Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation has critical roles in the nervous system and has been traditionally considered to be restricted to CpG dinucleotides in metazoan genomes. Here we show that the single base-resolution DNA methylome from adult mouse dentate neurons consists of both CpG (~75%) and CpH (~25%) methylation (H = A/C/T). Neuronal CpH methylation is conserved in human brains, enriched in regions of low CpG density, depleted at protein-DNA interaction sites and anticorrelated with gene expression. Functionally, both methylated CpGs (mCpGs) and mCpHs can repress transcription in vitro and are recognized by methyl-CpG binding protein 2 (MeCP2) in neurons in vivo. Unlike most CpG methylation, CpH methylation is established de novo during neuronal maturation and requires DNA methyltransferase 3A (DNMT3A) for active maintenance in postmitotic neurons. These characteristics of CpH methylation suggest that a substantially expanded proportion of the neuronal genome is under cytosine methylation regulation and provide a new foundation for understanding the role of this key epigenetic modification in the nervous system.
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PMID:Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. 2436 62

Neuronal Per Arnt Sim domain 4 (Npas4), a brain-specific helix-loop-helix transcription factor, was recently shown to regulate the development of GABAergic inhibitory neurons. Npas4 mRNA expression levels were decreased in the hippocampus of mice exposed to stress, which was accompanied by brain dysfunction. We have suggested that transient stress reduced Npas4 transcription through the glucocorticoid receptor. In the present report, we investigated the potential contribution of epigenetic modifications induced by stress on Npas4 gene expression. The Npas4 promoter region contains two CpG islands; in the hippocampus, chronic restraint stress increases the DNA methylation levels of both of these CpG islands. In the Neuro2a cell line, treatment with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, increased Npas4 mRNA levels and markedly reduced the DNA methylation levels of CpG island 2 in the Npas4 promoter. The DNA methylation sites in CpG island 2 overlap with two cyclic adenosine monophosphate response element (CRE) sequences. Mutation of these CRE sequences reduced Npas4 promoter activity. These results suggest that transcription of the Npas4 gene is downregulated by stress through DNA methylation of its promoter.
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PMID:Stress increases DNA methylation of the neuronal PAS domain 4 (Npas4) gene. 2622 56

Neuronal differentiation and cell-cycle exit are tightly coordinated, even in pathological situations. When pathological neurons re-enter the cell cycle and progress through the S phase, they undergo cell death instead of division. However, the mechanisms underlying mitotic resistance are mostly unknown. Here, we have found that acute inactivation of retinoblastoma (Rb) family proteins (Rb, p107 and p130) in mouse postmitotic neurons leads to cell death after S-phase progression. Checkpoint kinase 1 (Chk1) pathway activation during the S phase prevented the cell death, and allowed the division of cortical neurons that had undergone acute Rb family inactivation, oxygen-glucose deprivation (OGD) or in vivo hypoxia-ischemia. During neurogenesis, cortical neurons became protected from S-phase Chk1 pathway activation by the DNA methyltransferase Dnmt1, and underwent cell death after S-phase progression. Our results indicate that Chk1 pathway activation overrides mitotic safeguards and uncouples neuronal differentiation from mitotic resistance.
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PMID:Dnmt1-dependent Chk1 pathway suppression is protective against neuron division. 2892 82