaster Down’s syndrome cell adhesion molecule 1 (Dscam1) splice variants in Science Advances. This study shows that RNA structures counteract the first-come, first-served principle to drive stochastic choice in variable splice variants of Dscam1.
Drosophila Dscam1, which generates 38,016 isoforms by mutually exclusive variable splicing, is an extreme example of variable RNA splicing and has been described as a classic case in many textbooks. In 2005, Graveley proposed the model hypothesis in Cell that competitive RNA pairing regulates mutually exclusive variable splicing in Dscam1 exon 6. This model hypothesis adequately explains the mutually exclusive nature of Dscam1 exon 6 variable splicing. However, it cannot explain how competitive RNA pairing regulates random selection of exon 6: If it is performed on a first-come, first-served basis of co-transcriptional splicing, then proximal exon 6 would have a stronger selection preference, but this preference was not observed in all experimental data. This preference was not observed in all experimental data. This study has solved this scientific mystery.
In this study, Yongfeng Jin's group discovered a new class of RNA secondary structures (called balanced RNA secondary structures) while studying the variable splicing mechanism of Dscam1. By using CRISPR-Cas9 and other techniques, they have uncovered the dual function of this balanced RNA secondary structure in regulating exon 6 variable splicing: Inhibition of proximity and promotion of distance. On the one hand, the balanced RNA secondary structure can cooperate with the complementary pairing of anchor sites and selective sequences to form an RNA secondary structure with multiple structural domains to promote splicing of distal variable exon 6. On the other hand, the balanced RNA secondary structure can counteract the complementary pairing of anchor site and proximal selective sequence to inhibit splicing of proximal variable exon 6. In this way, the balanced RNA secondary structure serves a dual function by suppressing proximity and promoting distance to counteract the first come, first served splicing preference to promote random selection of variable exon 6. The results of this study expand the conceptual and mechanistic understanding of the dynamics and biological functions of complex RNA secondary structures.
In addition, the study corrects a partial misrepresentation of the RNA secondary structure mediating variable Dscam splicing in textbooks (Molecular Biology of the Gene, 6th edition, pp. 432-448; 7th edition, pp. 489-491). This experimental study has shown that the specific RNA secondary structure controlling the first variable exon 6 (6.1) does not appear to exist; the RNA secondary structures controlling splicing of exons 6.22 and 6.38 are not consistent with the experimental results of this study and need to be corrected.
The work was translated from the official website of College of Life Sciences, Zhejiang University, the original artical can be accessed at https://www.science.org/doi/10.1126/sciadv.abm1763.
About Dr Yongfeng Jin:
Dr Jin graduated from Zhejiang Agricultural University in 1997 and became a professor in College of Life Sciences, Zhejiang University from 2004. He is currently an Adjunct Professor of Shanghai Institute for Advanced Study of Zhejiang University (SIAS).
Dr Jin’s research interests include RNA processing and editing, New non-coding RNA function andmechanism, Silkworm expressing cholera toxinB subunit-insulin fusion protein against autoimmune diabetes and Alzheimer's disease and its functional mechanism.
About SIAS:
Shanghai Institute for Advanced Study of Zhejiang University (SIAS) is a jointly launched new institution of research and development by Shanghai Municipal Government and Zhejiang University in June, 2020. The platform represents an intersection of technology and economic development, serving as a market leading trail blazer to cultivate a novel community for innovation amongst enterprises.
SIAS is seeking top talents working on the frontiers of computational sciences who can envision and actualize a research program that will bring out new solutions to areas include, but not limited to, Artificial Intelligence, Computational Biology, Computational Engineering and Fintech.