General Research InterestResearch in my lab seeks to understand how post-transcriptional processes regulate gene expression and the overall behavior of the cell.
Research DescriptionThe Schoenberg lab is nationally recognized for discoveries in fundamental mechanisms of post-transcriptional gene regulation and the application of this knowledge to signal transduction, cancer and inherited diseases. The four projects currently under study look at the molecular mechanisms of endonuclease-mediated mRNA decay, mRNA decay in beta-thalassemia, cytoplasmic capping and ribozyme inactivation of microRNAs. Endonuclease catalyzed mRNA decay is a minor pathway that acts on specific sets of mRNAs. It is linked to cancer through activation of this process by the c-Src tyrosine kinase and recent work showing activation of this decay process stimulates cellular motility. The second project studies the molecular basis for beta-thalassemia (Cooley’s anemia), the most prevalent inherited disease throughout the world. This is caused by inheritance of two copies of beta-globin genes with a premature termination codon, which in turn activates endonuclease cleavage of the defective mRNA. The basic science here is to lay the groundwork for developing rational drug treatments for this disease. The third project looks at the question how mRNAs that are silenced, for example by microRNAs, can be reactivated and returned to the translating pool. We identified a population of capping enzyme in the cytoplasm and a pool of uncapped mRNAs that appear to be re-capped by this enzyme. In addition this enzyme likely catalyzes the capping of a new family of small RNAs. The final project is a collaboration with the Gopalan lab at Ohio State that seeks to develop RNase P-based ribozymes as tools for targeted microRNA degradation. The focus is on miR-122, the most abundant microRNA in liver, which is involved in cholesterol metabolism, the replication of hepatitis C virus, and hepatocellular carcinoma.
Transinstitutional WorkAt Ohio State we collaborate with Venkat Gopalan’s lab in the Department of Biochemistry on the project studying ribozyme-catalyzed degradation of miR-122. This is funded by a joint R21 grant from the National Institute of Allergy and Infectious Diseases.
Our work on endonuclease-mediated mRNA decay includes a long-standing collaboration with Scott Tenenbaum at SUNY-Albany, studying the nature of mRNP complexes and how these arise by protein binding to specific sequence elements within related mRNAs. The problem of endonuclease decay is particularly good for this because the enzyme does not bind RNA itself but joins a specific set of mRNAs while they are bound by translating ribosomes. It is recruited to this by tyrosine phosphorylation, making endonuclease decay an ideal model for dissecting the relationship between sequence elements within the mRNA and their recognition by specific proteins. Tenenbaum and co-workers have developed sophisticated computer programs for identifying these elements and linking mRNAs to related processes.
The other major collaboration is with Greg Hannon’s lab at Cold Spring Harbor Laboratory. His lab identified a family of capped small RNAs that appear to be generated by the cytoplasmic capping enzyme complex identified in the Schoenberg lab. We will be working closely with them using deep sequencing to identify and characterize the uncapped transcriptome, its relationship to silencing by microRNAs and translational control, and to develop genetic tools for studying this in the context of development and cancer.