DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling
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ABSTRACT:
PROVIDER: PRJNA736989 | ENA |
REPOSITORIES: ENA
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Project description:DNA 6-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.
2021-12-12 | GSE177059 | GEO
Project description: Not available
| S-EPMC8760519 | biostudies-literature
Project description:We identified that the m6A demethylase FTO demethylates and stabilizes a lncRNA long intergenic noncoding RNA for kinase activation (LINK-A) during ESCC chemoresistance. LINK-A directly interacts with minichromosome maintenance complex component 3 (MCM3) and increases the phosphorylation of MCM3 at Ser112 by cyclin-dependent kinase 1 (CDK1), which facilitates MCM3 incorporation into the MCM2-7 complex and subsequent chromatin loading, promoting cell cycle progression. On the other hand, LINK-A insulates the interaction between MCM3 and HIF-1α to free HIF-1α. The enhancement of HIF-1α transcriptional activity reprograms metabolic status from OXPHOS to glycolysis. Additionally, targeting LINK-A substantially sensitized ESCC patient-derived xenografts (PDXs) to first-line chemotherapy, thus indicating LINK-A is a promising target for cancer treatment.
2023-10-15 | GSE224079 | GEO
Project description:We describe a unique regulation of the succinylacetone/PHD2/HIF-1α axis by a metabolic enzyme GSTZ1. The total RNA was isolated from HepG2 cells stably transfected with or without GSTZ1-KO and analyzed using RNA-seq. Our work demonstrates that GSTZ1-deficient promotes HCC angiogenesis through stabilizing HIF-1α due to succinylacetone accumulation. In addition, the combination of targeting HIF-1α and PD-L1 could limit tumorigenesis and progression for Gstz1-/-mice, thus providing a potential target for HCC therapy.
2023-11-06 | GSE192760 | 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
Project description:The Fe(II)- and α-ketoglutarate-dependent AlkB family dioxygenases are implicated in nucleotide demethylation. AlkB homolog1 (ALKBH1) is shown to demethylate DNA adenine methylation (6mA) preferentially from single-stranded or unpaired DNA, while its demethylase activity and function in the chromatin context are unclear. In this work we found that loss-of-function of the rice ALKBH1 gene led to increased 6mA in R-loop regions of the genome but had a limited effect on the overall 6mA level. However, the ALKBH1 mutation or over-expression mainly affected the expression of genes with a specific combination of chromatin modifications in the body region marked with H3K4me3 and H3K27me3 but depleted of DNA CG methylation. Further analysis revealed that the ALKBH1 protein preferentially binds to genes marked by the chromatin signature and has a function to maintain a high H3K4me3/H3K27me3 ratio by impairing the binding of Polycomb Repressive Complex2 (PRC2) to the targets, which is required for both the basal and stress-induced expression of the genes.These results unravel a function of ALKBH1 to control the balance between the antagonistic histone methylations for gene activity and provide insight into the regulatory mechanism of PRC2-mediated H3K27me3 deposition within the gene body region.
2023-07-26 | GSE222734 | GEO
Project description:Natural control of HIV infection in Elite Controllers (EC) is a characteristic of <1% of HIV infected individuals. Extensive research has tried to elucidate the mechanism of control without any concrete results due to a large heterogeneity in the EC group, both between the sexes and how they obtain control. Therefore, we sought to identify signaling pathways associated with the EC phenotype by proteomics (all male) and transcriptomic (male and female) analysis. Further, we integrated the proteomics and transcriptomic analysis in the male cohort. We found that HIF signaling and downstream glycolysis are specific traits of the EC phenotype. Within this pathway ENO1 was upregulated in EC on a protein level irrespective of sex. We also performed targeted transcriptomic analysis where we identified HIF target genes as specifically de-regulation of in EC group. Namely, we observed an increase in the antiviral transcript GPS2, while CXCR4 and EIF5A were down regulated. Although we could not detect any difference in protein levels of HIF-1α in total PBMCs, we observed a higher portion of HIF-1α and HIF-1β in the nuclei of CD4+ and CD8+ T cells indicating an increased activation of HIF signaling in the male EC. Furthermore, the intracellular glucose levels were elevated in EC even as metabolite transporter expression of Glut1 and MCT-1 was decreased in lymphocytes showing that the EC have a unique metabolic uptake and secretion profile. Combined our data indicate the role HIF-1 signaling and glycolysis has in natural control of HIV infection.
2021-04-01 | PXD023990 | Pride
Project description:Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arteries is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanisms behind invasion of these cells is perturbed. The placenta initially develops in a low oxygen environment of 1-2% oxygen until after the 10th week of pregnancy. During this time oxygen concentration exerts a major influence over trophoblast activity and, in vitro, hypoxia inducible factors are proposed to be one of many key regulators of first trimester trophoblast behaviour. We used a global gene expression microarray approach to identify signalling pathways involved in invasion of the first trimester trophoblast cell line HTR8/SVneo under hypoxic conditions where HIF-1 was active. Additionally, first trimester placental samples from different gestational age groups were labelled with anti HIF-1 and HIF-2 to evaluate whether HIFs are differentially expressed and localised across the period of development characterised by hypoxia (6-8 weeks) and maternal blood perfusion (10-12 weeks). Eighty-eight genes were differentially expressed between cells cultured in 1% oxygen (where HIF-1 was localised to the nucleus) and 5% oxygen (where HIF-1 was cytoplasmic). 65% of the genes were predicted to contain HIF-1α:ARNT transcription factor binding sites. Increased nuclear localisation of HIF-1α was seen in extravillous cytotrophoblasts in early first trimester compared with late, while cellular expression of HIF-2α in the villous stroma was higher in late first trimester. While HIFs and their downstream targets are clearly induced in trophoblasts during early placental development, and in vitro hypoxic conditions, the mechanism and pathways by which invasion is increased under hypoxic conditions is not clear from the gene expression profile. Further insight beyond the transcription level is required to fully understand this complex phenomenon.
2015-10-01 | GSE65271 | GEO
Project description:Skin is the largest organ in the body and comprises several types of cells. The intercellular plasticity of keratinocytes, fibroblasts, and skin adipocytes contributes to wound healing and dermal adipogenesis. Although keratinocyte activates dermal adipose tissue (dWAT) differentiation upon hair follicular cycle, regulating dWAT hyperplasia through keratinocyte reprogramming is still unknown. We used the CRISPR/Cas9 base editor to induce single nucleotide polymorphisms in Forkhead-box N1 (Foxn1) and identified the p.L19M variant that induced the formation of a thicker dWAT regardless of hair follicular cycle or wound healing. Foxn1 p.L19M activates Wnt5β through transcriptional activity. Wnt5β signaling induces the conversion of dWAT dermal fibroblasts into adipose precursor cells (APCs) and promotes APC adipocyte differentiation through keratinocyte epithelial-mesenchymal transition (EMT) and adipogenic signaling. Wnt5β is involved in the entire process of dWAT hyperplasia through APC supply and adipogenic signaling as a single factor. Foxn1 p.L19M and Wnt5β are expressed in keratinocytes, and a keratinocyte-derived adipogenic signal is critical for dermal adipogenesis. In addition, transient expression of Foxn1 p.L19M or Wnt5β using adeno-associated virus reproduced dermal adipocyte hyperplasia in mice. Considering the increasing importance of dWAT in functions such as the immune response, wound healing, hair follicle growth, and temperature control, this finding has potential applications in skin regeneration
2023-08-05 | GSE239791 | 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