Does DNA methylation repress gene expression?

Posted by Biome on 11th April 2013 - 0 Comments

In a study recently published in Genome Biology a team led by Richard Meehan, of the University of Edinburgh, have brought some clarity to the longstanding question of causation in the role of DNA methylation in transcriptional regulation. Together with colleagues including Wendy Bickmore, John Greally and Emma Whitelaw, Meehan reports that DNA hypomethylation in cultured mouse cells results in ectopic gene expression, suggesting that an intact DNA methylome is in fact required to maintain a correctly regulated transcriptome.

Regulation of gene activity is key to the maintenance of a cell’s identity, as well as the progress of stem cells through development. For example, aberrant gene expression has recently been proposed to be a factor of aging, and is known to be closely associated with cancer, a key hallmark of which is the deterioration of tissue-specific characteristics.

A myriad of transcriptional activators and repressors, histone acetylases and deacetylases, and methylases and demethylases, are thought to work together to enforce appropriate gene expression, but quite how these they work together is not clearly defined. One particularly poorly understood example is the negative correlation between expression of a given gene and the extent of DNA methylation at that gene’s promoter region. This DNA methylation is found in all mammalian cells and this correlation has been known about for some decades. Nevertheless, the direction of causality has not yet been established: is DNA methylation responsible for the repression of gene expression, or is DNA methylation a response to gene silencing – perhaps as a form of molecular aide memoire – with the initial repression mediated by other factors?

Many of the upregulated genes identified in the study were known to be targets of PRC2 (Polycomb-repressor complex 2), a known transcriptional repressor. To investigate how reduced DNA methylation might be curbing gene repression, Meehan and colleagues measured two things: the amount PRC2 bound to promoters of upregulated genes in the hypomethylated cells; and the level of H3K4me3, a modified histone specifically associated with the presence of PRC2. Interestingly, a striking loss of both PRC2 and H3K4me3 was observed at these promoters upon hypomethylation; further, genome-wide mapping of H3K4me3 revealed a substantial global redistribution of this histone marker.

Collectively, these experiments show that DNA methylation is a necessary component of PRC2-recruitment to gene promoters and so, for PRC2-targeted genes at least, the methylome is not merely an innocent bystander in gene repression. This study did not address events preceding hypomethylation so it does not resolve the question of whether reduced gene expression is required as a trigger for either deposition or removal of methyl groups.

Future work will no doubt address the many outstanding, and longstanding, questions about the relationship between the epigenome and gene regulation. The dramatic results reported here are certainly a significant step toward that goal, and will be of interest to a broad range of researchers.



Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes

Reddington JP, Perricone SM, Nestor CE, Reichmann J, Youngson NA, Suzuki M, Reinhardt D, Dunican DS et al.
Genome Biology 2013, 14:R25

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