Epitranscriptomic m6A Regulation of Axon Regeneration in the Adult Mammalian Nervous System
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ABSTRACT:
PROVIDER: PRJNA416850 | ENA |
REPOSITORIES: ENA
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Project description:N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury. Loss of either m6A methyltransferase complex component Mettl14 or m6A-binding protein Ythdf1 globally attenuates injury induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system.
2018-01-17 | GSE106423 | GEO
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Project description:In this study we performed MeRIP-Seq to study N6-methyl adenosine (m6A) and and N6,2′ -O-dimethyladenosine (m6Am) modification of mRNA. We investigated the effect of the microbiota on the transcriptome and epitranscriptomic modifications in murine liver and cecum. We compared m6A/m modification profiles in cecum of conventionally raised (CONV) and germ-free (GF) mice. We additionally included GF mice colonised with the flora of CONV mice for four weeks (ex-GF), for which show that they exhibit similar patterns of the most abundant genera of gut bacteria as CONV mice. We added mice treated with several antibiotics to deplete the gut flora (abx)and vancomycin treated mice in which the genera Akkermansia, Escherichia/Shigella and Lactobacillus were enriched. Furthermore, we included GF mice colonised with the commensal bacterium Akkermansia muciniphila (Am), Lactobacillus plantarum (Lp) and Escherichia coli Nissle (Ec) and analysed their m6A/m modification profiles. In addition, we analysed changes in m6A/m- modified liver RNA for CONV, GF, and Am, Lp and Ec mice.
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Project description:Total RNA samples from human bronchial epithelial BEAS-2B passage-matched control cells and Cr(VI)-transofmred BEAS-2B cells were submitted to ArraySatr for total RNA m6A epitranscriptomic microarray analysis
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Project description:N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury. Loss of either m6A methyltransferase complex component Mettl14 or m6A-binding protein Ythdf1 globally attenuates injury-induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system.
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Project description:Current treatments for neurodegenerative diseases and neural injuries fall short of success. One primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons to support spontaneous axon regeneration following peripheral nerve injury. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and inhibiting axon regeneration, while simultaneously activating various axon regeneration promoting factors. In particular, our study demonstrated that the GABA transporter 2 encoded by the gene Slc6a13 acted downstream of Ezh2 to control axon regeneration. Our study suggested that modulating chromatin accessibility was a promising strategy to promote CNS axon regeneration.
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Project description:Gut microbiota and their metabolites influence host gene expression and physiological status through diverse mechanisms. Here we investigate how gut microbiota and their metabolites impact host's mRNA m6A epitranscriptome in various antibiotic-induced microbiota dysbiosis models. With multi-omics analysis, we find that the imbalance of gut microbiota can rewire host mRNA m6A epitranscriptomic profiles in brain, liver and intestine. We further explore the underlying mechanisms regulating host mRNA m6A methylome by depleting the microbiota with ampicillin. Metabolomic profiling shows that cholic acids are the main down-regulated metabolites with Firmicutes as the most significantly reduced genus in ampicillin-treated mice comparing to untreated mice. Fecal microbiota transplantations in germ-free mice and metabolites supplementations in cells verify that cholic acids are associated with host mRNA m6A epitranscriptomic rewiring. Collectively, this study employs an integrative multi-omics analysis to demonstrate the impact of gut microbiota dysbiosis on host mRNA m6A epitranscriptomic landscape via cholic acid metabolism.
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Project description:Current treatments for neurodegenerative diseases and neural injuries fall short of success. One primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons to support spontaneous axon regeneration following peripheral nerve injury. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and inhibiting axon regeneration, while simultaneously activating various axon regeneration promoting factors. In particular, our study demonstrated that the GABA transporter 2 encoded by the gene Slc6a13 acted downstream of Ezh2 to control axon regeneration. Our study suggested that modulating chromatin accessibility was a promising strategy to promote CNS axon regeneration.
2023-12-22 | GSE247315 | GEO
Project description:Gut microbiota and their metabolites influence host gene expression and physiological status through diverse mechanisms. Here we investigate how gut microbiota and their metabolites impact host′s mRNA m6A epitranscriptome in various antibiotic-induced microbiota dysbiosis models. With multi-omics analysis, we find that the imbalance of gut microbiota can rewire host mRNA m6A epitranscriptomic profiles in brain, liver and intestine. We further explore the underlying mechanisms regulating host mRNA m6A methylome by depleting the microbiota with ampicillin. Metabolomic profiling shows that cholic acids are the main down-regulated metabolites with Firmicutes as the most significantly reduced genus in ampicillin-treated mice comparing to untreated mice. Fecal microbiota transplantations in germ-free mice and metabolites supplementations in cells verify that cholic acids are associated with host mRNA m6A epitranscriptomic rewiring. Collectively, this study employs an integrative multi-omics analysis to demonstrate the impact of gut microbiota dysbiosis on host mRNA m6A epitranscriptomic landscape via cholic acid metabolism.
2024-04-21 | GSE216620 | GEO
Project description:Current treatments for neurodegenerative diseases and neural injuries fall short of success. One primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons to support spontaneous axon regeneration following peripheral nerve injury. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and inhibiting axon regeneration, while simultaneously activating various axon regeneration promoting factors. In particular, our study demonstrated that the GABA transporter 2 encoded by the gene Slc6a13 acted downstream of Ezh2 to control axon regeneration. Our study suggested that modulating chromatin accessibility was a promising strategy to promote CNS axon regeneration.
2023-12-22 | GSE247318 | GEO