3'UTR-dependent mechanisms of gene regulation

Post-transcriptional gene regulation by small RNAs and RNA-binding proteins, via sequence motifs in the 3'UTRs of mRNAs, has emerged as a critical mechanism in controlling levels of protein expression. C. elegans has been one of the major model organisms through which mechanisms of 3'UTR regulation have been elucidated, including the discovery of microRNAs. microRNAs act to repress the expression of mRNAs harboring sequences in their 3'UTRs that are partially complementary to the microRNA. I have intensively examined two 3 UTRs that confer cell-specific down-regulation to the expression of mRNA transcripts in the ASEL and ASER neurons of C. elegans. One of the 3 'UTRs, cog-1, is a known target of the microRNA lsy-6 in ASEL. I have systematically dissected the lsy-6/cog-1 regulatory relationship utilizing gfp based 3'UTR-sensor transgenes. This analysis has demonstrated that the proposed "seed-rule"-paradigm of microRNA-mediated regulation does not account for complexity observed in the lsy-6/cog-13'UTR relationship. This work has shown that 3'UTR context is a critical determinant in microRNA/target recognition. Additionally, an analysis of the die-13'UTR has identified three regulatory sequence motifs responsible for its ASER-specific down-regulation. These sequence motifs are currently being studied in an attempt to identify the trans-acting factor(s) responsible for the observed regulation. Together, the detailed molecular analysis of these 3'UTRs has expanded our understanding of microRNA/target recognition and the involvement of 3'UTR-mediated regulation in the generation of the ASE neurons of C. elegans.