The goal of this research is to discover the principles and mechanisms that control expression of genes. This knowledge will enhance understanding of the causes of disease and advance therapeutic strategies to correct deleterious gene expression.
These researchers are working to understand how messenger RNAs are regulated. Regulation of translation, degradation, and localization of mRNAs contributes to the enormous dynamic range of protein expression. Dysregulation can cause disease, developmental defects, or death. Sequence-specific RNA-binding factors, both protein and small RNAs, play a central role in mRNA regulation. This research focuses on two important classes of regulatory proteins: Pumilio proteins and deadenylases.
- Pumilio proteins: Pumilio proteins are a family of regulators that bind certain mRNAs with exquisite specificity and repress their expression. Pumilio proteins have diverse biological roles in development, stem cell proliferation, and fertility. Pumilio also control neurological processes including motor neuron function, learning and memory formation. The researchers' goals are to identify the mRNAs that Pumilio proteins regulate and determine the molecular mechanism of repression. To accomplish this, they use a combination of biochemistry, genetics, bioinformatics, transcriptomics, and high throughput assays in multiple organisms including humans and Drosophila. This research has direct impact on genetic mechanisms that control development, neurological function, and cancer.
- Deadenylases: Ribonucleases play critical roles in regulating mRNAs. Deadenylases are specialized ribonucleases that degrade the poly(Adenosine) tails of mRNAs. Regulation of poly(A) tail length is emerging as a critical control point for translation and mRNA degradation in a wide variety of biological contexts. The researchers have found that specific deadenylases play a central role in Pumilio-mediated regulation. Pumilio proteins enhance deadenylation of the mRNAs they bind by directly recruiting the deadenylase enzyme complex. The versatility of regulation by deadenylation is greatly expanded in higher eukaryotes through diversification of deadenylases. For instance, humans possess twelve deadenylase orthologs. Genetic analysis indicates that each deadenylase controls unique biological functions including cell division and growth, metabolism, development, bone morphogenesis and anti-viral responses. This group is exploring the questions: how many active deadenylases are there, do their catalytic activities differ, which mRNAs do they act upon, and how are their activities controlled? This research has broad relevance to fertility, development, and metabolism with relationships to obesity and cancer.