Targets in the amino acid coding region (CDS) of a gene’s mRNA may be as frequent as those in the previously known 3´UTR, according to Nature paper.

A group of researchers and computational scientists have revealed a new region of a gene’s mRNA that miRNAs access. In fact, they showed that miRNA targets in this area, the amino acid coding region (CDS), may be as frequent as those in the mRNA’s 3´ untranslated region (3´UTR). Previously, miRNAs were assumed to interact primarily through the 3´UTR.

The investigators used three miRNAs whose expression increases upon differentiation of mouse embryonic stem cells (ESCs). They observed that transcription factors Nanog, Oct4, and Sox2 (central to maintaining the pluripotency of mouse ESCs and determining the initiation of differentiation) are controlled via their CDS region by the three studied miRNAs.

By introducing mutations at the identified target locations, the scientists showed that they could prevent the down-regulation of these transcription factors and delay stem cell differentiation.

They also found that the sequence of the majority of validated miRNA targets was not conserved in mice and rhesus monkeys for Nanog, Oct4, and Sox2. This implies that seeking supposed miRNA targets by aligning the instances of a gene across different organisms will underestimate the number of genuine miRNA targets.

The miRNAs under evaluation showed a trend toward multiple targets in the CDS region of the same gene. The researchers explain that this may suggest an underlying need for redundancy that can ensure the down-regulation of the intended target. The investigators also noticed that several of the studied targets stride exon-exon junctions, which might mean that miRNAs play a role in the selective targeting of a gene’s splice variants.

The study was done by investigators at IBM’s T.J. Watson Research Center, the Genome Institute of Singapore, and Harvard Medical School. The paper appears online in Nature.

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