EPIGENETIC PROGRAMMING OF DIFFERENTIAL GENE-EXPRESSION IN DEVELOPMENT AND EVOLUTION

This review covers data on changing patterns of DNA methylation and the regulation of gene expression in mouse embryonic development. Global demethylation occurs from the eight-cell stage to the blastocyst stage in preimplantation embryos, and global de novo methylation begins at implantation. We have used X-chromosome inactivation in female embryos as a model system to study specific CpG sites in the X-linked Pgk-1 and G6pd housekeeping genes and in the imprinted regulatory Xist gene to elucidate the role of methylation in the initiation and maintenance of differential gene activity. Methylation of the X-linked housekeeping genes occurs very close in time to their inactivation, thus raising the question as to whether methylation could be causal to inactivation, as well as being involved in its maintenance. A methylation difference between sperm and eggs in the promoter region of the Xist gene, located at the X-chromosome inactivation centre, is correlated with imprinted preferential inactivation of the paternal X chromosome in extraembryonic tissues. Based on our data, a picture of the inheritance of methylation imprints and speculation on the significance of the Xist imprint in development is presented. On a more general level, an hypothesis of evolution by ''adaptive epigenetic/genetic inheritance'' is considered. This proposes modification of germ line DNA in response to a change in environment and mutation at the site of modification (e.g., of methylated cytosine to thymine). Epigenetic inheritance could function to shift patterns of gene expression to buffer the evolving system against changes in environment. if the altered patterns of gene activity and inactivity persist, the modifications may become ''fixed'' as mutations; alternatively, previously silenced gene networks might be recruited into function, thus ap pearing as if they are ''acquired characteristics.'' An extension of this hypothesis is ''foreign gene acquisition and sorting'' (selection or silencing of gene function according to use). ''Kidnapping'' and sorting of foreign genes in this way could explain the observation that increased complexity in evolution is associated with more ''junk'' DNA. Adaptive epigenetic/genetic inheritance challenges the ''central dogma'' that information is unidirectional from the DNA to protein and the idea that Darwinian random mutation and selection are the sole mechanisms of evolution. (C) 1995 Wiley-liss, Inc.