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M6A/m-Seq of mouse adult cortex of Mettl3 cKO or Fto cKO mice

ABSTRACT: N6-Methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo are currently unknown. Here, we investigated the effect of gene deletion of Mettl3, a m6A methyltransferase, and Fto, a m6A and m6Am demethlyase, induced in adulthood in excitatory neurons of the neocortex and hippocampus (Camk2a-Cre Mettl3 or Fto cKO) on the cortical epitranscriptome. PolyA-RNA-fragments from 3-5 replicates per group were processed both as m6A/m-sample (RNA immunoprecipiation RIP with an m6A and m6Am antibody) and RNA-input sample.

ORGANISM(S): Mus musculus

PROVIDER: GSE113793 | GEO | 2018/07/10

REPOSITORIES: GEO

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mRNA-Seq of mouse Mettl3 cKO and Fto cKO hippocampus after fear conditioning

Project description:N6-Methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo are currently unknown. Here, we investigated the effect of gene deletion of Mettl3, a m6A methyltransferase, and Fto, a m6A and m6Am demethlyase, induced in adulthood in excitatory neurons of the CA1 and CA3 in the hippocampus (Nex-CreERT2 Mettl3 or Fto cKO) on the transcriptome of CA1 and CA3 as well as the transcriptomic response of the CA1 and CA3 transcriptome to fear conditioning.

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m6A/m-Seq of human B-lymphocyte cell lines from healthy controls and major depressive disorder patients

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Project description:N6-methyladenosine (m6A) and N6,2′-O‐dimethyladenosine (m6Am) are two abundant modifications found in mRNAs and ncRNAs that can regulate multiple aspects of RNA biology and function mainly through regulation of interaction with specific RNA-binding proteins. Both modifications are linked to development, disease and stress response. To date three methylases and two demethylases have been identified that modify adenosines in mammalian (m)RNAs. Here we provide a comprehensive study of the in vivo protein-protein interactome of the key methyltransferases and demethylases using the BioID proximity biotinylation approach, which allows capturing of stable and short-lived interactions. Our results show that METTL3, METTL16, CAPAM, FTO and ALKBH5 occupy specific non overlapping protein interacting territories. Moreover, the individual interactomes help to understand the biological functions of these enzymes

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Proteomics of HEPG2 cells following FTO overexpression and knockdown

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Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in Cell Nucleus and Cytoplasm

Project description:FTO, the first RNA demethylase discovered, mediates the demethylation of N6-methyladenosine (m6A), installed internally on messenger RNA, and N6,2′-O-dimethyladenosine (m6Am), occurring at the +1 position from the 5’ cap. Despite extensive recent research on FTO, its physiological impact on cellular processes has yet to be fully elucidated. Here, we demonstrate that the cellular distribution of FTO is distinct among different cell lines, which critically affects the access of FTO to different RNA substrates. FTO binds multiple RNA substrates, including mRNA, U6 RNA, and tRNA. It mainly targets internal m6A when located in the cell nucleus and preferentially demethylates m6Am when residing in the cytoplasm. The expression levels of transcripts containing internal m6A are associated with the alteration of the FTO more so than transcripts containing m6Am. We also discover that N1-methyladenosine (m1A) in tRNA is a main substrate of FTO, with the FTO-catalyzed demethylation of target tRNAs repressing protein synthesis. Collectively, FTO-mediated RNA demethylation affects both mRNA level and translation through distinct pathways.

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Project description:Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5′ end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2′-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5′ cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.

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The role of m6A/m-RNA methylation in stress response regulation

Project description:N6-Methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo are currently unknown. Here, we provide a detailed analysis of the stress-epitranscriptome using m6A/m-Seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region- and time-specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alter the m6A/m epitranscriptome, increase fear memory, alter the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder (MDD) patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m-response may contribute to the pathophysiology of stress-related psychiatric disorders.

2018-07-10 | GSE113801 | GEO

An atlas of single-base-resolution N6-methyl-adenine methylomes redefines RNA demethylase function as suppressors of disruptive RNA methylation

Project description:Various methylases and demethylases catalyze methylation and demethylation of N6-methyladenosine (m6A) and N6,2?-O-dimethyladenosine (m6Am) but precise methylomes uniquely mediated by each methylase/demethylase are still lacking. Here, we developed m6A-Crosslinking-Exonuclease-sequencing (m6ACE-seq) to map m6A and m6Am at transcriptome-wide single-base-resolution. m6ACE-seq's ability to quantify relative differences in methylation levels across samples enabled the generation of a comprehensive atlas of distinct methylomes uniquely mediated by every individual known methylase/demethylase. We determined METTL16 to indirectly impact manifold methylation targets beyond its consensus target motif, and highlighted the importance of precision in mapping PCIF1-dependent m6Am. Rather than reverse RNA methylation, we found that both ALKBH5 and FTO demethylases instead maintain their regulated sites in an unmethylated steady-state. In FTO's absence, anomalous m6Am disrupts snRNA interaction with nuclear export machinery, potentially causing aberrant pre-mRNA splicing events. We propose a model whereby RNA demethylases ensure normal RNA metabolism by suppressing disruptive RNA methylation in the nucleus.

2019-09-20 | GSE124509 | GEO

Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48 [ChIP-seq]

Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

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