Characterisation of CpG methylation in the upstream control region of mouse Nat2: Evidence for a gene–environment interaction in a polymorphic gene implicated in folate metabolism

Wakefield, Larissa; Boukouvala, Sotiria; Sim, Edith

doi:10.1016/j.gene.2009.12.002

Cited by 39 publications

(25 citation statements)

References 42 publications

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“…This is supported by the fact that NAT1 promoter-specific mRNA expression can vary depending on environmental conditions. For example, P1-dependent NAT1 mRNA can be induced by androgens and heat shock factor 1 in androgen receptor-positive prostate 22Rv1 cells , and core promoter-dependent mRNA expression for the murine NAT1 equivalent (Nat2) was found to vary with folate administration (Wakefield et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

Bonifas

Scheitza²,

Clemens³

et al. 2010

J Pharmacol Exp Ther

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N-acetyltransferase 1 (NAT1)-mediated N-acetylation in keratinocytes is an important detoxification pathway for the hair dye ingredient para-phenylenediamine (PPD). Because NAT1 can be regulated by various exogenous compounds, including some NAT1 substrates themselves, we investigated NAT1 expression in keratinocytes and the interactions between PPD and NAT1. NAT1 activity was found to be cell-cycle phasedependent. Maximum NAT1 activities (mean: 49.7 nmol/mg/ min) were estimated when HaCaT keratinocytes were arrested in G 0 /G 1 phase, whereas nonsynchronized cells showed the lowest activities (mean: 28.9 nmol/mg/min). It is noteworthy that we also found an accelerated progression through the cell cycle in HaCaT cells with high NAT1 activities. This evidence suggests an association between NAT1 and proliferation in keratinocytes. Regarding the interaction between NAT1 and PPD, we found that keratinocytes N-acetylate PPD; however, this N-acetylation was saturated with increasing PPD concentrations. HaCaT cultured in medium supplemented with PPD (10 -200 M) for 24 h showed a significant concentration-dependent decrease (17-50%) in NAT1 activity. PPD also induced down-regulation of NAT1 activity in human primary keratinocytes. Western blot studies using a NAT1-specific antibody in HaCaT showed that the loss of enzyme activity was associated with a decline in the amount of NAT1 protein, whereas no changes in the amounts of NAT1 P1 (NATb)-dependent mRNA were found by quantitative reverse transcription-polymerase chain reaction analysis, suggesting the involvement of a substrate-dependent mechanism of NAT1 down-regulation. In conclusion, these data show that overall N-acetylation capacity of keratinocytes and consequently detoxification capacities of human skin is modulated by the presence of NAT1 substrates and endogenously by the cell proliferation status of keratinocytes.

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Section: Discussionmentioning

confidence: 99%

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

Bonifas

Scheitza²,

Clemens³

et al. 2010

J Pharmacol Exp Ther

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“…Methylation of the NAT1 gene has been reported in both mice and humans (Kim et al, 2008;Wakefield et al, 2010), although which of the two promoters of the human gene is methylated remains unknown. Studies on the relationship between histone acetylation and DNA methylation of the NAT1 gene are warranted.…”

Section: Downloaded Frommentioning

confidence: 99%

Histone Deacetylase Inhibitors Increase Human Arylamine N-Acetyltransferase-1 Expression in Human Tumor Cells

Paterson

Sin²,

Tiang³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Arylamine N-acetyltransferase-1 (NAT1) has been associated with disorders involving folate metabolism, such as spina bifida, as well as numerous human cancers. As a result, the transcriptional and post-transcriptional regulation of NAT1 activity has been extensively studied. However, little work has been reported on the epigenetic control of NAT1 expression. Here, we demonstrate that the histone deacetylase inhibitor trichostatin A (TSA) increases NAT1 activity in human cancer cells by increasing transcription from the proximal promoter NATb. A specific Sp1 binding site was identified as essential for optimal induction of NAT1 by TSA. However, TSA did not increase the expression of Sp1 in HeLa cells. Instead, TSA increased the acetylation of histones associated with the NATb promoter. This allowed recruitment of Sp1 to the promoter along with acetylated histones. We propose that NAT1 transcription is partially repressed by the local chromatin condensation in the vicinity of NATb and that histone deacetylase inhibition leads to up-regulation of NAT1 expression via a direct change in chromatin conformation.

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“…The chosen genomic loci are usually linked with a disease of interest, such as cancer or diabetes, for example the N-acetyltransferase 2 (Nat2) gene, whose human homologue, NAT1, is associated with cancer development including breast carcinogenesis (Anderson et al, 2012). Wakefield and co-authors demonstrated that the Nat2 gene in adult rats exposed to a high-folate diet was under-expressed, demonstrating increase in methylation (Wakefield et al, 2010). Kim and co-authors evaluated the impact of folate deficiency on the methylation status of the p53 tumor suppressor gene in rats subjected to a low-folate diet (Kim et al, 1997).…”

Section: 21)mentioning

confidence: 99%

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

Voutounou

Glen

Dubrova

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Characterisation of CpG methylation in the upstream control region of mouse Nat2: Evidence for a gene–environment interaction in a polymorphic gene implicated in folate metabolism

Cited by 39 publications

References 42 publications

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine

Histone Deacetylase Inhibitors Increase Human Arylamine N-Acetyltransferase-1 Expression in Human Tumor Cells

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

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