Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation

Abstract

The initial differential treatment of the two X chromosomes during X-chromosome inactivation is controlled by the X-inactivation centre (Xic). This locus determines how many X chromosomes are present in a cell ('counting') and which X chromosome will be inactivated in female cells ('choice'). Critical control sequences in the Xic include the non-coding RNAs Xist and Tsix, and long-range chromatin elements. However, little is known about the process that ensures that X inactivation is triggered appropriately when more than one Xic is present in a cell. Using three-dimensional fluorescence in situ hybridization (FISH) analysis, we showed that the two Xics transiently colocalize, just before X inactivation, in differentiating female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, we demonstrated that Xic colocalization is linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, are required for the transient interaction of Xics. We propose that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

“…45 Mutations of the CTCF binding site within the XIST promoter result in skewed XCI choice. 46,47 XCI is initiated by transient colocalisation of the X-chromosomes, 48 and CTCF is required for such pairing. 49 The enhancer-blocking function of CTCF has been implicated in XCI.…”

Epigenetics in development

“…Within the past year, there has been a surge of papers documenting nuclear colocalization of domains on two different chromosomes (Spilianakis et al, 2005;Bacher et al, 2006;Grimaud et al, 2006;Lomvardas et al, 2006;Xu et al, 2006). In naive T-helper cells, there is an interchromosomal association between the cytokine LCR mentioned above and interferon-␥, a determinant of the T H 1 cell fate.…”

Inactivation du chromosome X

“…Une fois Xist activé, une seconde phase d'appariement homologue des Xic permet de rendre son expression monoallélique (éta-pes de comptage/choix). Cette seconde phase d'appariement concerne non seulement la région Xpr mais également la région Tsix/Xite, impliquée dans la régulation négative de Xist [7,10,11]. Une fois initiée, l'inactivation est stable et maintenue au cours des divisions cellulaires.…”