A deletion at the mouse Xist gene exposes trans-effects that alter the heterochromatin of the inactive X chromosome and the replication time and DNA stability of both X chromosomes

Silvia V. Diaz-Perez, David O. Ferguson, Chen Wang, Gyorgyi Csankovszki, Chengming Wang, Shih Chang Tsai, Devkanya Dutta, Vanessa Perez, Sun Min Kim, C. Daniel Eller, Jennifer Salstrom, Yan Ouyang, Michael A. Teitell, Bernhard Kaltenboeck, Andrew Chess, Sui Huang, York Marahrens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The inactive X chromosome of female mammals displays several properties of heterochromatin including late replication, histone H4 hypoacetylation, histone H3 hypomethylation at lysine-4, and methylated CpG islands. We show that cre-Lox-mediated excision of 21 kb from both Xist alleles in female mouse fibroblasts led to the appearance of two histone modifications throughout the inactive X chromosome usually associated with euchromatin: histone H4 acetylation and histone H3 lysine-4 methylation. Despite these euchromatic properties, the inactive X chromosome was replicated even later in S phase than in wild-type female cells. Homozygosity for the deletion also caused regions of the active X chromosome that are associated with very high concentrations of LINE-1 elements to be replicated very late in S phase. Extreme late replication is a property of fragile sites and the 21-kb deletions destabilized the DNA of both X chromosomes, leading to deletions and translocations. This was accompanied by the phosphorylation of p53 at serine-15, an event that occurs in response to DNA damage, and the accumulation of γ-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.

Original languageEnglish (US)
Pages (from-to)1115-1133
Number of pages19
JournalGenetics
Volume174
Issue number3
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Genetics

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