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DNA Methylation in Eukaryotes: 20 Years On

Robin Holliday


The proposals published in 1975, and reprinted in this volume, were based on certain features of development that were not understood at the time and, in large part, are still not understood. One such feature is the stability of the differentiated state; that is, the fact that differentiated cells, whether they are postmitotic or commonly undergo mitosis, stably retain their phenotype. Any differentiated cell has a large number of active genes coding for “housekeeping” enzymes or other proteins and a subset of genes coding for specialized “luxury” functions. This also means that genes coding for other luxury functions, appropriate to another specialized cell type, are stably repressed. A second feature of development, obviously related to the first, is the formation of different cell types by the switching on of specific sets of genes and the inactivity of other sets. The 1975 paper in Cytogenetics and Cell Genetics concentrated on the switch that inactivates one X chromosome in female mammals. The 1975 paper in Science discussed several switching mechanisms, including stem-line situations, the inactivation of the X chromosome, transdetermination in imaginal discs of Drosophila, and other developmental contexts. A third feature of development we1 considered to be important was the likely existence of developmental clocks; that is, the existence of specific controls on the number of cell divisions in particular situations, before some developmental switch occurred. In this connection, we referred to some of the concepts developed by Holtzer, in which differentiation events are tied to cell division (Holtzer et al...

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