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doi:10.1534/genetics.105.051375
A more recent version of this article appeared on November 1, 2006.
REGULAR RESEARCH PAPERS |
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 Diaz-Perez 1, David Ferguson 2, Chen Wang 3, Gyorgyi Csankovszki 2, Chendong Wang 4, Shih-Chang Tsai 1, Devkanya Dutta 5, Vanessa Perez 1, SunMin Kim 1, C. Daniel Eller 1, Jennifer Salstrom 1, Yan Ouyang 1, Michael A. Teitell 1, Bernhard Kaltenboeck 4, Andrew Chess 5, Sui Huang 3 and York Marahrens 1*
1 UCLA
2 University of Michigan
3 Northwestern University
4 Audburn University
5 Harvard Medical School
* To whom correspondence should be addressed. E-mail: ymarahrens{at}mednet.ucla.edu.
Submitted on September 22, 2005
Revised on October 25, 2005
Accepted on 26 August 2006
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 gamma-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.
Key Words: X-inactivation, genome stability, histone acetylation, histone methylation, replication time
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