Stability and Inheritance of DNA methylation
Albert Jeltsch, University of Stuttgart, Germany

The widely-cited model of maintenance of DNA methylation at CpG sites implies that DNA methylation is introduced by the Dnmt3 de novo DNA methyltransferases during early development, and methylation at hemimethylated CpG sites is specifically maintained by the Dnmt1 maintenance methyltransferase. I will present and summarize, substantial experimental evidence from the past decade indicates that this simple model needs to be revised. DNA methylation can be described by a dynamic stochastic model, in which the DNA methylation at each site is determined by the local activity of DNA methyltransferases, DNA demethylases and the DNA replication rate. Through the targeting and regulation of these enzymes DNA methylation is controlled by the network of chromatin marks. At this point, I will present recent data on the regulation of Dnmts by interactors and PTMs. In support of the dynamic model, I will also present novel data obtained after targeted installment of DNA methylation and histone 3 lysine 9 methylation at the VEGF-A locus using zinc finger protein-fused catalytic domains of DNA or histone methyltransferase. Although dense deposition of promoter DNA methylation or histone H3K9 di- and trimethylation was achieved which led to down-regulation of gene expression the epigenetic mark was not stably propagated and upon cessation of the targeted epigenetic rewriter, the epigenetic marks, chromatin environment and gene expression levels returned to their original state. The lack of maintenance of the transiently induced silenced chromatin state suggests that the stability of epigenetic signaling is based on epigenetic networks consisting of several molecular marks and for stable reprogramming either multivalent deposition of functionally related epigenetic marks or longer-lasting trigger stimuli might be necessary.

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