平特五不中

Dr Jack D. Keene
James B. Duke Professor
Molecular Genetics & Microbiology
Duke University Medical Center

鈥淐oordinated Dynamics of RNA Regulation by RNA-Binding Proteins鈥�

While RNA-binding proteins (RBPs) coordinate many key decisions during cell growth and differentiation, the dynamics of RNA stability and translation that depend upon RBPs have not been studied on a global basis. Recent findings demonstrate that multiple mRNAs are co-regulated by sequence-specific RBPs that orchestrate their splicing, export, stability, localization and translation. These observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinated dynamically during cell growth and differentiation as post-transcriptional RNA operons or regulons. I will review recently discovered examples of post-transcriptional RNA operons in mammalian cells, trypanosomes and budding yeast, and their potential importance in processes such as immune response, oxidative stress and disease. I will demonstrate how quantitative RNA dynamics involving the HuR RBP can be assessed probabilistically using the RIP-chip method to derive a quantitative phenotype from the drug-gene-phenotype Connectivity Map that allows us to identify small molecule drugs affecting posttranscriptional regulatory networks during T-cell activation. In addition, I will discuss the use of the novel PAR-CLIP approach of Tuschl and coworkers to identify precise HuR RBP binding sites and how those data can complement RIP-chip data to visualize coordination of global RNA dynamics affecting distinct functional outcomes.

Morris, A. et al. (2008) Ribonomic analysis of human Pum1 reveals cis-trans conservation across species despite evolution of diverse mRNA target sets. Molecular and Cellular Biology 28: 4093-4103.
Mukherjee, N. et al. (2009) Coordinated post-transcriptional mRNA population dynamics during T-cell activation. Molecular Systems Biology 5: 288.
Morris, A.D. et al. (2009) Systematic analysis of posttranscriptional gene expression. Wiley Interdisciplinary Reviews, WIRES: Systems Biology and Medicine. [doi:10.1002/wsbm.54]
Hafner, M. et al. (2010) Transcriptome-wide identification of RNA-binding protein and microRNA binding sites by PAR-CLIP. Cell 141: 129-141.