Wolf Reik - Head of Laboratory
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Reik Laboratory

We are interested in regulation of imprinted genes as a paradigm for epigenetic gene programming and reprogramming. Imprinted genes often occur in clusters, with imprinting centres within a cluster regulating gene expression or silencing throughout the region. A particular way in which regional coordination can occur is by specific organisation of higher order chromatin structure, so that remote control elements come into contact with each other. For example, in the Igf2-H19 imprinting cluster, enhancers distal to H19 need to come into physical proximity to the Igf2 promoters 100kb away on the paternal allele in order to activate the gene. On the maternal allele, this interaction is prevented by a chromatin insulator, situated between the two genes upstream of H19.

Another principle of regional gene silencing involves non-coding RNAs. The imprinting cluster next to Igf2-H19 has at its centre a long non-coding RNA called Kcnq1ot1, which is transcribed only from the paternal allele; the maternal allele is silenced by promoter methylation originating in the maternal germ line. The flanking genes are paternally silenced during early development and this is accompanied by repressive modification of the nucleosomal histones, such as K9 and K27 methylation. Because of the overt similarities of gene silencing in this cluster with X chromosome inactivation, we are now interested if the ncRNA 'coats' the gene cluster that it inactivates, and if interactions between ncRNA and chromatin could impart specific higher order structures to the locus in the nucleus. How such repressive structures can lead to heritable gene silencing is also of great interest.

The complex epigenetic gene regulation in imprinting clusters has evolved relatively recently. In animals, imprinting only exists in marsupials, and eutherians (all other placental mammals), and this is explained by the 'genetic conflict' theory over resource provision by the parents to offspring. Thus with the evolution of the placenta, and potentially of feeding by lactation, the mother becomes the major provider of resources, and this leads to differences in expression of maternal and paternal alleles of resource providing genes (hence imprinting). We are interested in how the mechanisms of imprinting have evolved. Within the SAVOIR consortium (Sequence Analysis of Vertebrate Orthologous Imprinted Regions) we carry out comparative sequence analysis and bioinformatics of imprinting clusters in species without imprinting (eg chicken), and those with imprinting (marsupials, eutherians). We are aiming to identify sequence arrangements and elements that appear when imprinting first appears in mammals.

Epigenetic programming and reprogramming occurs in the early embryo and in the primordial germ cells (PGCs) on a large scale, involving for example genome wide losses of DNA methylation at both stages. We are interested in understanding the mechanisms and the biological purposes of epigenetic reprogramming. Erasure of DNA methylation patterns in the PGCs is crucial for reprogramming of imprints followed by re-establishment of gamete specific patterns later on. Reprogramming of gametic epigenetic patterns in early embryos may be important for early embryos and stem cells to regain pluripotency; we are carrying out genome wide screens for methylation to examine this idea in more detail. Particularly fascinating is the dramatic demethylation of the paternal genome in the zygote which is likely to involve 'active demethylation', and we are investigating candidate pathways for demethylation. Finally, we are attempting to establish more general genetic screens in E coli and in mammalian cells for reprogramming factors. Understanding and being able to manipulate reprogramming will be of importance for regenerative medicine and novel cancer therapies.