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Originally published as Genetics Published Articles Ahead of Print on September 15, 2006.

Genetics, Vol. 174, 1115-1133, November 2006, Copyright © 2006
doi:10.1534/genetics.105.051375

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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{dagger}, Chen Wang{ddagger}, Gyorgyi Csankovszki§, Chengming Wang**, Shih-Chang Tsai*, Devkanya Dutta{dagger}{dagger}, Vanessa Perez*, SunMin Kim*, C. Daniel Eller*, Jennifer Salstrom*, Yan Ouyang*, Michael A. Teitell{ddagger}{ddagger}, Bernhard Kaltenboeck**, Andrew Chess{dagger}{dagger}, Sui Huang{ddagger} and York Marahrens*,1

* Department of Human Genetics and {ddagger}{ddagger} Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, {dagger} Department of Pathology and § Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, {ddagger} Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, ** Department of Pathobiology, Auburn University, Auburn, Alabama 36849 and {dagger}{dagger} Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts 02114

1 Corresponding author: Department of Human Genetics, UCLA, Gonda Center, 695 Charles E. Young Dr., South Los Angeles, CA 90095-7088.
E-mail: ymarahrens{at}mednet.ucla.edu

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.


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