Our research focuses on the production, activity and function of 3' Untranslated Regions (3'UTRs), which are located at the end of mRNAs between the STOP codon and the polyA tail. Their importance in post- transcriptional regulation of gene expression is emerging as they contain numerous, largely uncharacterized regulatory elements that make them a core target for miRNAs and RNA binding proteins. Recently our group and others have shown that alternative polyadenylation (APA), a process where the same mRNA is produced with different 3'UTR isoforms, is widespread in metazoans. We do not know why so many genes are transcribed with multiple 3'ends, and how the processing machinery discriminates between different cleavage signals within the same mRNA leading to alternative 3'UTR isoforms. The widespread abundance of APA in transcripts of all metazoans led us to hypothesize the presence of a more complex picture, where there are not only negative regulatory networks though miRNAs, but also novel unexplored positive regulatory networks operated though APA. In this view genes that switch 3'UTR isoforms in different cellular or tissue contexts during development are the main drivers of these positive networks, either allowing or escaping miRNA targeting. In this view, both miRNAs and APA can in principle dramatically reshape gene expression output, suggesting they both play key roles in the establishment and maintenance of cell and tissue identity. This idea has yet to be tested and validated in a living organism. The powerful genetics of C. elegans and the unparalleled resources available make this model system ideal for understanding the basic principles of mRNA 3'end formation and post-transcriptional regulation. We want to produce wet-bench and bioinformatic tools to allow the generation of high-quality tissue-specific 3'UTR localization dynamics for all genes in nine major somatic tissues, in order to understand the basic principles of APA, its dynamics in development, as well as its production and regulation in vivo using a systems biology approach. We will also study the function of APA by focusing on negative miRNA regulation and developing miRNA expression and targeting data in three major worm tissues, and then superimpose the results to our tissue specific APA data to produce the first miRNA-APA Interactome in a living organism. We will also perform mechanistic studies of APA production and their function in 12 genes highlighted by our preliminary results. Taken together, these aims combine high-throughput genomics, bioinformatics, genetics, biochemistry and systems biology in innovative ways to study APA and its role in post-transcriptional gene regulation.

Public Health Relevance

Alternative Polyadenylation (APA), a poorly understood mechanism in which the same gene is processed with multiple 3'ends, is pervasive in metazoans. APA could provide a powerful regulatory mechanism using combinatorial variation between cis-elements and trans-acting factors, perhaps to regulate gene expression in a tissue-specific manner, but except for a few single gene anecdotes, this idea has not been systematically explored and requires the use of high-throughput technology to discover general rules. This proposal integrates the production, function, and activity of APA and their role in modulating gene expression with miRNA networks, taking advantage of the extensive genetic knowledge of the round nematode C. elegans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Bender, Michael T
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Arizona State University-Tempe Campus
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United States
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Wolter, Justin M; Le, Hoai Huang Thi; Linse, Alexander et al. (2017) Evolutionary patterns of metazoan microRNAs reveal targeting principles in the let-7 and miR-10 families. Genome Res 27:53-63
Blazie, Stephen M; Geissel, Heather C; Wilky, Henry et al. (2017) Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues. Genetics 206:757-774