Post-transcriptional mRNA regulation in the mammalian nervous system

The overall goal of research in my lab is to deepen our understanding of the roles of post-transcriptional gene regulation in the mammalian nervous system and how its dysregulation underlies human disease. In the next five years, we will build upon our previous work on neuronal mRNA metabolism and translation control and focus on three interconnected areas: 1} The impact of microsatellite repeat expansion on mRNA processing and translation. We will conduct targeted and genome-wide analyses to systematically identify the cis-elements and trans-factors that modulate noncanonical processing and translation of repeat-containing RNAs. 2} The functions and regulation of alternative translation initiation. Through our in-depth investigation of a conserved bi-functional mRNA that encodes two proteoforms of the neuronal pentraxin receptor (NPR}, we hope to uncover general principles that will inform our understanding of the regulatory impact of alternative start codon usage. 3} Quantitative measurement of mRNA translation efficiency (TE}. While ribosome footprint profiling, or Ribo-seq, is widely used to measure TE at a transcriptome scale, our recent findings suggest that conventional Ribo-seq procedures may not accurately capture the magnitude of TE regulation. By comparing Ribo-seq to directly measure TE data and optimizing Ribo-seq procedures, we will reexamine fundamental questions about translation control in mammalian cells. Results from these analyses may challenge existing dogmas and open up new lines of investigations.