Molecular basis of splicing regulation by a special group of RNA elements at the intron ends

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How have different species evolved to such diverse complexities ranging from yeast to humans? And how will the evolvement be shaped by future environmental changes? One key step in this process is apparently the breakup of genes into pieces from yeast to humans, so that the pieces (called exons and introns) could be selectively used with other exons as needed to generate diverse gene products (mRNA or proteins) from a single gene (called alternative pre-mRNA splicing). This fundamental biochemical step of gene regulation contributes greatly to gene product diversity. Though it has been studied in different species, how it has evolved and the underlying molecular basis remain largely unknown. One obstacle in studying the evolvement of intronic RNA elements in splicing is the lack of evolutionary conservation between distant species such as fish and humans, making it difficult to track their evolutionary changes. The research program supported by my NSER discovery grant is to understand how genes have evolved to produce diverse RNA and protein products through alternative pre-mRNA splicing. In the past 10 years, trainees (mostly MSc and PhD students) in my laboratory have uncovered a special group of controlling RNA elements called REPAG that allowed us to track their changes through diverse species from yeast, fish to humans. The work has demonstrated their evolutionary changes among more than a thousand species/strains and the importance in generating multiple proteins from a single gene. In this proposal, I and my students plan to explore novel molecular mechanisms for the REPAG control of alternative splicing using state-of-the-art biochemical and molecular biology techniques. Once finished, the work will provide previously unknown molecular details for us to understand splicing control and its evolution with widespread impact on such areas as biochemistry, molecular biology, biotechnology, and health. Moreover, it will also help us to better predict how splicing in higher organisms are going to evolve and how the evolvement is going to be affected by changes in the environment.