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.
|