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Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

ABSTRACT: Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

PROVIDER: PRJNA601768 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10904900_1.fastq.gz	Fastqsanger.gz
	SRR10904900_2.fastq.gz	Fastqsanger.gz
	SRR10904901_1.fastq.gz	Fastqsanger.gz
	SRR10904901_2.fastq.gz	Fastqsanger.gz
	SRR10904906_1.fastq.gz	Fastqsanger.gz

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Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

Project description:Maternal RNA degradation is critical for embryogenesis and is tightly controlled by maternal RNA-binding proteins. Fragile X mental-retardation protein (FMR1) binds target mRNAs to form ribonucleoprotein (RNP) complexes/granules that control various biological processes, including early embryogenesis. However, how FMR1 recognizes target mRNAs and how FMR1-RNP granule assembly/disassembly regulates FMR1-associated mRNAs remain elusive. Here we show that Drosophila FMR1 preferentially binds mRNAs containing m6A-marked “AGACU” motif with high affinity to contributes to maternal RNA degradation. The high-affinity binding largely depends on a hydrophobic network within FMR1 KH2 domain. Importantly, this binding greatly induces FMR1 granule condensation to efficiently recruit unmodified mRNAs. The degradation of maternal mRNAs then causes granule de-condensation, allowing normal embryogenesis. Our findings reveal that sequence-specific mRNAs instruct FMR1-RNP granules to undergo a dynamic phase-switch, thus contributes to maternal mRNA decay. This mechanism may represent a general principle that regulated RNP-granules control RNA processing and normal development.

2021-12-16 | GSE143821 | GEO

Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

Project description:To search for the functional “m6A readers” specifically in the context of Drosophila early embryos, we incubated m6A-modified or unmodified RNA probes with cytosolic lysates from early embryos, and performed immunoprecipitation experiments followed by mass spectrometry analysis. We found that Drosophila FMRP (FMR1) was highly abundant in complexes immuno-precipitated by the m6A-modified probe. We performed data-independent acquisition (DIA) quantitative proteomics on the wild type and fmr1 maternal mutant embryos at multiple developmental stages, including 0-1 h, 2-3 h, and 5-6 h stages. To screen the FMR1-associated partners, we collected the 2–3-hour embryos and performed immunoprecipitation using the anti-Drosophila FMR1 antibody, followed by mass spectrometric analysis.

2021-12-19 | PXD026356 | iProX

TRAP from CA1 pyramidal neurons and cerebellar granule cells in Fmr1 KO and wildtype mice

Project description:TRAP (translating ribosome affinity purification) from CA1 pyramidal neurons and cerebellar granule cells in wildtype and Fmr1 KO littermate pairs. These data show a global downregulation of FMRP targets in Fmr1 KO mice in these cell types.

2020-01-07 | GSE127845 | GEO

TRAP from CA1 pyramidal neurons and cerebellar granule cells in Fmr1 KO and wildtype mice

Project description:TRAP from CA1 pyramidal neurons and cerebellar granule cells in Fmr1 KO and wildtype mice

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RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome

Project description:Ribonucleoprotein (RNP) granules are non-membrane bound organelles thought to assemble by protein-protein interactions of RNA-binding proteins. We present evidence that a wide variety of RNAs self-assemble in vitro into either liquid-liquid phase separations or more stable assembles, referred to as RNA tangles. Self-assembly in vitro is affected by RNA length, ionic conditions, and sequence. Remarkably, self-assembly of yeast RNA in vitro under physiological salt mimics the composition of mRNAs within yeast stress granules. This suggests that the biophysical principles that drive RNA self-assembly in vitro contribute to determining the stress granule transcriptome. Consistent with RNA self-assembly contributing to RNP granule formation, an excess of purified RNA injected into C. elegans syncytium coalesces into droplet-like assemblies. We suggest that diverse RNA-RNA interactions in trans contribute to RNP granule formation and may explain the prevalence of large RNA-protein assemblies in eukaryotic cells.

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Uncovering the metabolic pleiotropy of FMR1-deficiency in Fragile X Syndrome

Project description:ene pleiotropy defines the capacity of a gene to impact multiple phenotypic characters. The Fragile X Mental Retardation 1 (FMR1) gene is a candidate for pleiotropy, as it controls protein synthesis through its product, the translational regulator FMRP. As FMR1 loss-of-function leads to neurodevelopmental defects and Fragile X Syndrome (FXS), intellectual disability and autism, FMR1 functions have been mostly studied in the brain. FMR1-deficiency could also have yet unexplored consequences in periphery and impact metabolism through translational repression in peripheral organs. We combined 1H NMR-based metabolic phenotyping and proteomics to reveal the pleiotropic metabolic effects associated with FMR1-deficiency in mouse and human. We demonstrate that Fmr1-deficiency in the mouse increases hepatic translation, improves glucose tolerance and insulin sensitivity and reduces adiposity, while enhancing -adrenergic driven lipolysis and utilization of lipid energetic substrates. Last, we provide converging evidences in FXS patients that the levels of glucose, insulin and free fatty acids are modified, suggesting that FMR1-deficiency also drives metabolic readjustments in human. As part of a larger study investigating the involvement of fmr in metabolic alteration in fmr1-KO mice, fmr1-KO mouse livers were analysed by MS.

2022-02-28 | PXD007241 | Pride

No upregulation of homologous sequence expression in zebrafish larvae homozygous for the hu2787 nonsense mutant allele of fmr1.

Project description:The zebrafish has proven to be a versatile and valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). Reduction of expression of the zebrafish FMR1-ortholgous gene, fmr1, causes developmental and behavioural phenotypes related to the human syndrome. The hu2787 nonsense mutation allele of fmr1 is now the most widely used zebrafish model of FXS, although the FXS-relevant phenotypes seen from morpholino antisense oligonucleotide (morpholino) suppression of fmr1 transcript translation were not observed when this allele was first described. The subsequent discovery of genetic compensation, whereby morpholino-directed knockdown can give a more “pure” loss-of-function phenotype while mutations causing nonsense mediated decay of transcripts cause compensatory upregulation of homologous transcripts, suggested an explanation for the differences observed. To test for molecular evidence of genetic compensation in fmr1hu2787 homozygous mutants, we compared the transcriptomes of homozygous mutant and wild type larvae at 2 days post fertilisation. We observed statistically significant changes in the expression of a number of gene transcripts, but none with sequence homology to fmr1. Curiously, the majority of differentially expressed genes are located, like fmr1, on chromosome 14. Quantitative PCR tests on genomic DNA did not support that the apparent expression differences were artefacts due to changes in relative chromosome abundance. The coordinate dysregulation of chromosome 14 genes due to mutation of fmr1 supports this gene’s involvement in a chromosome-wide gene regulation complex.

2020-05-30 | GSE151443 | GEO

Identification of the stress granule transcriptome via RNA-editing in bulk S2 cells, single S2 cells and in Drosophila neurons

Project description:Stress granules are phase separated assemblies formed around mRNAs that have now been identified after stress granule purification from cell culture. Here, we present a purification free method to detect stress granules RNAs in single cells and in tissues, including those displaying cell heterogeneity. We adapted TRIBE (Target of RNA-binding proteins Identified by Editing) to detect stress-granule RNAs by fusing a stress-granule RNA-binding protein (FMR1) to the catalytic domain of an RNA-editing enzyme (ADAR). RNAs colocalized with this fusion are edited, producing mutations that are detectable by sequencing. We then show that this “in situ" method can reliably identify stress granule RNAs in single S2 cells and in Drosophila neurons, and that they encode cell cycle, transcription and splicing factors. The identification of stress granule RNAs without perturbation opens the possibility to examine cell-to-cell variability and identify the RNA content not only in stress granules, but also in other RNA based assemblies in single cells derived from tissues.

2021-05-30 | GSE175782 | GEO

Expression data from FACS sorted astrocytes FMR1 KO mice vs control

Project description:Fmr1 mutation results in autistic behaviors and the FMR1 KO mice model is one of the popular methods to study autism spectrum disorders. In this dataset, we include the expression data obtained from astrocytes isolated from cortex of control and FMR1-KO mice.

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Regulation of RNA localization by FMR1

Project description:We use subcellular fractionation to probe the regulation of RNA localization by FMR1 in neuronal cells.

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