The methyl donor S-adenosyl methionine reverses the DNA methylation signature of chronic neuropathic pain in mouse frontal cortex

Topham, Lucas; Grégoire, Stéphanie; Kang, HyungMo; Salmon‐Divon, Mali; Lax, Elad; Millecamps, Magali; Szyf, Moshe; Stone, Laura S.

doi:10.1097/pr9.0000000000000944

Cited by 8 publications

(6 citation statements)

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“…The complex and sex-dependent pattern of pain (as measured through mechanical and cold hypersensitivity and guarding) seen here has never been reported before simply because no one has tested long enough and with both sexes. Of the 23 articles we identified having tested mice or rats for pain behavior past 3 months postinjury, 1,6,7,10,13,14,18,21,[23][24][25]28,29,35,36,38,42,43,46,47,49,50,52 only 7 have included female mice, and only 3 have directly compared the sexes in the same experiment. Shepherd et al 36 found no sex difference in mechanical hypersensitivity in C57BL/ 6 mice up to 120 days (4 months) post-SNI.…”

Section: Sex Differences In Long-term Pain After Spared Nerve Injurymentioning

confidence: 99%

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice

Millecamps

Sotocinal

Austin

et al. 2022

Pain

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Section: Sex Differences In Long-term Pain After Spared Nerve Injurymentioning

confidence: 99%

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice

Millecamps

Sotocinal

Austin

et al. 2022

Pain

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“…To further elucidate the underlying mechanism of PHGDH‐regulated IL‐6 expression, we used transcriptome data for gene set enrichment analysis and found that glycine, serine and threonine metabolisms were significantly enriched and inhibited in PHGDH‐siRNA‐treated HaCaT cells (Figure 3a). The downstream metabolite SAM of serine metabolism is involved in regulating DNA methylation and histone methylation 20,23–25 . PHGDH knockdown decreased SAM levels in HaCaT cells (Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

“…The downstream metabolite SAM of serine metabolism is involved in regulating DNA methylation and histone methylation. 20,[23][24][25] PHGDH knockdown decreased SAM levels in HaCaT cells (Figure 3b). To further investigate whether PHGDH regulates IL-6 expression via SAM, we pretreated PHGDH-siRNA-transfected HaCaT cells with SAM.…”

Section: Phgdh Regulates Il-6 Expression Via Sam-mediated Dna Methyla...mentioning

confidence: 94%

Serine deficiency exacerbates psoriatic skin inflammation by regulating S‐adenosyl methionine‐dependentDNAmethylation andNF‐κBsignalling activation in keratinocytes

Meng,

Liu,

Yao

et al. 2023

Acad Dermatol Venereol

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BackgroundSerine metabolism is crucial for tumor oncogenesis and immune responses. S‐adenosyl methionine (SAM), a methyl donor, is typically derived from serine‐driven one‐carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear.ObjectivesTo investigate the association between serine metabolism and psoriatic skin inflammation.MethodsClinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism‐regulated psoriatic keratinocyte inflammation An imiquimod (IMQ)‐induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation.ResultsThe expression of serine synthesis pathway enzymes, including the first rate‐limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic‐related signaling pathways, including the tumor necrosis factor‐alpha (TNF‐α) signaling pathway, interleukin (IL)‐17 signaling pathway, and NF‐κB signaling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL‐6 in keratinocytes with or without IL‐17A, IL‐22, IL‐1α, oncostatin M, and TNF‐α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL‐6 by inhibiting SAM‐dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL‐6 by increasing the activation of NF‐κB via SAM inhibition. SAM treatment effectively alleviated IMQ‐induced psoriasis‐like skin inflammation in mice.ConclusionsOur study revealed the crucial role of PHGDH in antagonizing psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.

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“…Numerous studies have demonstrated the possibility of attenuating chronic pain by modulating DNA methylation [22,25,45,46] . For example, restoring DNA methylation levels through the methyl donor s-adenosyl methionine, improved cognitive and emotional functions damaged by spared nerve injury [47] . Increased DNMT3a in the DRG led to undesirable opioid analgesic effects, and blocking this increase restored the analgesic effects of morphine or loperamide and attenuated the development of their analgesic tolerance under NPP [48] .…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal 5-Azacytidine Alleviates Nerve Injury-Induced Pain in Rats by Modulating DNA Methylation

Liu

Dai

et al. 2023

Mol Neurobiol

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To investigate the role of DNA methylation in modulating chronic neuropathic pain (NPP), identify possible target genes of DNA methylation involved in this process, and preliminarily con rm the medicinal value of the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-AZA) in NPP by targeting gene methylation. MethodsTwo rat NPP models, chronic constriction injury (CCI) and spinal nerve ligation (SNL), were used. The DNA methylation pro les in the lumbar spinal cord were assayed using an Arraystar Rat RefSeq Promoter Array. The underlying genes with differential methylation were then identi ed and submitted to Gene Ontology and pathway analysis. Methyl-DNA immunoprecipitation quantitative PCR (MeDIP-qPCR) and quantitative reverse transcription-PCR (RT-qPCR) were used to con rm gene methylation and expression.The protective function of 5-AZA in NPP and gene expression were evaluated via behavioral assays and RT-qPCR, respectively. ResultsAnalysis of the DNA methylation patterns in the lumbar spinal cord indicated that 1205 differentially methylated fragments in CCI rats were located within DNA promoter regions, including 638 hypermethylated fragments and 567 hypomethylated fragments. The methylation levels of Grm4, Htr4, Adrb2, Kcnf1, Gad2 and Pparg, which are associated with long-term potentiation (LTP) and glutamatergic synapse pathways, were increased with a corresponding decrease in their mRNA expression, in the spinal cords of CCI rats. Moreover, we found that the intraperitoneal injection of 5-AZA (4 mg/kg) attenuated CCI-or SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, the mRNA expression of hypermethylated genes such as Grm4, Htr4, Adrb2, Kcnf1 and Gad2 was reversed after 5-AZA treatment. ConclusionIncreasing methylation is a novel negative regulatory mechanism of target gene expression in chronic NPP. In rats, the intraperitoneal injection of 5-AZA alleviated spinal nociception, an effect accompanied by the reversed expression of hypermethylated genes. Thus, DNA methylation inhibition represents a promising strategy for protection against chronic NPP following nerve injury. Our study lays a theoretical foundation for 5-AZA to become a clinical targeted drug.1. Introduction hypermethylated gene mRNA expression induced by chronic NPP following CCI-or spinal nerve ligation (SNL). Materials And Methods AnimalsIn this study, male Sprague-Dawley (SD) rats weighing 220-250 g were employed. All animals were kept in a setting with a temperature of 22 ± 1°C, a relative humidity of 50 ± 1%, and a cycle of light and dark of 12 hr. They had access to food and water at all times in their separate cages. All protocols were approved by the ethics committee of the Fujian Cancer Hospital and adhered to Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Experimental paradigmBehavioral testing was performed before surgery and at 3, 5, 7, 10 and 14 Days after surgery in each rat. Under deep anesthesia, all the rats were killed and their ipsilateral lum...

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The methyl donor S-adenosyl methionine reverses the DNA methylation signature of chronic neuropathic pain in mouse frontal cortex

Cited by 8 publications

References 82 publications

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice

Serine deficiency exacerbates psoriatic skin inflammation by regulating S‐adenosyl methionine‐dependentDNAmethylation andNF‐κBsignalling activation in keratinocytes

Intraperitoneal 5-Azacytidine Alleviates Nerve Injury-Induced Pain in Rats by Modulating DNA Methylation

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