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FMRP-associated MOV10 facilitates and antagonizes miRNA-mediated regulation

ABSTRACT: The fragile X mental retardation protein FMRP is an RNA binding protein that regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway and we show here that it is associated with MOV10, a putative helicase that is also associated with the microRNA pathway. We show that FMRP associates with MOV10 in an RNA-dependent manner and facilitates MOV10-association with RNAs in brain. We identified the RNA sequences recognized by MOV10 using iCLIP and found an increased number of G-quadruplexes in the CLIP sites. We provide evidence that MOV10 facilitates microRNA-mediated translation regulation and also has the novel role of increasing the expression of a subset of RNAs by sterically hindering Argonaute2 association. In summary, we have identified a new mechanism for FMRP-mediated translational regulation through its association with MOV10.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50499 | GEO | 2014/11/20

SECONDARY ACCESSION(S): PRJNA217781

REPOSITORIES: GEO

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FMRP-associated MOV10 facilitates and antagonizes miRNA-mediated regulation

Project description:The fragile X mental retardation protein FMRP is an RNA binding protein that regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway and we show here that it is associated with MOV10, a putative helicase that is also associated with the microRNA pathway. We show that FMRP associates with MOV10 in an RNA-dependent manner and facilitates MOV10-association with RNAs in brain. We identified the RNA sequences recognized by MOV10 using iCLIP and found an increased number of G-quadruplexes in the CLIP sites. We provide evidence that MOV10 facilitates microRNA-mediated translation regulation and also has the novel role of increasing the expression of a subset of RNAs by sterically hindering Argonaute2 association. In summary, we have identified a new mechanism for FMRP-mediated translational regulation through its association with MOV10. Comparison of MOV10 siRNA knockdown, irrelevant siRNA control and MOV10 overexpression on total RNA levels

2014-11-20 | E-GEOD-50499 | biostudies-arrayexpress

FMRP recruits AGO2, modulating access to miRNA recognition elements in G-Quadruplexes through association with Mov10.

Project description:FMRP modulates AGO's association with microRNA Recognition elements.

2019-11-04 | GSE129885 | GEO

FMRP recruits AGO2, modulating access to miRNA recognition elements in G-Quadruplexes through association with Mov10.

Project description:FMRP recruits AGO2, modulating access to miRNA recognition elements in G-Quadruplexes through association with Mov10.

| PRJNA533090 | ENA

Regulatory Discrimination of mRNAs by FMRP Controls Adult Neural Stem Cell Differentiation

Project description:Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), a translation-inhibitor RNA binding protein. The impact of FMRP-deficiency on neural function is widespread, including its regulation of adult neural stem cell (aNSC) differentiation. To assess FMRP activity, we performed ribosome profiling of aNSCs from normal and Fmr1 knockout mice, which revealed diverse gene expression changes at the mRNA and translation levels. Many mitosis and neurogenesis genes were dysregulated primarily at the mRNA level, while numerous synaptic genes were mostly dysregulated at the translation level. Translational “buffering” was also evident, whereby changes in ribosome association with mRNA is compensated by alterations in RNA abundance. Our data revealed that FMRP-regulated neurogenesis is mediated by the transcriptional factor necdin and that FMRP determines mitochondrial mRNA expression and energy homeostasis. Thus, FMRP controls diverse transcriptional and post-transcriptional gene expression programs critical for the adult neural stem cell differentiation.

2018-11-20 | GSE112502 | GEO

FMRP phosphorylation modulates neuronal translation through YTHDF1

Project description:Translation activation of local synaptic mRNA is critical to learning and memory. Despite extensive studies on how phosphorylations of ribosome units and translation factors enable fast response to exogenous stimuli, our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation of N6-methyladenosine (m6A)-modified transcripts. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized with low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide translation alterations with the inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.

2023-10-31 | GSE214882 | GEO

FMRP facilitates the nuclear export of N6-methyladenosine-containing mRNAs

Project description:FMRP facilitates the nuclear export of N6-methyladenosine-containing mRNAs.

2019-11-21 | GSE133724 | GEO

MOV10 knockout and gene expression

Project description:Transposable elements constitute nearly half of the mammalian genome and play important roles in genome evolution. While a multitude of both transcriptional and post-transcriptional mechanisms exist to silence transposable elements, control of transposition in vivo remains poorly understood. MOV10, an RNA helicase, is an inhibitor of mobilization of retrotransposons and retroviruses in cell culture assays. Here we report that MOV10 restricts LINE1 retrotransposition in mice. Although MOV10 is broadly expressed, its loss causes only incomplete penetrance of embryonic lethality, and the surviving MOV10-deficient mice are healthy and fertile. Biochemically, MOV10 forms a complex with UPF1, a key component of the nonsense-mediated mRNA decay pathway, and primarily binds to the 3' UTR of somatically expressed transcripts in testis. Consequently, loss of MOV10 results in an altered transcriptome in testis. Analyses using a LINE1 reporter transgene reveal that loss of MOV10 leads to increased LINE1 retrotransposition in somatic and reproductive tissues from both embryos and adult mice. Moreover, the degree of LINE1 retrotransposition inhibition is dependent on the Mov10 gene dosage. Furthermore, MOV10 deficiency reduces reproductive fitness over successive generations. Our findings demonstrate that MOV10 attenuates LINE1 retrotransposition in a dosage-dependent manner in mice.

2023-03-07 | GSE217336 | GEO

Serine 970 of RNA helicase MOV10 is phosphorylated and controls unfolding activity and fate of mRNAs targeted for AGO2-mediated silencing [RNA-Seq]

Project description:MOV10 is an RNA helicase that is required for organismal development and is highly expressed in postnatal brain. MOV10 was identified as an AGO2 associated protein that is also necessary for AGO2-mediated silencing. MOV10 has been shown to be ubiquitinated, leading to its degradation and release from bound mRNAs but no other post-translational modifications with functional implications have been described. Using mass spectrometry, we show that MOV10 is phosphorylated in cells at the C-terminus, specifically at serine 970 (S970). Substitution of S970 to phospho-mimic aspartic acid (S970D) blocked unfolding of an RNA G-quadruplex, similar to when the helicase domain was mutated (K531A). In contrast, the alanine substitution (S970A) of MOV10 unfolded the model RNA G-quadruplex. To examine its role in cells, RNA-seq analysis showed that the expression of S970D causes decreased expression of MOV10 eCLIP targets compared to WT. Introduction of S970A had an intermediate effect, suggesting that S970 was protective of mRNAs. In whole cell extracts, MOV10 and its substitutions bound AGO2 comparably; however, knockdown of AGO2 abrogated the S970D-induced mRNA degradation. Thus, MOV10 activity protects mRNA from AGO2; phosphorylation of S970 restricts this activity resulting in AGO2-mediated mRNA degradation. S970 is positioned C-terminal to the defined MOV10-AGO2 interaction site and is proximal to a disordered region that likely modulates AGO2 interaction with target mRNAs upon phosphorylation. In summary, we provide evidence for a model whereby MOV10 phosphorylation facilitates AGO2 association with the 3’UTR of translating mRNAs that leads to their degradation.

2023-02-28 | GSE226235 | GEO

Serine 970 of RNA helicase MOV10 is phosphorylated and controls unfolding activity and fate of mRNAs targeted for AGO2-mediated silencing [eCLIP-Seq]

2023-02-28 | GSE226240 | GEO

Identification of the cellular RNAs bound by MOV10

Project description:Using the iCLIP protocol we have identified the cellular RNA entities that are bound by MOV10. We report the location and sequence of the MOV10 binding region on each RNA entity. To identify the RNAs that bound MOV10, we UV-cross-linked HEK293F cells and immunoprecipitated with an irrelevant antibody (ir or "control") followed by a MOV10-specific antibody (MOV10) to isolate associated RNAs after stringent washing.

2014-11-20 | E-GEOD-51443 | biostudies-arrayexpress

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