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Review
. 2007 May 1;618(1-2):163-74.
doi: 10.1016/j.mrfmmm.2006.05.038. Epub 2007 Jan 21.

Connections between epigenetic gene silencing and human disease

Timothy J Moss  1 , Lori L Wallrath
Affiliations
Review

Connections between epigenetic gene silencing and human disease

Timothy J Moss et al. Mutat Res. .

Abstract

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.

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Figures

Figure 1
Figure 1
Diagram showing the connections between epigenetic gene silencing factors. (a) Gene silencing associated with K27H3. HDACs deacetylate nucleosomes, allowing for methylation of K27H3 by EZH2, providing a bindings site for Polycomb. Components of Polycomb complexes interact with DMNTs involved in methylating cytosine residues (small filled circles). Lines indicate interactions between the gene silencing factors. (b) Gene silencing associated with K9H3 methylation. HDACs deacetylate nucleosomes, allowing for methylation of K9H3 by SUV39h, providing a binding site for HP1. DNA methyltransferases modify cytosine residues (small filled circles) to repress gene expression. Lines indicate interactions between the gene silencing factors. In cancer cells hypermethylation typically occurs within CpG islands of promoter regions, while isolated CpGs at other locations are hypomethylated (small open circles).
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