Similar Datasets
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:N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis via disrupting NRF1 binding capacity
| PRJNA883982 | ENA
Project description:N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis via disrupting NRF1 binding capacity [ALKBH1-RNA-seq]
| PRJNA883983 | ENA
Project description:N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis via disrupting NRF1 binding capacity [ALKBH1-6mA-seq]
| PRJNA883984 | ENA
Project description: Not available
| S-EPMC8192600 | biostudies-literature
Project description:Vascular calcification (VC) predicts cardiovascular morbidity and mortality in chronic kidney disease (CKD). To date, the underlying mechanisms remain unclear. We detected leukocyte DNA N6-methyladenine (6mA) levels in patients with CKD with or without aortic arch calcification. We used arteries from CKD mice infected with vascular smooth muscle cell-targeted (VSMC-targeted) adeno-associated virus encoding alkB homolog 1 (Alkbh1) gene or Alkbh1 shRNA to evaluate features of calcification. We identified that leukocyte 6mA levels were significantly reduced as the severity of VC increased in patients with CKD. Decreased 6mA demethylation resulted from the upregulation of ALKBH1. Here, ALKBH1 overexpression aggravated whereas its depletion blunted VC progression and osteogenic reprogramming in vivo and in vitro. Mechanistically, ALKBH1-demethylated DNA 6mA modification could facilitate the binding of octamer-binding transcription factor 4 (Oct4) to bone morphogenetic protein 2 (BMP2) promoter and activate BMP2 transcription. This resulted in osteogenic reprogramming of VSMCs and subsequent VC progression. Either BMP2 or Oct4 depletion alleviated the procalcifying effects of ALKBH1. This suggests that targeting ALKBH1 might be a therapeutic method to reduce the burden of VC in CKD.
| S-EPMC8279589 | biostudies-literature
Project description:BackgroundReversible N6-methyladenosine (m6A) modifications in messenger RNAs can be categorized under the field of "RNA epigenetics." However, the potential role of m6A-related genes in gastric cancer (GC) prognosis has not been systematically researched.AimsThis study was aimed at providing insights into the prognostic role of m6A-related gene expression, at both mRNA and protein levels.MethodsKaplan-Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m6A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored.ResultsAmong nine m6A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients.ConclusionsAberrant expression of demethylase genes, FTO and ALKBH1, has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis.
| S-EPMC6522448 | biostudies-literature
Project description:DNA N6-adenine methylation (6mA), as a novel adenine modification existing in eukaryotes, shows essential functions in embryogenesis and mitochondrial transcriptions. ALKBH1 is a demethylase of 6mA and plays critical roles in osteogenesis, tumorigenesis, and adaptation to stress. However, the integrated biological functions of ALKBH1 still require further exploration. Here, we demonstrate that knockdown of ALKBH1 inhibits adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Using a combination of RNA-seq and N6-mA-DNA-IP-seq analyses, we identify hypoxia-inducible factor-1 (HIF-1) signaling as a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1α and its downstream target GYS1. Simultaneous overexpression of HIF-1α and GYS1 restores the adipogenic commitment of ALKBH1-deficient cells. Taken together, our data indicate that ALKBH1 is indispensable for adipogenic differentiation, revealing a novel epigenetic mechanism that regulates adipogenesis.
| S-EPMC8760519 | biostudies-literature
Project description:Neural Tube Defects (NTDs) are a class of severe congenital developmental defects caused by abnormal closure of the neural tube during early embryonic development, including conditions such as anencephaly, spina bifida, and encephalocele. Currently, NTDs are considered to result from the combined effects of genetic and environmental factors, particularly maternal folate intake during pregnancy, leading to widespread epigenetic dysregulation. However, the role of N6-methyladenine (N6-mA) in embryonic neural development remains largely unknown. Here, we found significant upregulation of Alkbh1 and concomitant significant downregulation of overall 6mA in brain tissue of a mouse model of NTDs. Further investigation through MeDIP, CUT&TAG, and single-cell sequencing revealed crosstalk between N6-mA and H3K9me3-marked heterochromatin, primarily impacting the involvement of embryonic glial cells in the formation of the hindbrain during embryonic neural tube development. These findings collectively suggest a potential epigenetic role of N6-mA in mammalian brain development, potentially exhibiting cell type specificity.
2025-05-01 | GSE268661 | GEO