ALKBH1-Mediated Transfer RNA Demethylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA273642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3322593.fastq.gz | Fastqsanger.gz | |||
| SRR3322594.fastq.gz | Fastqsanger.gz | |||
| SRR3322595.fastq.gz | Fastqsanger.gz | |||
| SRR3322596.fastq.gz | Fastqsanger.gz | |||
| SRR3322597.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 21 |
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Project description:Transfer RNA (tRNA) is a central component of protein synthesis and cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N1-methyladenosine (m1A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in their reduced partition in polysomes and their decreased usage in protein synthesis. This process is dynamic and responds to glucose availability to affect translation. Our results uncover reversible methylation of tRNA as a new regulatory mechanism of post-transcriptional gene expression.
2016-10-13 | GSE65299 | GEO
Project description:DNA N6-methyladenine (6mA) is an emerging epigenetic modification that regulates various biological processes. Here, we demonstrated the role of DNA 6mA modification in gastric cancer (GC). GC cells and tumors displayed a marked reduction in 6mA levels compared with normal gastric tissues and GES1 cells. 6mA-IP-seq revealed that 6mA was abundant in the surrounding transcription start sites and occurred at consensus motifs. Among the 6mA regulators, ALKBH1, a demethylase, was significantly overexpressed in GC tissues compared to adjacent normal tissues (n=32, P<0.05). Moreover, high ALKBH1 expression was associated with poor survival of patients with GC in three independent GC cohorts (cohort I: n=276, P=0.0093; cohort II: n=136, P=0.001; TCGA dataset: n=381, P=0.0061). Functionally, ALKBH1 knockout increased DNA 6mA and suppressed GC cell growth and cell migration in vitro, and inhibited tumorigenicity and metastasis in vivo. ALKBH1 knockout in mice impairs chemically induced gastric carcinogenesis. Mechanistically, ALKBH1 mediates DNA 6mA demethylation to repress gene expression. In particular, the 6mA sites were enriched in NRF1 binding sequences and targeted for demethylation by ALKBH1. ALKBH1-induced 6mA demethylation inhibited NRF1-driven transcription of downstream targets, including multiple genes involved in the AMPK signaling pathway. Accordingly, ALKBH1 suppressed AMPK signaling, causing a metabolic shift towards the Warburg effect that facilitates tumorigenesis. In conclusion, we revealed, for the first time, that ALKBH1 plays an oncogenic role in GC. ALKBH1 demethylates 6mA within the NRF1-binding regions of tumor suppressor genes to attenuate the binding of NRF1, which subsequently inactivates AMPK signaling and promotes the “Warburg” phenotype.
2025-09-22 | GSE214126 | GEO
Project description:DNA N6-methyladenine (6mA) is an emerging epigenetic modification that regulates various biological processes. Here, we demonstrated the role of DNA 6mA modification in gastric cancer (GC). GC cells and tumors displayed a marked reduction in 6mA levels compared with normal gastric tissues and GES1 cells. 6mA-IP-seq revealed that 6mA was abundant in the surrounding transcription start sites and occurred at consensus motifs. Among the 6mA regulators, ALKBH1, a demethylase, was significantly overexpressed in GC tissues compared to adjacent normal tissues (n=32, P<0.05). Moreover, high ALKBH1 expression was associated with poor survival of patients with GC in three independent GC cohorts (cohort I: n=276, P=0.0093; cohort II: n=136, P=0.001; TCGA dataset: n=381, P=0.0061). Functionally, ALKBH1 knockout increased DNA 6mA and suppressed GC cell growth and cell migration in vitro, and inhibited tumorigenicity and metastasis in vivo. ALKBH1 knockout in mice impairs chemically induced gastric carcinogenesis. Mechanistically, ALKBH1 mediates DNA 6mA demethylation to repress gene expression. In particular, the 6mA sites were enriched in NRF1 binding sequences and targeted for demethylation by ALKBH1. ALKBH1-induced 6mA demethylation inhibited NRF1-driven transcription of downstream targets, including multiple genes involved in the AMPK signaling pathway. Accordingly, ALKBH1 suppressed AMPK signaling, causing a metabolic shift towards the Warburg effect that facilitates tumorigenesis. In conclusion, we revealed, for the first time, that ALKBH1 plays an oncogenic role in GC. ALKBH1 demethylates 6mA within the NRF1-binding regions of tumor suppressor genes to attenuate the binding of NRF1, which subsequently inactivates AMPK signaling and promotes the “Warburg” phenotype.
2025-09-22 | GSE214125 | GEO
Project description:tRNA is a central component of protein synthesis and the cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here, we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N1-methyladenosine (m1A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and decreased usage of tRNAs in protein synthesis. This process is dynamic and responds to glucose availability to affect translation. Our results uncover reversible methylation of tRNA as a new mechanism of post-transcriptional gene expression regulation.
| S-EPMC5119773 | biostudies-literature
Project description:The RNA modification 5-formylcytidine (f5C) is poorly explored in mammals. Low f5C levels reported in mRNA may reflect spurious 5-methylcytidine (m5C) oxidation or targeted demethylation by TET or ALKBH1 dioxygenases. Here we analyze f5C in RNA of mouse embryonic stem cells (mESCs) using LC-MS/MS and chemical-assisted sequencing. We reveal that the previously reported pyridine-borane-sequencing method misidentifies N4-acetylcytidine (ac4C) and unmodified, hyper-reactive cytidines in a CUMC context as f5C. To overcome these limitations, we developed FIBo-seq with enhanced specificity and sensitivity for f5C-sequencing. We find no evidence for a role of TET enzymes in generating f5C, unlike for ALKBH1. Moreover, no f5C sites are detectable in mRNA. Instead, the bulk of mammalian f5C resides in the well-established mitochondrial tRNA Methionine (mt-tRNAMet) and is mediated by ALKBH1. The results argue against an instructive function for f5C outside tRNA in mammals.
2025-10-21 | GSE288506 | GEO
Project description:Here we show a novel role for arsenic in regulating the abundance and function of the demethylase activity of ALKBH1 in arsenic-induced skin cancer. We demonstrate that ALKBH1 is upregulated in response to acute and chronic arsenic exposure. In chronic arsenic-exposed keratinocytes, ALKBH1 promotes tumorigenicity, as knockdown of ALKBH1 leads to decreased tumorigenicity. ALKBH1 as a demethylase has several substrates and knockdown of ALKBH1 in arsenic-induced keratinocytes lead to increased m6A in mRNA. We identify that ALKBH1 demethylates m6A in vitro in an arsenic-dependent manner. Arsenic binds to the ALKBH1 protein via two cysteine residues to regulate the m6A RNA demethylase activity of ALKBH1. m6A sequencing identifies that ALKBH1 regulates m6A demethylation on the NR2C2 transcript to modulate NR2C2 protein translation in a YTHDF1-dependent manner. Knockdown of ALKBH1 leads to increased NR2C2 expression, which, in turn, leads to decreased mTOR signaling and global translation. Our findings demonstrate a novel role for arsenic in regulating ALKBH1 abundance and activity and add new mechanistic insights into arsenic-induced skin tumorigenicity.
2025-08-15 | GSE285900 | GEO
Project description:ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing
| PRJNA623501 | ENA
Project description:Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy.
2025-07-23 | GSE260905 | GEO
Project description:AlkB homolog 1 (ALKBH1) has been reported to act as a DNA 6mA demethylase to remove 6mA modificatione in ukaryotic genomes. Our previous data showed downregalted ALKBH1 in mouse and human fatty liver and increased DNA 6mA levels in mouse fatty liver. We hypothesize that ALKBH1 may be involved in hepatic lipid metabolism. To test this hypothesis, we generated liver-specific ALKBH1 knockout (Alkbh1 f/f, Albumine-cre; AKO) mice and used high-throughput RNA sequence and other assays to directly study the role of ALKBH1 during the development of hepatic steatosis.
2022-10-26 | GSE193497 | GEO
Project description:AlkB homolog 1 (ALKBH1) has been reported to act as a DNA 6mA demethylase to remove 6mA modification in eukaryotic genomes. Our previous data showed downregulated ALKBH1 in mouse and human fatty liver and increased DNA 6mA levels in mouse fatty liver. We developed liver-specific ALKBH1 knockout (AKO) mice to directly study the role of ALKBH1 mediated DNA 6mA modification during the development of hepatic steatosis. Deletion of liver ALKBH1 promoted hepatic steatosis and insulin resistance. Overexpression of ALKBH1 resulted in opposite phenotypes. To investigate the mechanism of ALKBH1 in regulating target gene expression. We performed ChIP-seq for identifying ALKBH1 binding sites on mouse hepatocytes genomes and validated its demethylase activity for DNA 6mA modification on the target genes via ChIP-qPCR assays.
2022-10-26 | GSE197185 | GEO