From Genome to Life:

AVNER Philip

Unité Génétique Moléculaire Murine - Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France

title: A Functional Genomics Approach to X-INACTIVATION

In female mammals, one of the two X chromosomes is converted from an active euchromatic state into transcriptionally inert heretochromatin, by a process of dosage compensation known as X-chromosome inactivation, which ensures the equalisation of transcripts from the X chromosome in the female (XX) and the male (XY) cell. X-chromosome inactivation is the most outstanding example of epigenetic regulation occurring in mammals, with transcriptional silencing of the 1500-2000 genes on the X chromosome being achieved during early embryogenesis. The onset of X-inactivation is controlled by a master locus, the X-inactivation centre (Xic). The Xic is a unique region of the X chromosome that is necessary for ensuring that only a single X chromosome is inactivated in each diploid female cell, for choosing the X chromosome to be inactivated and for initiating the subsequent nucleation of silent chromatin on the X chromosome. The onset of X-inactivation and the change from the active to inactive chromatin state is critically associated with the accumulation of a large non-coding RNA encoded by the Xist gene lying with the Xic, which appears to spread in cis from the Xic to decorate and paint the entire inactive X chromosome. Transcriptional silencing occurs rapidly following the initiation of X-inactivation (probably within one to two cell divisions) and is associated with extensive but as yet poorly characterised modifications of the chromatin structure of the inactive X chromosome which include delayed DNA replication timing, methylation modifications of histone H3 (amongst the earliest signs of X-inactivation), DNA methylation of CpG islands, and the accumulation of a novel histone, macroH2A1. An overview of recent progress in our understanding of the early steps in X-chromosome inactivation and of the functions of the Xic will be presented.