CAREER: Pre-mRNA Splicing and the Coordinated Network of Gene Expression Machineries

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One of the most important challenges in biology is understanding how genetic information is expressed and how this expression is regulated. Human genes (and the genes from other eukaryotic organisms) are interrupted by long stretches of noncoding DNA sequence. Once the DNA is "read" by the cellular machinery to make messenger RNA (the intermediate, information-containing genetic material that directs protein synthesis), the noncoding RNA must be removed, and the remaining protein-coding regions are joined. This process, "pre-messenger RNA splicing," takes place with exquisite accuracy and is crucial for proper gene expression. Another remarkable feature of the genome is that its DNA is packaged in a compact protein/DNA structure, chromatin. In order for the DNA sequence to be read for messenger RNA synthesis, the chromatin must undergo extensive modification that regulates DNA accessibility. While the reactions involved in gene expression have typically been studied as independent, isolated processes, there is new evidence that RNA synthesis and splicing are, in fact, tightly coordinated. The RNA synthesis reaction can affect the process of splicing, and pre-mRNA splicing can affect RNA synthesis; however, the mechanism by which this occurs remains to be elucidated. Using the biochemically and genetically tractable model organism, the yeast Saccharomyces cerevisiae, this CAREER project characterizes interactions between components of the pre-mRNA splicing and RNA synthesis machineries and the role that these interactions play in modulating gene expression. Additionally, this work describes an unexpected role for splicing factors in modulating chromatin modification and explores how this activity coordinates RNA synthesis and pre-mRNA splicing. The educational component of this CAREER project focuses on (1) development of an undergraduate course to explore emerging models of eukaryotic gene expression and (2) increasing access and opportunities for underrepresented students by working in collaboration with local high school teachers and students developing inquiry-based science curricula exploring the molecular biology of gene expression.