Housekeeping genes escape miRNA repression through alternative polyadenylation
Changing where the polyA tail is added to an mRNA transcript can fine-tune the tissue-specific expression of many genes, reports a Caenorhabditis elegans study published in the June issue of GENETICS. Blazie et al. show alternative polyadenylation (APA) allows transcripts to evade microRNA (miRNA) silencing in some tissues, allowing for tissue-specific expression of those genes. In a thorough study of transcription in eight different tissues, APA stands out as a widespread and previously unappreciated way to regulate genes that are expressed in multiple tissues.
APA occurs after an mRNA is transcribed. Before the transcript can be translated, it must be processed, which includes the addition of a run of adenine bases as the “tail.” Sometimes, post-transcriptional changes to mRNA processing can result in a different protein product or a different expression pattern. Alternative polyadenylation (APA) is a kind of post-transcriptional modification that changes the length of the 3’ untranslated region (UTR) by adding the poly-A tail to an alternative site in the transcript.
The authors obtained the tissue-specific transcriptome of five different C. elegans somatic tissues using a technique called PAT-Seq, which isolates transcripts from a target tissue by expressing a tagged poly-A binding protein in a tissue-specific pattern. PAT-Seq also allows for the precise detection of APA. Combined with previous transcriptome data from three other somatic tissues, this dataset represents the most thorough collection yet of tissue-specific mRNAs in C. elegans, accounting for the tissue-specific expression dynamics of nearly 60% of all annotated protein-coding genes.
Blazie et al. found evidence of APA in all eight somatic tissues they examined—most notably in genes that were expressed in all eight types. Shortening the 3’UTR can have important biological consequences because that is where miRNA target sites are usually found. These short, non-coding RNAs bind to complementary sequences in mRNAs and trigger a pathway that represses the bound transcript. Tissue-specific APA that shortens the 3’UTR and eliminates these miRNA targeting sites releases this regulation and allows translation to occur. Though many of the APA-regulated genes are expressed in multiple tissues, this post-transcriptional modification restricts their biological effect. On average, ubiquitously transcribed genes had longer 3’UTRs enriched with miRNA target sites, and APA eliminates an estimated 37% of these targets.
A closer analysis of the genes rack-1 and tct-1 provides an example—these two genes escape miRNA repression through APA leading to a shorter 3’UTR in muscle tissue. The authors used fluorescently tagged transcripts to show that those with shorter 3’UTRs were not repressed by miRNA in muscle tissue. Knocking down the expression of these genes in muscle tissue also caused embryonic lethality, suggesting that this process is an important regulatory mechanism for development.
Scientists have long known about APA in many organisms, but its significance has not been clear. The development of specific tissue and cell types requires a dynamic genome with multiple layers of gene, transcript, and protein regulation. Not only does this study provide a new resource for future investigation of tissue-specific transcript behavior, it also highlights APA as a regulatory mechanism with widespread consequences.
Blazie, S. M., Geissel, H. C., Wilky, H., Joshi, R., Newbern, J., & Mangone, M. (2017). Alternative Polyadenylation Directs Tissue Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues. GENETICS, 206(2): 757-774. DOI:10.1534/genetics.116.196774
Khraiwesh, B. & Salehi-Ashtiani, K. (2017). Commentary: Alternative Poly(A) Tails Meet miRNA Targeting in Caenorhabditis elegans. GENETICS, 206(2): 755-756. DOI:10.1534/genetics.117.202101