Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.
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...SAM is generated and maintained by coupling one-carbon metabolism and mitochondrial energy metabolism.169,170 α-KG, which is generated by the tricarboxylic acid cycle (TCA) cycle in mitochondria and the cytosol, is a cofactor of ten–eleven translocation methylcytosine dioxygenase DNA methylases, histone demethylases (HDMs) and the lysine demethylases KDMs/JMJDs.171,172 However, the activities of KDMs/JMJDs and TETs can be inhibited by fumarate, succinate, and 2-hydroxyglutarate.173 Mutations that affect the succinate dehydrogenase complex and fumarate hydratase can induce the accumulation of succinate and fumarate, respectively.174 Oxidized flavin adenine dinucleotide (FAD) is an essential cofactor of the HDM LSD1, a member of the KDM family.175 In addition, acetyl-CoA, the source of acetyl groups that are consumed by histone acetyltransferases, is generated by ATP citrate lyase and pyruvate dehydrogenase in the cytosol and mitochondria, respectively.176 In addition, oxidized nicotinamide adenine dinucleotide (NAD+) is a cofactor for sirtuins (SIRTs), a family of deacetylases that includes nuclear-localized SIRT1, SIRT6, and SIRT7, cytosolic SIRT2, and three mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) (Fig....
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...α-KG is a necessary cofactor for TET DNA methylases, histone demethylases (HDMs), and lysine demethylases KDMs/JMJDs.(167,168) Mitochondria also regulate the levels and redox state of FAD, a cofactor of the histone demethylase LSD1....
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...The metabolites of mitochondrial TCA, such as pyruvate, fumarate, malate, OAA, and α-KG, not only directly regulate energy production but also play an important role in the epigenetic regulation of neurons and longevity.164,173,187–189 For example, SAM provides methyl groups for histone and DNA methyltransferases (HMTs and DNMTs).165,166 α-KG is a necessary cofactor for TET DNA methylases, histone demethylases (HDMs), and lysine demethylases KDMs/JMJDs.167,168 Mitochondria also regulate the levels and redox state of FAD, a cofactor of the histone demethylase LSD1....
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References
5,760 citations
"Consistent decrease in global DNA m..." refers background in this paper
...DNA methylation, 1 of the fundamental epigenetic mechanisms, regulates gene transcription and can result in long-term changes in cellular function (Jaenisch and Bird, 2003)....
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5,155 citations
"Consistent decrease in global DNA m..." refers background in this paper
...DNA hydroxymethylation is a newly described epigenetic modification derived from the oxidation of methylated cytosines by ten-eleven translocation (TET) enzymes (Kriaucionis and Heintz, 2009; Tahiliani et al., 2009)....
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3,941 citations
"Consistent decrease in global DNA m..." refers background in this paper
...Furthermore, examination of correlations with markers associated with the disease, such as cognitive decline, synaptic deficits, and neuronal loss, is of high importance (Coleman and Yao, 2003; Rutten et al., 2005; Selkoe, 2002)....
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2,558 citations
"Consistent decrease in global DNA m..." refers background in this paper
...DNA hydroxymethylation is a newly described epigenetic modification derived from the oxidation of methylated cytosines by ten-eleven translocation (TET) enzymes (Kriaucionis and Heintz, 2009; Tahiliani et al., 2009)....
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2,108 citations
"Consistent decrease in global DNA m..." refers background in this paper
...Methylation of CpG di-nucleotides is catalyzed by DNAmethyltransferases (Dnmts), disrupts the binding of transcription factors and recruits proteins known as methylCpGebinding domain proteins (MBDs) that are associated with chromatin compaction and gene silencing (Cedar and Bergman, 2009)....
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