Our laboratory studies 3' Untranslated regions (3'UTRs), which are portions of mRNAs that contain cis-regulatory elements targeted by factors that impact protein abundance through altering mRNA stability, translational efficiency or localization. These regulatory mechanisms are still poorly understood but play key roles in diverse developmental and metabolic processes, and are implicated in disease, including autism, depression, diabetes, Alzheimer's and cancer.
In recent years, 3'UTRs have been subject to intense study since they were found to be targets of a new class of transcriptional regulators termed microRNA (miRNAs). miRNAs are short non-coding RNAs that bind to complementary sequences in the 3'UTRs of metazoans in the cytoplasm. miRNA dysfunction is involved in the establishment of major diseases, including neurodegenerative diseases, diabetes and cancer. miRNAs can function either as potential oncogenes or tumor suppressor genes, depending on the cellular context and the target genes they regulate. Their signature is important in predicting tumor behavior.
Today, 3'UTRs are widely recognized as 'gateways' to understanding how post-transcriptional gene regulation works. It is striking, however, that their cis-regulatory elements for miRNA and RNA-binding protein targets are still largely unknown in metazoan genomes, including humans. In addition, there is no agreed standard on how to identify their targets or validate their biological function.
Based on bioinformatics analysis, it has been proposed that each miRNA controls hundreds of gene products. Unfortunately, these networks are predictive, and only a handful of targets have been demonstrated in vivo, so far. For example, let-7, one of the most studied miRNAs and a potent tumor suppressor gene, has been predicted to regulate more than 70 different transcripts in worm, however, only a dozen have actually been observed and validated.
It is now clear that the majority of metazoan coding genes is transcribed with multiple 3'UTRs. In C. elegans these 3'UTR isoforms are produced either by the usage of alternative polyadenylation signals within the pre-mRNA, or by alternative splicing (Figure 1).
Alternative 3'UTR isoforms could provide a powerful regulatory mechanism using combinatorial variation between cis-elements and transacting factors, perhaps regulating gene expression in a tissue-specific manner. For instance, the let-7 family of miRNAs regulates hbl-1 expression levels by targeting hbl-1 through key elements embedded within its 3'UTR. We have shows that two 3'UTR isoforms of hbl-1 lack the let-7 recognition motif, enabling these transcripts to escape miRNA and/or protein regulation. Protein-RNA or RNA-RNA interactions could therefore be influenced by sequence elements contained in the variable regions of these 3'UTR isoforms, whose expression in turn could be regulated.