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ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development

ABSTRACT: ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development

PROVIDER: PRJNA966074 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24391500_1.fastq.gz	Fastqsanger.gz
	SRR24391500_2.fastq.gz	Fastqsanger.gz
	SRR24391501_1.fastq.gz	Fastqsanger.gz
	SRR24391501_2.fastq.gz	Fastqsanger.gz
	SRR24391502_1.fastq.gz	Fastqsanger.gz

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ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development.

Project description: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.

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ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development

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The effect of ZSWIM8 knockout on RNA levels in tissues of E18.5 mouse embryos [scRNA-seq]

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The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation [dataset3]

Project description:MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand the inferred role of TDMD in shaping miRNA levels in bilaterian animals.

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