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Demethylation Essay

586 words - 3 pages

Epigenetic modifications on histones and DNA exercise precise regulation of gene expression, and thus have a profound influence on cellular differentiation and function. The most widely studied modification on DNA is 5 methylcytosine (5mC) that frequently occurs in a CpG dinucleotide context. Initially, the de novo DNA methyltransferase (Dnmt) enzymes Dnmt3a and 3b mediate the transfer of the methyl group to cytosine, while the maintenance Dnmt1 ensures subsequent propagation of this mark through cell replication cycles. Because of prominent roles in gene repression, retro element silencing, X chromosome inactivation and gene imprinting, 5mC was initially thought to be irreversible. Thanks to burgeoning evidence, it is now clear that the methylcytosine can be removed through a number of mechanisms. Passive demethylation is proposed to remove 5mC over several cell replication cycles, through exclusion of the maintenance machinery from the replication ...view middle of the document...

Most of the DNA demethylation studies have focused on the global demethylation waves in the zygote, the developing embryo, embryonic stem cells and primordial germ cells. However, a decent number of reports highlight the locus specific loss of repressive methylcytosine mark during transcription activation in differentiated cells. In this regard, in vitro studies have been conducted using various nuclear receptor ligands and other chemicals. For instance, valproate induced demethylation of an in vitro methylated CMV-GFP plasmid in HEK293T cells, which was associated with histone acetylation and accompanied by expression of the GFP gene. In this report, methyl binding domain protein 2 (MBD2) was proposed to be partly responsible for the demethylation event (Detich et al. 2003). Also, trichostatin A, a histone deacetylase inhibitor caused DNA demethylation in a histone acetylation dependent manner (Cervoni & Szyf 2001). The vitamin A metabolite, all-trans retinoic acid caused promoter demethylation and activation of E-cahderin in human colon cancer cells (Woo & Jang 2012), as well as promoter hypomethylation and activation of p16 and p21 genes via depression of Dnmts 1, 3a and 3b in HepG2 cells (Lim et al. 2011). Analysis of an estrogen responsive gene showed that there is cyclical demethylation and remethylation of the promoter region (Kangaspeska et al. 2008; Métivier et al. 2008). Further, exposure of hepatoma cells to dexamethasone caused demethylation of the enhancer of the corticosteroid responsive Tat gene. This report described epigenetic memory, in that cells that were earlier exposed to dexamethasone had a higher response to subsequent dexamethasone exposure as compared to naïve, Tat methylated cells (Thomassin et al. 2001; Grange et al. 2001). Phenobarbital, an anticonvulsive has been shown to induce Cyp2b10 expression in the adult mouse liver, while causing DNA demethylation at the gene’s promoter (Thomson et al. 2013; Thomson et al. 2012). In our current study, there is evidence that TCDD causes demethylation at the Cyp1a1 promoter region by 6h post administration. This we attributed to a DNA replication-independent active process, given the short timeline within which it occurred.

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