Post-transcriptional gene regulation

Program Director/Principal Investigator (Last, First, Middle): Bartel, David P. TITLE: Post-transcriptional gene regulation PROJECT SUMMARY: Much of eukaryotic gene regulation occurs post-transcriptionally, through differential mRNA stability and/or translational efficiency. The research of this proposal seeks to answer fundamental questions within two interrelated areas of post-transcriptional gene control: microRNAs and non-coding features of mRNAs. MicroRNAs (miRNAs) are ~22-nt RNAs that pair to mRNAs to direct their destabilization and translational repression. More than 600 miRNA genes have been identified in humans, and because most human genes are conserved targets of miRNAs, it is no surprise that miRNAs play important roles in mammalian development and physiology, as well as human diseases, including viral infections and cancers. Molecular, computational, and structural approaches will be used to determine 1) the biochemical basis of miRNA–target recognition and improved methods for predicting the most repressed targets, 2) the reasons that some miRNAs direct the slicing of bound mRNA targets much more readily than others, and 3) the mechanism and the biological scope of a biochemical pathway that cells use to target specific miRNAs for degradation. Results of these studies are expected to enhance the fundamental understanding of this important class of gene- regulatory molecules and provide resources helpful for many biologists, including those studying the roles of miRNAs in human diseases. The noncoding features of mRNAs, including excised introns, stably folded mRNA structures, and mRNA poly(A) tails, can mediate regulatory phenomena. Molecular and computational approaches will be used to determine 1) the molecular basis of excised-intron stabilization in yeast, 2) the mechanism of G-quadruplex unfolding in cells, and 3) why longer poly(A) tails enhance translation in metazoan oocytes and early embryos, and why this relationship between tail length and translation efficiency disappears as the embryo develops. Results are expected to provide fundamental insight into growth control in yeast and post-translational gene regulation in metazoan development, with potential implications for human fertility, developmental defects, or other diseases.