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

Genetics. 2006 Nov;174(3):1115-33. doi: 10.1534/genetics.105.051375. Epub 2006 Sep 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Transformed
  • Cell Transformation, Viral
  • Cells, Cultured
  • DNA Replication
  • DNA Replication Timing*
  • Embryo, Mammalian
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Deletion*
  • Heterochromatin*
  • Histones / biosynthesis
  • Methylation
  • Mice
  • Phosphorylation
  • RNA, Long Noncoding
  • RNA, Messenger / analysis
  • RNA, Untranslated / genetics*
  • Spectral Karyotyping
  • Tumor Suppressor Protein p53 / metabolism
  • X Chromosome*


  • Heterochromatin
  • Histones
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Untranslated
  • Tumor Suppressor Protein p53
  • XIST non-coding RNA
  • gamma-H2AX protein, mouse