Approximately one fifth of the human genome is made up of Long Interspersed Elements 1 (Line 1), which need to be prevented from spreading and moving through the genome; a process called retrotransposition. An open question was how this is achieved in very early mouse development during which two known repressors of retrotransposition are inactive. The Ciaudo lab found an additional mechansim keeping L1 retrotransposition in check in mouse embryonic stem cells in which Dicer was knocked out. The Dicer knock out leads to an increased expression of the RNA helicase MOV10 which forms cytoplasmic aggregates with L1 Ribonuclein Protein Complexes. Their findings have been published in the article "Sequestration of LINE-1 in cytosolic aggregates by MOV10 restricts retrotransposition" in EMBO Reports and could provide the basis to treat diseases accompanied by L1 upregulation such as several types of neurological disorders and cancers.
L1 high expression but low mobility in miRNA_KO mESCs is due to upregulation of the RNA helicase MOV10, triggered by the lack of MOV10-targeting miRNAs. Increased MOV10 expression induces L1 RNP aggregation in the cytoplasm, preventing L1 mobility.
- In mESCs, miR-16-5p, miR-153-3p, miR-30-5p, and miR-138-5p directly modulate expression of MOV10, a known regulator of L1 retrotransposition.
- Concomitant upregulation of L1 ORF1p and MOV10 induces accumulation of L1 RNPs in the cytoplasm as aggregates. Sequestration of L1 RNPs in the cytoplasm prevents import of L1 RNPs into the nucleus, thereby impacting the rate of retrotransposition.
- Ectopic expression of MOV10 together with L1 ORF1p is sufficient to induce L1 RNP aggregate formation in mESCs.
LINE-1 (L1) retroelements have retained their ability to mobilize. Mechanisms regulating L1 mobility include DNA methylation in somatic cells and the piRNA pathway in the germline. During preimplantation stages of mouse embryonic development, however, both pathways are inactivated leading to a window necessitating alternate means of L1 regulation. We previously reported an increase in L1 levels in Dicer_KO mouse embryonic stem cells (mESCs), which was accompanied by only a marginal increase in retrotransposition, suggesting additional mechanisms suppressing L1 mobility. Here, we demonstrate that L1 ribonucleoprotein complexes (L1 RNP) accumulate as aggregates in the cytoplasm of Dicer_KO mESCs along with the RNA helicase MOV10. The combined overexpression of L1 ORF1p and MOV10 is sufficient to create L1 RNP aggregates. In Dicer_KO mESCs, MOV10 is upregulated due to the loss of its direct regulation by miRNAs. The newly discovered posttranscriptional regulation of Mov10, and its role in preventing L1 retrotransposition by driving cytosolic aggregation, provides routes to explore for therapy in disease conditions where L1s are upregulated.