Philip Avner, Corinne Chureau, Philippe Clerc, Lynda Deuve, Agnès Dubois, Céline Morey, Sara Merzouk, Julie Prudhomme

Male mammals carrying one X and one Y chromosome and females with two X chromosomes could be courting potential disaster due to the imbalance in the number of copies of X-linked genes between the sexes. Nature’s answer to this is to arrange for the transcriptional silencing of all the 1500 odd genes present on one of the two X chromosomes in the female during early embryonic development. This process, known as X-inactivation, is a striking example of epigenetic gene regulation, and requires that the two chromosome homologues are differentially treated within the same nucleus. X-inactivation is under the control of a master control region on the X chromosome, the Xic (X-inactivation centre). The onset or initiation of X-inactivation involves the cell counting how many X-chromosomes are present, then ensuring that only a single X chromosome remains active in the diploid cell. Initiation is also thought to include a recognition process linked to the choice of the X chromosome to be inactivated (e.g. imprinting).
A key player in the Xic is the Xist gene which is transcribed as a non coding RNA. Expressed from each X chromosome before differentiation, the Xist transcript is stabilized and coats the inactive X chromosome once inactivation is initiated (see figure on right).
Once X-inactivation is initiated, the chosen X-chromosome is epigenetically modified, accumulating successively a series of other modifications that often characterise heterochromatin. Changes include modifications of histone proteins, accumulation of polycomb group proteins and CpG DNA methylation.

Xist decoration during X-chromosome

inactivation:

The laboratory’s main interests concern

1) The early regulation of X-inactivation through the genetic dissection of the Xic. Varied approaches including targeted mutagenesis, transgenesis, genomic and transcriptional analysis and biochemical characterisation are being used.

2) The chromatin modifications associated with the accumulation of Xist RNA on the X-chromosome, and which result in transcriptional silencing.

Much of our work in the laboratory depends on exploiting ex vivo model systems for X inactivation - embryonic stem (ES) cells, trophoblastic stem (TS) cells and extraembryonic endoderm (XEN) cells. Female ES cells possess two active X chromosomes, one of which is inactivated upon differentiation. The entire sequence of events that characterizes random X-inactivation in vivo is observed in ES cells. TS and XEN cells show imprinted X-inactivation, similar to that observed in murine extraembryonic tissues.

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Go back to the front page for project details :

Initiation of X-chromosome inactivation Dynamics of nuclear organisation

Link to the Avner group at the EMBL