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Proteomics of HEPG2 cells following FTO overexpression and knockdown

ABSTRACT: Proteomics of HEPG2 cells following FTO overexpression and knockdown. Data accompany our paper entitled “Dynamic Regulation of N6,2′-O-dimethyladenosine (m6Am) in Obesity” scheduled for publication in Nature Communications, 2021

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

SUBMITTER: Moshe Shay Ben-Haim

LAB HEAD: Gideon Rechavi

PROVIDER: PXD029268 | Pride | 2021-10-27

REPOSITORIES: Pride

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			Action	DRS
	QEP2_5242_GREC_CONT-A_1_F1a_150617.dat	Other
	QEP2_5242_GREC_CONT-A_1_F1a_150617.raw	Raw
	QEP2_5242_GREC_CONT-A_1_F2a_150617.dat	Other
	QEP2_5242_GREC_CONT-A_1_F2a_150617.raw	Raw
	QEP2_5242_GREC_CONT-A_1_F4a_150617.dat	Other

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Publications

Dynamic regulation of N6,2'-O-dimethyladenosine (m6Am) in obesity.

Ben-Haim Moshe Shay MS Pinto Yishay Y Moshitch-Moshkovitz Sharon S Hershkovitz Vera V Kol Nitzan N Diamant-Levi Tammy T Beeri Michal Schnaider MS Amariglio Ninette N Cohen Haim Y HY Rechavi Gideon G

Nature communications 20211210 1

The prevalent m6Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m6A mRNA modification. However, the deposition and dynamics of m6Am in regulating obesity are unknown. Here, we investigate the liver m6A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost m6< ...[more]

PMID: 34893620

Similar Datasets

Proteomics of liver from ob/ob and WT mice

Project description:Proteomics of liver tissue from ob/ob and WT mice. Data accompany our paper entitled “Dynamic Regulation of N6,2′-O-dimethyladenosine (m6Am) in Obesity” scheduled for publication in Nature Communications, 2021

2021-10-27 | PXD029217 | Pride

Proteomics of liver from mice fed high fat diet (HFD) or regular chow diet

Project description:Proteomics of liver tissue from mice fed a high fat diet (HFD) or regular chow diet. Data accompany our paper entitled “Dynamic Regulation of N6,2′-O-dimethyladenosine (m6Am) in Obesity” scheduled for publication in Nature Communications, 2021

2021-10-27 | PXD029280 | Pride

m6A/m-Seq of mouse adult cortex of Mettl3 cKO or Fto cKO mice

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 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.

2018-07-10 | GSE113793 | GEO

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.

2018-07-10 | GSE113796 | GEO

Reversible methylation of m6Am in the 5′ cap controls mRNA stability

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.

2016-12-21 | GSE78040 | GEO

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.

2018-09-14 | GSE106395 | GEO

FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell

Project description:Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m6Am (N6,2'-O-dimethyladenosine) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a novel, reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

2021-01-20 | GSE165115 | 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

The comprehensive interactomes of human adenosine RNA methylases and demethylases revealed by proximity labelling-mass spectrometry.

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

2021-11-02 | PXD021566 | Pride

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.

2024-08-26 | GSE228605 | GEO