title: 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.
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 gamma-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles 90095, USA.
authors.forename: Silvia V
authors.initials: SV
authors.lastname: Diaz-Perez
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Gyorgyi
authors.initials: G
authors.lastname: Csankovszki
authors.forename: Chengming
authors.initials: C
authors.lastname: Wang
authors.forename: Shih-Chang
authors.initials: SC
authors.lastname: Tsai
authors.forename: Devkanya
authors.initials: D
authors.lastname: Dutta
authors.forename: Vanessa
authors.initials: V
authors.lastname: Perez
authors.forename: SunMin
authors.initials: S
authors.lastname: Kim
authors.forename: C Daniel
authors.initials: CD
authors.lastname: Eller
authors.forename: Jennifer
authors.initials: J
authors.lastname: Salstrom
authors.forename: Yan
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kaltenboeck
authors.forename: Andrew
authors.initials: A
authors.lastname: Chess
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
authors.forename: York
authors.initials: Y
authors.lastname: Marahrens
mesh_terms: D000107:Acetylation; D000818:Animals; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004261:DNA Replication; D042522:DNA Replication Timing; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D006570:Heterochromatin; D006657:Histones / Q000096:biosynthesis; D008745:Methylation; D051379:Mice; D010766:Phosphorylation; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000032:analysis; D022661:RNA, Untranslated / Q000235:genetics*; D032681:Spectral Karyotyping; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014960:X Chromosome
chemical_list: D006570:Heterochromatin; D006657:Histones; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; D016159:Tumor Suppressor Protein p53; C077885:XIST non-coding RNA; C475961:gamma-H2AX protein, mouse