Program Director/Principal Investigator (Last, First, Middle): Bartel, David P.
TITLE: Post-transcriptional gene regulation
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