Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases

Okano, Masaki; Xie, Shaoping; Li, En

doi:10.1038/890

Cited by 1,446 publications

(1,163 citation statements)

References 14 publications

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“…We also observed some recombination in the kidney, where Dnmt3a transcripts have been detected (Okano et al, 1998;Chen et al, 2002). Though we cannot rule out the possibility of a peripheral deficit contributing to the phenotype, we did not observe gross histological changes in the kidney.…”

Section: Discussionmentioning

confidence: 51%

“…Genomic DNA methylation patterns are established during development by the action of the de novo methyltransferases Dnmt3a and Dnmt3b and are subsequently maintained by the methyltransferase Dnmt1 (Li et al, 1992;Okano et al, 1999). Complete ablation of the activity of either Dnmt1 or Dnmt3b results in embryonic lethality (Li et al, 1992;Okano et al, 1998), whereas deletion of Dnmt3a causes perinatal lethality (Okano et al, 1999). An important role of DNA methylation in the nervous system is indicated by Rett syndrome, a neurodevelopmental disorder caused by mutations in MeCP2, a transcriptional repressor that binds to methylated CpGs (Amir and Zoghbi, 2000;Guy et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Nguyen¹,

Meletis²,

Fu³

et al. 2007

Developmental Dynamics

175

134

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DNA methylation is an epigenetic mechanism involved in gene regulation and implicated in the functioning of the nervous system. The de novo DNA methyltransferase Dnmt3a is expressed in neurons, but its specific role has not been clarified. Dnmt3a is activated around embryonic day 10.5 in mouse neuronal precursor cells and remains active in postmitotic neurons in the adult. We assessed the role of neuronal Dnmt3a by conditional gene targeting. Mice lacking functional Dnmt3a in the nervous system were born healthy, but degenerated in adulthood and died prematurely. Mutant mice were hypoactive, walked abnormally, and underperformed on tests of neuromuscular function and motor coordination. Loss of Dnmt3a also led to fewer motor neurons in the hypoglossal nucleus and more fragmented endplates in neuromuscular junctions of the diaphragm muscle. Our results implicate a role for Dnmt3a in the neuromuscular control of motor movement.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Nguyen¹,

Meletis²,

Fu³

et al. 2007

Developmental Dynamics

175

134

View full text Add to dashboard Cite

show abstract

“…PU.1-mediated transcriptional repression by DNA methylation M Suzuki et al each other (Okano et al, 1998). We speculated that Dnmt3a-and Dnmt3b-mediated transrepression of pTK100-PUx3-Luc depends on their DNA methyltransferase activity and/or on the histone deacetylase activity through the formation of a complex with HDACs.…”

Section: Resultsmentioning

confidence: 90%

“…DNA methylation is catalysed by the activation of several DNA methyltransferases (Dnmts) during cell replication. There are at least three different major catalytically active Dnmts, Dnmt1 (Bestor et al, 1988), Dnmt3a and Dnmt3b (Okano et al, 1998), which are involved in cellular DNA methylation. In somatic cells, Dnmt1 has the maintenance methyltransferase activity as a consequence of its affinity for hemimethylated DNA.…”

Section: Introductionmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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“…DNMT3A and DNMT3B are highly expressed in ES cells, early embryos, and developing germ cells where de novo methylation takes place, but expressed at lower rate in somatic tissues of postnatal animals [22]. These enzymes have no preference for hemimethylated DNA [22,23] and can methylate de novo unmethylated CpGs when ectopically expressed in mammalian cells or transgenic flies [24,25].…”

mentioning

confidence: 99%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases

Cited by 1,446 publications

References 14 publications

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Dynamic and reversibility of heterochromatic gene silencing in human disease

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