?How to Make Epigenetics Work for Us
By kjs86, Section Biology Posted on Fri Apr 30th, 2010 at 12:53:04 PM PST
The epigenome is controlled by numerous systems, chromatin remodelling and DNA methylation being two of the most prominent (though microRNA regulation has been shown to also be extremely important). The Histone Deacetylase (HDAC) and Histone Acetyltransferase (HAT) proteins affect the state of histones and the chromatin structure, while DNA methyltransferases (DNMTs) can hinder the availiability of DNA. Both methods control gene expression.

The epigenome is controlled by numerous systems, chromatin remodelling and DNA methylation being two of the most prominent (though microRNA regulation has been shown to also be extremely important). The Histone Deacetylase (HDAC) and Histone Acetyltransferase (HAT) proteins affect the state of histones and the chromatin structure, while DNA methyltransferases (DNMTs) can hinder the availiability of DNA. Both methods control gene expression. Therapies for cancer have been designed around these mechanisms, for example, using HDAC inhibitors to cause deacetylation of histones and shift the balance of acetylation-deacetylation, which results in hyperacetylation of histone tails and induction of the tumour suppressor genes. Histone methyltransferases (HMTase), for example EZH2, or DNA methyltransferase (DNMT) also affect the access to tumour suppressor genes and inhibitors of these proteins have been developed that will purportedly have anti-cancer activity. Some oncogenic pathways have been found to increase expression of DNMT and lead to inactivation of tumour suppressor genes. While these treatments show a great deal of promise, there is the possibility that inhibiting these enzymes could result in global hypomethylation and increase the expression of some oncogenic or metastatic genes. The dose of the DNMT inhibitors is lowered in hopes that metastatic genes will not be activate, but this seems a poor and unspecific solution. There are different isotypes of DNMTs which activate different genes, so the trick to specificity to find out the targets of particular isotypes and inhibit specific isotypes (Szyf 2009). I propose to analyze the sequences of all the DNMTs we have discovered so far, group them by similarity and pick out the points of major variation. If possible, we could try to clone the sequences into mammalian expression vectors and produced proteins that we could purify and test inhibitor activities on, so that we could match variation in sequence to protein structure and function. After that, the difficult part arises: how to find out which isotypes target which genes? I foresee a huge amount of ChIP and DamID analysis in some graduate student's future.  Szyf, Moshe. "Epigenetics, DNA Methylation and Chromatin Modifying Drugs." Annual Review of Pharmacology and Toxicity. 2009, 49:243-263.

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