Gene regulation: diverse, complex, and utterly fascinating
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The success of every organism requires each gene to be expressed in the right amount at the right place at the right time. On the one hand, gene expression must be robust to ensure that processes, such as development, occur reproducibly. On the other hand, organisms, and cells, face numerous changes in their internal and external environments, and gene expression must adapt to these myriad challenges. Controlling gene expression is thus necessarily multi-faceted and combinatorial, and every step from transcription to protein degradation provides an opportunity for regulation.
Once an mRNA is exported to the cytoplasm, it is subject to the interconnected processes of translation and mRNA decay. For decades, it has been known that both processes are linked because they use the same mRNA features—the cap and poly(A) tail—and many of the same proteins (like eIF4E and PABP). But the connections between translation and mRNA decay run deeper than that. We know now that mRNA decay often only makes sense in the context of translation. However, the molecular connections remain out of focus, and this gap fuels our curiosity. Using the powerful combination of classical molecular biology techniques and high-throughput ones, our goal is to understand how translation impacts mRNA stability, and to place gene regulation in the contexts of broader biological processes.
The impact of translation elongation speeds on mRNA stability. While mRNA stability has classically been thought to be modulated via specific motifs in 3'UTRs, recent work in prokaryotes and eukaryotes has uncovered an ancient regulatory pathway, where the speed of translation elongation impacts mRNA stability. We have recently extended these results to human cells, which raises a number of questions. How is slow elongation sensed in human cells? How does slow elongation trigger mRNA decay? How does elongation speed change in different cellular contexts and how does the cellular environment sculpt post-transcriptional regulation?
The impact of early development on gene regulation. Removal of unnecessary maternal gene products and their replacement with zygotic gene products is a highly synchronized, essential process in the early animal embryo. This process is called the “maternal-to-zygotic transition” (or MZT). Although our interest stemmed from removal of maternal mRNAs, we and others have shown that removal of maternal proteins also plays an important role in the MZT. Using Drosophila as a model system, we are now focused on understanding how the embryo removes maternal proteins. How do embryos target maternal proteins for degradation? How is protein degradation controlled during development? What are the developmental consequences when this process goes awry?
The impact of evolution on the fundamental molecular machines of translation and mRNA decay. Yeast and mammalian cells are classic model systems for studying translation and mRNA decay. But there is much more evolutionary diversity in eukaryotes that demands exploration. Giardia lamblia is a deeply branching eukaryote and human pathogen. A protist, Giardia also has dramatically simplified translation and mRNA decay machinery. For instance, the “essential” translation initiation factor eIF4G is absent in Giardia. How does Giardia control translation initiation? How does it degrade mRNA? And how has evolution shaped post-transcriptional gene regulation?
“[T]here is something in man which responds to the challenge of this mountain and goes out to meet it… What we get from this adventure is just sheer joy.”