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.
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.
Diaz-Perez
Silvia V
SV
Department of Human Genetics, University of California, Los Angeles 90095, USA.
Ferguson
David O
DO
Wang
Chen
C
Csankovszki
Gyorgyi
G
Wang
Chengming
C
Tsai
Shih-Chang
SC
Dutta
Devkanya
D
Perez
Vanessa
V
Kim
SunMin
S
Eller
C Daniel
CD
Salstrom
Jennifer
J
Ouyang
Yan
Y
Teitell
Michael A
MA
Kaltenboeck
Bernhard
B
Chess
Andrew
A
Huang
Sui
S
Marahrens
York
Y
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
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