Differential Expression of mRNA Splicing Isoforms Generates Transcript Length Variants in Atherosclerosis Progression

We are interested in studying alterations in the regulatory circuitry that controls mRNA stability and function, and more specifically in the interactions among miRNAs and mRNAs. We have previously reported transcriptome-wide changes in mRNA expression in an animal model of atherosclerosis (ATS) progression, and reversion upon treatment with an αCD40 specific siRNA. In this work, we have used our data on mRNAs downregulated during these processes to study length dynamics as an adaptive mechanism to thwart miRNA activity. We show that ATS progression was characterized by the lengthening of the 5’UTR and 3’UTR regions of these mRNAs. Furthermore, 3’UTR lengthening (but not that of the 5’UTR) was shown to be partially reversed by the treatment with the αCD40 specific siRNA. Study of the exonic composition of the transcriptome of these mRNAs suggested a role for alternative/cryptic/latent splicing in the generation of length variants. This was confirmed by the detection, during ATS progression, of a transcript variant switching process in which specific isoforms were replaced by others that differed in their pattern of alternative splicing, mainly at their 5’ or 3’UTRs. This work highlights alternative splicing as a mechanism contributing to the generation of 5’/3’UTR length and sequence variability during ATS progression and calls attention on factors regulating alternative splicing as possible targets of therapeutical intervention.