International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


PLENARY PRESENTATION

WEDNESDAY OCTOBER 20

10.45am – 11.15am

NON-CODING RNAS PLAY MULTIPLE ROLES IN INACTIVATION INITIATION

Avner P

Institut Pasteur, Paris, France

X chromosome inactivation, a chromosome wide mechanism of transcriptional silencing, is under the control of a complex master locus, the X-inactivation centre (Xic) that contains the Xist gene, the source of a large 17 kb non-coding RNA critical to the X-inactivation process. The onset of X-inactivation which occurs during early embryogenesis sees an up-regulation of Xist transcripts and the spreading of the Xist RNA along the X chromosome, followed by chromatin modifications involving both extensive histone modifications and the recruitment of polycomb group proteins to the inactivating X and the transcriptional repression of X-linked genes. Female ES cells are extensively used as models for the inactivation process as undifferentiated female ES cells have 2 X’s active and X-inactivation occurs with the onset of differentiation. More recently both TS cells (Trophoblast) and XEN cells (extra-embryonic endoderm) have been used as models for imprinted X-inactivation. Integral to the initiation of X-inactivation is the counting process in which the X chromosome/autosome ratio in the cell is sensed and a choice step in which one of the two X-chromosomes in the female cell will be selected for inactivation. Both of these processes involve a region of the Xic 3’ to Xist which also contains the non-coding Tsix antisense RNA which partially overlaps Xist. The Tsix RNA which acts to repress steady state levels of Xist expression and influences the choice process also plays a possibly critical role in the dynamics of X-inactivation by restricting the Xist RNA to its transcription site. Recent results now also suggest an association of Tsix antisense transcription with H3 Lys-4 methylation and chromatin remodelling around the Xist promoter prior to the onset of X-inactivation.

  Several other novel non-coding RNAs are present in the Xic, in particular in the region 5’ and upstream to Xist which has been suggested to function as a nucleation centre prior to Xist coating of the X chromosome possibly by acting as anchorage sites for Xist. Large scale chromatin modifications occur in this region during the onsed of X-inactivation and these changes may well be correlated with transcription activity within the genomic loci encoding these non-coding RNAs. An overview of recent progress will be given.

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