Temporal coordination of stimulus-induced gene expression by RNA-binding proteins

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SUMMARY Cellular responses to external stimuli require dynamic gene regulation to facilitate rapid activation and effective resolution. Although transcriptional responses are a textbook mechanism for stimulus-induced responses, post- transcriptional regulation of mRNA translation and decay are the other side of the coin and are essential for rapid and adaptable stimulus-induced responses. For example, immune activation generates a prototypical temporal expression pattern for cytokine mRNAs known as an impulse response, which is a rapid pulse-like increase and decrease in expression. The destabilization of cytokine mRNAs is required for proper resolution of the impulse response and prevention of excess cytokine production. It is increasingly recognized that RNA-binding proteins (RBPs) play critical roles in achieving an appropriate stimulus-induced gene expression response by regulating RNA processing, decay, and translation of target RNAs. The over-arching goal of our research program is to understand how RBPs temporally coordinate stimulus-induced gene expression and cellular phenotypes. The model system we will use to study how dynamic RBP-RNA regulatory interactions temporally coordinate stimulus-induced gene expression is human adrenal steroidogenesis. This is a classic ligand-induced system in which the small peptide Angiotensin II (AngII) binds to its receptor in adrenal zona glomerulosa cells to stimulate the production of aldosterone, the master regulator of blood pressure. Thus, tight control of regulatory timing is required since it must be rapidly produced de novo from cholesterol in response to AngII. We have recently demonstrated that AngII treatment of immortalized and primary adrenocortical cells results in an impulse response. Furthermore, we found specific RBPs and regulated RNA decay facilitates the rapid implementation and resolution of the AngII impulse response. In this proposal, we will test the hypothesis that MSI2 and ZFP36L2 are counteracting forces that, respectively, potentiate and attenuate the kinetics of stimulus-induced mRNA levels by modulating target mRNA decay and translation, to ensure the proper timing and amplitude of the impulse response. We will utilize cutting edge methods to gain temporal and quantitative insights into how stimulus-induced changes in RBP binding determine changes in target mRNA expression responses and ultimately cellular phenotype. The use of innovative approaches we use will help shift the field from a static to a dynamic view of RBP-mRNA interactions and achieve mechanistic insight on how regulatory RBP-mRNA interactions control mRNA fate decisions to govern cellular responses.