DNA Methylation and Its Basic Function
TL;DR: The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
About: This article is published in Neuropsychopharmacology.The article was published on 2013-01-01 and is currently open access. It has received 2399 citations till now. The article focuses on the topics: RNA-Directed DNA Methylation & DNA methylation.
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01 Jan 1993
TL;DR: In vitro footprinting indicates that MBD binding can protect a 12 nucleotide region surrounding a methyl-CpG pair, with an approximate dissociation constant of 10(-9) M.
Abstract: MeCP2isachromosomal protein whichbinds toDNA that ismethylated atCpG.Insitu immunofluorescence inmouse cells hasshownthattheprotein ismost concentrated inpericentromeric heterochromatin, suggesting that MeCP2mayplay arole intheformation ofInert chromatin. Herewe haveIsolated a minimal methyl-CpG binding domaln (MBD) fromMeCP2.MBD Is85aminoacids Inlength, andbindsexclusively to DNA thatcontains one or more symmetrically methylated CpGs.MBD hasnegligable non-specific affinity forDNA,confirming thatnon-specific and methyl-CpG specific binding domainsofMeCP2are distinct. Invitrofootprlnting Indicates thatMBDbinding can protect a 12nucleotide regionsurrounding a methyl-CpG pair, withan approximate dissociation constant of10-9M.
582 citations
TL;DR: There is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation and non-coding RNAs.
317 citations
TL;DR: The latest advances in the field of epigenetic regulation are summarized, focusing on histone modifications, DNA methylation, and noncoding RNAs.
309 citations
Cites background from "DNA Methylation and Its Basic Funct..."
...Epigenetic mechanisms of drug addictio Current Opinion in Neurobiology 2013, 23:1–8 Through deamination, glycosylation, and base excision repair, these newly discovered forms of cytosine modification can then be converted back into an unmethylated state [30,31]....
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TL;DR: Calcium signals that are induced by synaptic activity and propagate into the nucleus are a major route for synapse-to-nucleus communication and may underlie the aetiologies of various diseases, including neurodegeneration and cognitive dysfunction.
Abstract: Activity-dependent changes in neuronal gene expression require a means of synapse-to-nucleus signalling, and changes in nuclear calcium concentration provide a major route for such communication. Bading discusses how nuclear calcium signals are induced by synaptic activity and describes their role as regulators of gene expression in neuroadaptations.
303 citations
TL;DR: The integrative analysis clearly reveals the important and conserved role of the methylation level of the first intron and its inverse association with gene expression regardless of tissue and species.
Abstract: DNA methylation is one of the main epigenetic mechanisms for the regulation of gene expression in eukaryotes. In the standard model, methylation in gene promoters has received the most attention since it is generally associated with transcriptional silencing. Nevertheless, recent studies in human tissues reveal that methylation of the region downstream of the transcription start site is highly informative of gene expression. Also, in some cell types and specific genes it has been found that methylation of the first intron, a gene feature typically rich in enhancers, is linked with gene expression. However, a genome-wide, tissue-independent, systematic comparative analysis of the relationship between DNA methylation in the first intron and gene expression across vertebrates has not been explored yet. The most important findings of this study are: (1) using different tissues from a modern fish, we show a clear genome-wide, tissue-independent quasi-linear inverse relationship between DNA methylation of the first intron and gene expression. (2) This relationship is conserved across vertebrates, since it is also present in the genomes of a model pufferfish, a model frog and different human tissues. Among the gene features, tissues and species interrogated, the first intron’s negative correlation with the gene expression was most consistent. (3) We identified more tissue-specific differentially methylated regions (tDMRs) in the first intron than in any other gene feature. These tDMRs have positive or negative correlation with gene expression, indicative of distinct mechanisms of tissue-specific regulation. (4) Lastly, we identified CpGs in transcription factor binding motifs, enriched in the first intron, the methylation of which tended to increase with the distance from the first exon–first intron boundary, with a concomitant decrease in gene expression. Our integrative analysis clearly reveals the important and conserved role of the methylation level of the first intron and its inverse association with gene expression regardless of tissue and species. These findings not only contribute to our basic understanding of the epigenetic regulation of gene expression but also identify the first intron as an informative gene feature regarding the relationship between DNA methylation and gene expression where future studies should be focused.
257 citations
Cites background from "DNA Methylation and Its Basic Funct..."
...Under the so-called standard model of gene expression regulation, methylation of cytosine–guanine dinucleotides (CpGs) in the promoter regions of genes has received the most attention since it is generally associated with repression of transcription, either directly, by blocking the access of transcription factors (TFs), or indirectly, by recruiting other repressive proteins with methyl-binding domains [2, 3]....
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References
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TL;DR: It is demonstrated that two recently identified DNA methyltransferases, DnMT3a and Dnmt3b, are essential for de novo methylation and for mouse development and play important roles in normal development and disease.
5,708 citations
"DNA Methylation and Its Basic Funct..." refers background in this paper
...Unlike Dnmt1, both Dnmt3a and Dnmt3b when overexpressed are capable of methylating both native and synthetic DNA with no preference for hemimethylated DNA (Okano et al, 1999)....
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...Similar to Dnmt1, the knockout of Dnmt3b in mice is embryonic lethal (Okano et al, 1999)....
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...On the other hand, Dnmt3a knockout mice are runted but survive to B4 weeks after birth (Okano et al, 1999)....
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TL;DR: It is shown that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible, suggesting a causal relation among epigenomicState, GR expression and the maternal effect on stress responses in the offspring.
Abstract: Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
5,514 citations
"DNA Methylation and Its Basic Funct..." refers background in this paper
...For example, early-life stress in the form of maternal neglect was sufficient to alter DNA methylation in the brain of a rodent model (Weaver et al, 2004)....
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TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Abstract: DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
5,155 citations
"DNA Methylation and Its Basic Funct..." refers background or methods in this paper
...A few protocols are capable of distinguishing 5hmC from 5mC in the genome: CpG endlabeling followed by thin-layer chromatography (Tahiliani et al, 2009) and high-performance liquid chromatography (HPLC) with either UV detection (Liutkeviciute et al, 2009) or tandem mass spectrometry (Globisch et…...
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...Tet1 contains a DNA-binding motif similar to Ctf1, suggesting that both proteins target similar sites, in this case CpG islands, to maintain DNA demethylation (Tahiliani et al, 2009)....
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...Tet enzymes add a hydroxyl group onto the methyl group of 5mC to form 5hmC (Tahiliani et al, 2009; Ito et al, 2010)....
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...…progressively smaller tissue quantities, many of the most commonly used methods for profiling and quantification of DNA methylation, such as bisulfite sequencing and methylation-sensitive enzyme-based assays, are unable to distinguish between 5hmC and 5mC (Tahiliani et al, 2009; Huang et al, 2010)....
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TL;DR: This study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
Abstract: Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
4,503 citations
"DNA Methylation and Its Basic Funct..." refers background in this paper
...Of the MBD proteins, MeCP2 is the best studied in the CNS because its mutation results in Rett Syndrome, one of the most common forms of mental retardation in females (Amir et al, 1999)....
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...MBDs are more highly expressed in the brain than in any other tissue, and many MBDs are important for normal neuronal development and function (Amir et al, 1999)....
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...One of the most common forms of mental retardation, Rett Syndrome, is frequently caused by a mutation to the methyl-binding protein MeCP2 (Amir et al, 1999)....
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TL;DR: The first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors were presented in this article.
Abstract: DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.
4,266 citations