We seek to learn how cells control the translation and stability of mRNA transcripts and understand the role of this dynamic regulation in maintaining homeostasis and adapting to changing environments. Cells tightly control which genes they express as proteins, and the amount of each protein they make, and post-transcriptional regulation can modulate gene expression based on cellular needs and extracellular conditions. Indeed, rapid reprogramming of protein synthesis in dynamic environments often depends on modulating the translation and stability of existing transcripts.
The first step in studying translational control is simply measuring it accurately and completely. I developed a ribosome profiling technique that allows precise and quantitative analysis of genome-wide in vivo translation. Ribosome profiling measures expression at the level of translation, opening new windows on in vivo translation. It also reports on the exact position of translating ribosomes. This allows us to annotate the actual protein-coding sequences in complicated genomes and transcriptomes. Ribosome profiling also revealed extensive translation upstream of many genes. This unexpected translation points to the regulated use of alternate sites of initiation, including substantial initiation at non-AUG codons. We believe that start codon selection is an underappreciated point of control in gene expression. The use of alternate sites of initiation can produce functionally distinct protein isoforms as well as affect the amount of protein synthesized. We want to know the impact of this phenomenon–when does the cell change start codon usage, and what are the effects?
Regulation of mRNA translation and stability depends on mRNA-binding proteins, which are as numerous as sequence-specific transcription factors, suggesting a pervasive role for post- transcriptional regulation in cell physiology. We are thus very interested in a genetic and molecular understanding of these RNA-binding proteins, and much of our work focuses on developing comprehensive and high-throughput techniques for elucidating post-transcriptional regulatory networks.