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Target-directed microRNA degradation broadly regulates microRNA expression and embryonic growth in mammals

ABSTRACT: Target-directed microRNA degradation broadly regulates microRNA expression and embryonic growth in mammals

PROVIDER: PRJNA984280 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24941000.fastq.gz	Fastqsanger.gz
	SRR24941001.fastq.gz	Fastqsanger.gz
	SRR24941002.fastq.gz	Fastqsanger.gz
	SRR24941003.fastq.gz	Fastqsanger.gz
	SRR24941004.fastq.gz	Fastqsanger.gz

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Target-directed microRNA degradation broadly regulates microRNA expression and embryonic growth in mammals

Project description:MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutional or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in major developmental defects in heart and lung, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD. Deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8 null embryos, directly implicating the TDMD pathway as a key regulator of mammalian body size. These data reveal the broad landscape and developmental role of TDMD in mammals.

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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.

2020-12-18 | GSE163388 | GEO

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