ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development
- Charlie Y. Shi1,2,3,
- Lara E. Elcavage1,2,3,
- Raghu R. Chivukula4,
- Joanna Stefano1,2,3,
- Benjamin Kleaveland5 and
- David P. Bartel1,2,3
- 1Howard Hughes Medical Institute, Cambridge, Massachusetts 02142, USA;
- 2Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 3Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA
Abstract
MicroRNAs (miRNAs) pair to sites in mRNAs to direct the degradation of these RNA transcripts. Conversely, certain RNA transcripts can direct the degradation of particular miRNAs. This target-directed miRNA degradation (TDMD) requires the ZSWIM8 E3 ubiquitin ligase. Here, we report the function of ZSWIM8 in the mouse embryo. Zswim8−/− embryos were smaller than their littermates and died near the time of birth. This highly penetrant perinatal lethality was apparently caused by a lung sacculation defect attributed to failed maturation of alveolar epithelial cells. Some mutant individuals also had heart ventricular septal defects. These developmental abnormalities were accompanied by aberrant accumulation of more than 50 miRNAs observed across 12 tissues, which often led to enhanced repression of their mRNA targets. These ZSWIM8-sensitive miRNAs were preferentially produced from genomic miRNA clusters, and in some cases, ZSWIM8 caused a switch in the dominant strand or isoform that accumulated from a miRNA hairpin—observations suggesting that TDMD provides a mechanism to uncouple coproduced miRNAs from each other. Overall, our findings indicate that the regulatory influence of ZSWIM8, and presumably TDMD, in mammalian biology is widespread and consequential, and posit the existence of many yet-unidentified transcripts that trigger miRNA degradation.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278073.123.
-
Freely available online through the Genome Research Open Access option.
- Received May 4, 2023.
- Accepted July 31, 2023.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
