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Ythdf modulates Fmr1 target selection and restricts axonal growth in Drosophila

ABSTRACT: RIP-seq of Fmr1 in D. melanogaster whole brains.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE161655 | GEO | 2020/11/27

REPOSITORIES: GEO

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Ythdf modulates Fmr1 target selection and restricts axonal growth in Drosophila

Project description:Ythdf modulates Fmr1 target selection and restricts axonal growth in Drosophila

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Ythdf is a N6-methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila.

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Ythdf is a N6-methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila

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The m6A reader Ythdf restricts axonal growth in Drosophila through target selection modulation of the Fragile X mental retardation protein

Project description:The abundant mRNA modification N6-methyladenosine (m6A) regulates a variety of physiological processes through modulation of RNA metabolism. m6A is particularly enriched in the nervous system of several species and its dysregulation has been associated with neurodevelopmental defects as well as neural dysfunctions. In Drosophila, the loss of m6A alters fly behavior but the underlying mechanism and the role of m6A during nervous system development have remained elusive. Here we found that impairment of the m6A pathway leads to axonal overgrowth and misguidance at larval neuromuscular junctions as well as in the adult mushroom bodies. We identify the RNA binding protein Ythdf as the main m6A reader in the nervous system required for limiting axonal growth. Mechanistically, we show that Ythdf interacts directly with Fragile X mental retardation protein (Fmr1) to inhibit the translation of key transcripts involved in axonal growth regulation. Altogether, this study demonstrates that the m6A pathway controls development of the nervous system by modulating Fmr1 target selection.

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Project description:Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of FMRP that, with rare exceptions, results from CGG expansion in the promoter region of FMR1. The trinucleotide expansion has long been thought to induce epigenetic silencing of the FMR1 locus, resulting in complete loss of expression at the mRNA level. However, a recent study reported that FMR1 is transcribed in a substantial proportion of FXS tissues, yet due to mis-splicing, no FMRP protein is produced. The current study sought to independently validate this key finding in FXS iPSCs. FXS patient-derived iPSCs with a transcriptionally silenced FMR1 locus were treated with 5-AzadC for 48 hours to induce reactivation of the FMR1 locus. RNA was subsequently isolated from treated and untreated iPSCs and analyzed by RNA-sequencing. Our findings demonstrate that while FMR1 is reactivated following 5-AzadC treatment, no FMRP is expressed, likely due to mis-splicing of the FMR1 transcript. These results have important implications for understanding FXS pathogenesis and developing therapeutic strategies targeting the expanded FMR1 locus.

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Expression data from FACS sorted astrocytes FMR1 KO mice vs control

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Rescue of Fragile X syndrome by DNA methylation editing of the FMR1 [ChIP-seq]

Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by the silence of FMR1. Hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients was thought to epigenetically silence FMR1. Here, we applied our previously developed DNA methylation editing tool to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/gRNA switched the heterochromatin status of the FMR1 promoter to an active chromatin status and subsequently restored FMR1 expression in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs showed a similar electrophysiological property as wild-type neurons, and maintained FMR1 expression for months after engrafting into the mouse brain. Reactivation of FMR1 can be achieved in FXS neurons with demethylation of the CGG expansion. Lastly, we showed that targeted demethylation of the FMR1 promoter can reactivate FMR1 as well suggesting potential therapeutic approaches for FXS.

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