Alternative Poly(A) Tails Meet miRNA Targeting in Caenorhabditis elegans

Although alternative polyadenylation (APA) ofmessenger RNA is a well-known phenomenon, the biological consequences of APA, especially with respect to tissue-specificity, is not fully understood. In 2010, Mangone et al. (2010) reported a genome-scale study mapping polyadenylation in adult and several larval stages of C. elegans. The study showed a surprisingly widespread occurrence of APA usage, but did not include cellor tissue-specific information. To further dissect the intricacies of 39UTR and APA usage, Blazie et al. (2015) developed the PAT-Seq method to study the integration of 39-UTR usage dynamics with cellor tissuespecific gene expression in C. elegans. PAT-Seq allows the capture of polyadenylated mRNAs, in conjunction with gene expression in specific targeted cells or tissues, and can, therefore, define precise tissue-specific UTR usage within the target cells. In their present study, Blazie et al. (2017) applied the PAT-Seq approach to systematically isolate, sequence, and map 39UTRs from five highly studied C. elegans somatic tissues: GABAergic and NMDA neurons, arcade and intestinal valve cells, seam cells, and hypodermal tissues. The integration of these datasets with previously profiled transcriptomes of the intestine, pharynx, and body muscle tissues (Blazie et al. 2015) allowed the investigators to define tissue-specific expression dynamics for 60% of all annotated C. elegans protein-coding genes, providing a valuable resource for the worm scientific community. Importantly, the mapping of 15,956 unique, high-quality tissue-specific poly(A) sites in all eight somatic tissues revealed a pervasive tissue-specific 39UTR isoform switching through APA. In addition to widespread occurrences of APA, the obtained information suggests that APA may be a significant regulatory mechanism to fine-tune tissue-specific gene expression through post-transcriptional regulatory mechanisms. Almost all ubiquitously transcribed genes interrogated displayed APA, and harbored miRNA targets in their 39UTRs, which were frequently lost in a tissuespecific manner. The genes expressed with intestine or muscle-specific 39UTRs were significantly enriched with predicted, and experimentally validated, miRNA targets. These data suggest a crosstalk between APA and miRNAinduced post-transcriptional gene regulation. This interaction may, in turn, play a role in either promoting or maintaining tissue identity. That is, genes commonly transcribed in multiple tissues may use APA to modulate the repression mediated by ubiquitously expressed miRNAs. In support of this hypothesis, Blazie et al. (2017) discovered that tissue-specific APA correlated with gain or loss of miRNA target elements, indicating a role for APA in tissuespecific, post-transcriptional gene regulation. Within the studied cases, the C. elegans orthologs of human diseaserelated genes, rack-1 and tct-1, were found to use APA to Copyright © 2017 by the Genetics Society of America doi: https://doi.org/10.1534/genetics.117.202101 Manuscript received April 5, 2017; accepted for publication April 17, 2017 Available freely online through the author-supported open access option. Corresponding author: New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE. E-mail: [email protected]