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

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^*, SunMin Kim^*, C. Daniel Eller^*, Jennifer Salstrom^*, Yan Ouyang^*, Michael A. Teitell, Bernhard Kaltenboeck^**, Andrew Chess, Sui Huang and York Marahrens^*,1

^* Department of Human Genetics and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, Department of Pathology and Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, ^** Department of Pathobiology, Auburn University, Auburn, Alabama 36849 and 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 -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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