# mRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth

## TL;DR

This study shows how mRNA 3′ UTRs trigger microRNA degradation, linking this process to imprinted gene networks and growth regulation in mice.

## Contribution

The paper identifies new TDMD-triggering sites and demonstrates their role in imprinted gene networks and growth.

## Key findings

- Five new TDMD-triggering sites were identified and validated in mouse models.
- Collaborative TDMD sites in the same or different transcripts can destabilize microRNAs.
- TDMD of miR-322 and miR-503 by Plagl1 and Lrrc58 promotes growth in mice.

## Abstract

In this study, Lin et al. identify trigger RNAs that drive target-directed microRNA degradation (TDMD) of ZSWIM8-sensitive microRNA. They describe instances in which multiple trigger RNAs or TDMD sites can collaboratively destabilize a miRNA, as well as highlight a link between the TDMD pathway and genomic imprinting.

MicroRNAs direct downregulation of target mRNAs. Sometimes, however, this regulatory paradigm inverts, and a target RNA triggers degradation of a microRNA. This target-directed microRNA degradation (TDMD) requires ZSWIM8. Zswim8−/− mice exhibit reduced growth and perinatal lethality, accompanied by stabilization of >40 microRNAs. Nonetheless, studies of TDMD function in mammals have been limited because only two TDMD-triggering RNAs have been identified in mice. Here, we computationally identify and validate five new TDMD-triggering sites in mouse models. One site in Atp6v1g1 and two sites in Lpar4 direct degradation of miR-335-3p, showing that in mammals, two sites in the same transcript and multiple sites in different transcripts can collaborate to destabilize a microRNA. Moreover, sites in Plagl1 and Lrrc58 direct degradation of miR-322 and miR-503, respectively. Mice lacking the Plagl1 and Lrrc58 sites were smaller, demonstrating that target-directed degradation of miR-322 and miR-503 promotes growth. Both miR-335-3p and Plagl1 are maternally imprinted, implying their participation in parental conflict, but their corresponding triggers or target microRNA partners are not imprinted. Thus, 3′ UTRs can participate in parental conflict not only by regulating protein production but also by engaging TDMD to access an additional layer of regulation within a network of imprinted and biallelic genes.