How DNA methyltransferases read histone marks

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

DNA sequence by itself is not sufficient to instruct our development from a fertilised egg into the complex body plan. DNA sequence has to be interpreted correctly throughout development in different tissues and one means by which this is accomplished is through epigenetic modifications. Epigenetic modification refers to chemical tags added to DNA or to the chromosomes that allow specific sets of genes to be activated or silenced in different cell types. DNA methylation is perhaps the best understood epigenetic mark, however, we still do not fully understand the signals that specify where DNA methylation marks are placed. We are investigating DNA methylation in the mammalian egg. The egg is a particularly interesting model because a whole programme of DNA methylation is laid down in a specific developmental window. Moreover, the DNA methylation pattern of the egg needs to be specified correctly for the development of the embryo after fertilisation: methylation errors incurred in eggs perhaps as a result of poor maternal nutrition or assisted reproduction technologies could be passed onto and persist in offspring and lead to abnormal gene activity. Based on recent molecular profiling, we propose that sites of DNA methylation are specified by gene activity in the mammalian egg. This suggests that the proteins that deposit DNA methylation (DNA methyltransferases) may be guided by other epigenetic marks on the chromosomes associated with active genes, rather than the underlying DNA sequence. We are testing this prediction by engineering versions of the DNA methyltransferase that no longer sense these epigenetic marks. Determining the sequence of events and the players involved that ultimately lead to the correct DNA methylation pattern in the egg will help understand the origin of epigenetic errors associated with infertility or that could be induced by fertility treatments.

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