Functional coordination and HuR-mediated regulation of mRNA stability during T cell activation.

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2016-01-08

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Abstract

Global mRNA abundance depends on the balance of synthesis and decay of a population of mRNAs. To account for this balance during activation of T cells, we used metabolic labeling to quantify the contributions of RNA transcription and decay over a 4 h time course during activation of leukemia-derived Jurkat T cells. While prior studies suggested more than half of the changes in mRNA abundance were due to RNA stability, we found a smaller but more interesting population of mRNAs changed stability. These mRNAs clustered into functionally related subpopulations that included replicative histones, ribosomal biogenesis and cell motility functions. We then applied a novel analysis based on integrating global protein-RNA binding with concurrent changes in RNA stability at specific time points following activation. This analysis demonstrated robust stabilization of mRNAs by the HuR RNA-binding protein 4 h after activation. Our unexpected findings demonstrate that the temporal regulation of mRNA stability coordinates vital cellular pathways and is in part controlled by the HuR RNA binding protein in Jurkat T cells following activation.

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10.1093/nar/gkv1066

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Blackinton, Jeff G, and Jack D Keene (2016). Functional coordination and HuR-mediated regulation of mRNA stability during T cell activation. Nucleic Acids Res, 44(1). pp. 426–436. 10.1093/nar/gkv1066 Retrieved from https://hdl.handle.net/10161/15382.

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Keene

Jack Donald Keene

James B. Duke Distinguished Professor of Molecular Genetics and Microbiology

The Keene Laboratory has a long-term interest in the structure and function of viral and mammalian genomes. Having determined the first genomic sequences for rabies, Ebola, Marburg and vesicular stomatitis virus, and discerned the origins of defective interfering viruses, interests shifted to the cloning of six human genes involved in autoimmune reactivity. This resulted in the identification of numerous autoimmune RRM-type RNA-binding proteins the discovery of the RRM, and the RNA targets to which they bind. The current interests of the lab surround the functions of the human RRM-ELAV/Hu proteins that are bound to a subset of cellular mRNAs involved in growth regulation neuronal plasticiyt and cancer. The laboratory demonstrated that ELAV/Hu proteins bind and regulate the expression of early response gene transcripts such as those encoding the protooncogene and cytokine proteins.

In addition, it was shown that while stabilizing these mRNAs and/or activating their translation, the ELAV/Hu proteins participate in cellular , differentiation and carcinogenesis. More recently, the laboratory has examined dozens of RNA-binding proteins in order to identify large numbers of structurally
and/or functionally related mRNAs that cluster in vivo based upon their binding to these proteins. This has been termed ribonomics because it involves parallel analysis of mRNA subsets en masse based upon their presence in messenger ribonucleoprotein complexes. This new approach to functional genomics is being applied to virus-infected cells, tumors and cells treated with various agents. Ribonomics has led to the identification of mRNA clusters that are posttranscriptionally regulated, and represent the organizational state of genetic information between the genome and the proteome. Dr. Keen has propsed the existence of post-transcriptional operons based upon the association of structurally and functionally-linked mRNAs in vivo.


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