Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Morisawa, Shunpei; Yasuda, Hiroyuki; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

doi:10.3164/jcbn.16-111

Cited by 12 publications

(9 citation statements)

References 54 publications

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“…In particular, we demonstrated that TNFα significantly increased the expression of DNMT1, the enzyme responsible for the maintenance of DNA methylation status. Our finding is consistent with previous works in other cell types that indicates an increase of this enzyme along with a hypermethylation of target promoters after TNFα stimulation [ 30 , 33 , 59 , 60 ]. Despite the well-known action of DNMT1 in the maintenance of DNA methylation status, recent studies also highlighted the role of overexpressed DNMT1 in de novo methylation [ 61 , 62 ].…”

Section: Discussionsupporting

confidence: 93%

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Guarnieri

Sarchielli

Comeglio

et al. 2020

IJMS

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TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 93%

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Guarnieri

Sarchielli

Comeglio

et al. 2020

IJMS

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“…39 Both proteins have also been shown to be able to induce changes in DNA methylation that affect gene expression. 40,41 In this way, DNA methylation provides us with the unified framework linking hereditary and environmental factors with transcriptomic and phenotypic effects specific to KTCN.…”

Section: Discussionmentioning

confidence: 99%

Multiple Differentially Methylated Regions Specific to Keratoconus Explain Known Keratoconus Linkage Loci

Kabza

Karolak

Rydzanicz

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Keratoconus (KTCN) is a complex eye disorder resulting in loss of visual function. Its development is affected by genetic and environmental components. The aim of this study was to unravel the role of epigenetic factors in KTCN. METHODS. To verify if DNA methylation may play a role in KTCN development, reduced representation bisulfite sequencing of five KTCN and five non-KTCN human corneas was performed. RESULTS. Multiple KTCN-specific differentially methylated regions were detected and many of them overlap previously identified KTCN linkage loci (3p14.3, 5q35.2, 13q32.3, 15q24.1, and 20p13) and chromosome arms that have been linked to KTCN (2q, 4q, 5p, 9p, 14q, and 17q). Reanalysis of the previously described RNA sequencing dataset of 25 KTCN and 25 non-KTCN human corneas revealed that 12 genes downregulated in KTCN and 6 upregulated genes overlapped or were located in the near vicinity of the identified differentially methylated regions. Particularly interesting were the DNA methylation changes in WNT3 and WNT5A encoding Wnt ligands, as they provide a potential explanation for the Wnt signaling pathway dysregulation observed in KTCN. CONCLUSIONS. We presented the results of data analysis from the first study of DNA methylation changes in human KTCN corneas compared to non-KTCN samples. We were able to identify genomic regions with distinct patterns of DNA hypo-and hypermethylation and link them to previously found KTCN susceptibility loci as well as transcriptomic disruption of Wnt signaling pathway observed in KTCN.

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“…Conversely, the NF-κB regulates pro-inflammatory cytokines such as TNF-α and contributes to the pro-tumorigenic microenvironment [6]. Recently, TNF-α has been suggested to regulate certain gene expressions through DNA methylation [24,25]. Acharyya et al [24] reported that TNF-α promotes DNA methylation at the Notch-1 promoter in skeletal muscle cells by recruitment of histone and DNA methyltransferases (DNMT).…”

Section: Discussionmentioning

confidence: 99%

“…Acharyya et al [24] reported that TNF-α promotes DNA methylation at the Notch-1 promoter in skeletal muscle cells by recruitment of histone and DNA methyltransferases (DNMT). On the other hand, Morisawa et al [25] showed that TNF-α increased the levels of DNA methylation, but DNMT did not participate in TNF-α-induced DNA methylation at the EC-SOD promoter region in human dermal fibroblasts. Although how TNF-α is involved in the methylation of the RELA gene and subsequent expression of the NF-κB1 is not yet clear, there are several possible mechanisms such as regulation of DNMT1 expression by TNF-α [25], epigenetic feedback regulation [26,27], or DNA co-methylation between gene pairs [28].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Morisawa et al [25] showed that TNF-α increased the levels of DNA methylation, but DNMT did not participate in TNF-α-induced DNA methylation at the EC-SOD promoter region in human dermal fibroblasts. Although how TNF-α is involved in the methylation of the RELA gene and subsequent expression of the NF-κB1 is not yet clear, there are several possible mechanisms such as regulation of DNMT1 expression by TNF-α [25], epigenetic feedback regulation [26,27], or DNA co-methylation between gene pairs [28]. Because data on the DNA methylation status of NF-κB-related genes are still lacking, additional studies are needed to determine the DNA methylation status of the NF-κB-related genes in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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Methylation of the RELA Gene is Associated with Expression of NF-κB1 in Response to TNF-α in Breast Cancer

Jeong

Choi

2019

Molecules

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The nuclear factor (NF)-κB family of transcriptional factors plays a critical role in inflammation, immunoregulation, cell differentiation, and tumorigenesis. This study aims to investigate the role of methylation of genes encoding for the NF-κB family in breast cancer. We analyze the DNA methylation status of the NFKB1 gene and the RELA gene in breast cancer using pyrosequencing. The expression of NF-κB1 and RELA proteins is assessed and the level of RNA transcripts in frozen tissue is determined using RT-PCR. There is no statistically significant difference in the methylation status of the NFKB1 and the RELA genes between tumors and normal tissues. The methylation status of the NFKB1 gene and the RELA gene is not significantly associated with the levels of NF-κB1 transcripts in tumor tissues. However, the methylation level of the RELA gene is significantly associated with the level of tumor necrosis factor (TNF)-α. In addition, the level of NF-κB1 transcripts was associated with the levels of TNF-α and IL-4. In tumors with positive TNF-α, the increased methylation level of the RELA gene is significantly associated with the positive expression of NF-κB1 transcripts. These results demonstrate that the level of the RELA gene methylation is related to the levels of NF-κB1 transcripts under the influence of TNF-α. Further study is needed to determine how TNF-α is involved in the methylation of the RELA gene and the subsequent expression of NF-κB1.

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Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Cited by 12 publications

References 54 publications

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Multiple Differentially Methylated Regions Specific to Keratoconus Explain Known Keratoconus Linkage Loci

Methylation of the RELA Gene is Associated with Expression of NF-κB1 in Response to TNF-α in Breast Cancer

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