Developmental Epigenetics

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

Up to 25,000 genes are needed to encode all of the information needed to make an animal. Genes are linked together in large groups called chromosomes. In humans there are 23 chromosome pairs. Amongst these are the sex chromosomes, the X and the Y. Females have two X chromosomes whereas males have an X chromosome and a Y chromosome. Early on in female embryo development the genes on one of the X chromosomes are switched off, a process called X inactivation. X inactivation is important because it balances gene levels with males who only have a single X chromosome. The aim of our studies is to understand how this unusual form of genetic control works. ||In general terms X inactivation provides a useful model for understanding how genes are switched on and off. This is an important area of research because the combination of on and off states for all the genes defines the identity of different cell types, for example determining whether they are early embryo cells, red blood cells or brain cells. It is also an important area for understanding what goes wrong in disease, particularly cancer, where the identity of cells becomes corrupted and they start to grow uncontrollably.|

Technical Summary

Embryonic stem (ES) cell based genetic models, i.e. gene targeting and transgenics will be used in studying Xist regulation with respect to X chromosome choice, and for analysing the role of cis-acting sequences in X inactivation spreading. Analysis of the interaction of Eed-Ezh2 with Xist RNA will involve branching into more biochemical approaches. Analysis of dynamic changes in epigenetic modifications (DNA methylation and histone N-terminal modification) during progression of X inactivation will be undertaken, at a pilot study level, by establishing X chromosome genomic contigs on microarrays for probing with immunoprecipitated material. Studies on X chromosome reactivation in developing germ cells and in cell fusion systems will utilise developmental and cell biological approaches, coupled to genetic analysis.

Publications


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Popova BC (2006) Attenuated spread of X-inactivation in an X;autosome translocation. in Proceedings of the National Academy of Sciences of the United States of America