A novel regulatory element in the dnmt1 gene that responds to co-activation by Rb and c-Jun

Slack, Andrew; Pinard, Marc; Araujo, Felipe D.; Szyf, Moshe

doi:10.1016/s0378-1119(01)00427-9

Cited by 19 publications

(13 citation statements)

References 33 publications

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“…A role of c-Jun in the regulation of DNMT1 has been previously suggested [25–27]. Moreover, c-Jun has been shown to prevent methylation at the CDK6 promoter [28, 29].…”

Section: Resultsmentioning

confidence: 99%

c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas

et al. 2016

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High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

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“…A role of c-Jun in the regulation of DNMT1 has been previously suggested [25–27]. Moreover, c-Jun has been shown to prevent methylation at the CDK6 promoter [28, 29].…”

Section: Resultsmentioning

confidence: 99%

c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas

et al. 2016

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“…Previous studies have examined regulation of the DNMT1 gene promoter, but to date, none has examined the effect of DNA methylation on the currently annotated major promoter of this gene (22–24). In order to gain insight into the likely consequences of placenta-specific methylation, we carried out in vitro reporter analysis using a 910-bp amplified region of the human DNMT1 promoter (containing 56 CpG sites) that spans several highly conserved sequence regions in vertebrates known to confer constitutive promoter activity (22) (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation-mediated Down-regulation of DNA Methyltransferase-1 (DNMT1) Is Coincident with, but Not Essential for, Global Hypomethylation in Human Placenta

Novakovic

Wong

Sibson

et al. 2010

Journal of Biological Chemistry

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The genome of extraembryonic tissue, such as the placenta, is hypomethylated relative to that in somatic tissues. However, the origin and role of this hypomethylation remains unclear. The DNA methyltransferases DNMT1, -3A, and -3B are the primary mediators of the establishment and maintenance of DNA methylation in mammals. In this study, we investigated promoter methylation-mediated epigenetic down-regulation of DNMT genes as a potential regulator of global methylation levels in placental tissue. Although DNMT3A and -3B promoters lack methylation in all somatic and extraembryonic tissues tested, we found specific hypermethylation of the maintenance DNA methyltransferase (DNMT1) gene and found hypomethylation of the DNMT3L gene in full term and first trimester placental tissues. Bisulfite DNA sequencing revealed monoallelic methylation of DNMT1, with no evidence of imprinting (parent of origin effect). In vitro reporter experiments confirmed that DNMT1 promoter methylation attenuates transcriptional activity in trophoblast cells. However, global hypomethylation in the absence of DNMT1 down-regulation is apparent in non-primate placentas and in vitro derived human cytotrophoblast stem cells, suggesting that DNMT1 down-regulation is not an absolute requirement for genomic hypomethylation in all instances. These data represent the first demonstration of methylation-mediated regulation of the DNMT1 gene in any system and demonstrate that the unique epigenome of the human placenta includes down-regulation of DNMT1 with concomitant hypomethylation of the DNMT3L gene. This strongly implicates epigenetic regulation of the DNMT gene family in the establishment of the unique epigenetic profile of extraembryonic tissue in humans.

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“…However, there is ample evidence obtained in in vitro (Grayson et al, 2009) and in vivo (Day and Sweatt 2010;Tremolizzo et al, 2005;Zhang et al, 2010;Meaney, 2010) experiments that changes in DNMT levels are cause-related to changes in target gene expression, including the expression of GAD 67 . Given that DNMT promoters contain consensus sequences for inducible transcription factors such as c-jun and c-fos (Bigey et al, 2000;Slack et al, 2001), it could be hypothesized that nAChR stimulation can regulate DNMT expression by altering the availability of these transcription factors. These factors could include the 'growth arrest and DNA damage-inducible protein 45b,' an inducible immediate early gene funtioning as a molecular factor in the DNA demethylation process in the brain (Ma et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons

Maloku

Kadriu

Zhubi

et al. 2011

Neuropsychopharmacol

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Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD 67 ) expression. Here we explored the impact of synthetic a 4 b 2 and a 7 nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at a 4 b 2 and a lower affinity full agonist at a 7 neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD 67 mRNA and protein. This upregulation of GAD 67 was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP 2 binding to GAD 67 promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD 67 expression were obtained after administration of A-85380, an agonist that binds to a 4 b 2 but has negligible affinity for a 3 b 4 or a 7 subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric a 7 nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD 67 expression. The present study suggests that the a 4 b 2 nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the a 7 nAChR agonists.

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A novel regulatory element in the dnmt1 gene that responds to co-activation by Rb and c-Jun

Cited by 19 publications

References 33 publications

c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas

c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas

DNA Methylation-mediated Down-regulation of DNA Methyltransferase-1 (DNMT1) Is Coincident with, but Not Essential for, Global Hypomethylation in Human Placenta

Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons

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