Distinct expression of select and transcriptome-wide isolated 3'UTRs suggests critical roles in development and transition states

Mature mRNA molecules are typically considered to be comprised of a 5-UTR, a 3-UTR and a coding region (CDS), all attached until degradation. Unexpectedly, however, there have been multiple recent reports of widespread differential expression of mRNA 3-UTRs and their cognate coding regions, resulting in the expression of isolated 3-UTRs (i3-UTRs); these i3-UTRs can be highly expressed, often in reciprocal patterns to their cognate CDS. Similar to the role of other lncRNAs, isolated 3-UTRs are likely to play an important role in gene regulation but little is known about the contexts in which they are deployed. To begin to parse the functions of i3-UTRs, here we carry out in vitro, in vivo and in silico analyses of differential 3-UTR/CDS mRNA ratio usage across tissues, development and cell state changes both for a select list of developmentally important genes as well as through unbiased transcriptome-wide analyses. Across two developmental paradigms we find a distinct switch from high i3-UTR expression of stem cell related genes in proliferating cells compared to newly differentiated cells. Our unbiased transcriptome analysis across multiple gene sets shows that regardless of tissue, genes with high 3-UTR to CDS ratios belong predominantly to gene ontology categories related to cell-type specific functions while in contrast, the gene ontology categories of genes with low 3-UTR to CDS ratios are similar and relate to common cellular functions. In addition to these specific findings our data provide critical information from which detailed hypotheses for individual i3-UTRs can be tested-with a common theme that i3-UTRs appear poised to regulate cell-specific gene expression and state.