A Deletion at the MouseXistGene ExposesTrans-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 g-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

“…A link between BRCA1 and XIST has been investigated intensively (35)(36)(37)(38)(39). Furthermore, the deletion of Xist in mice leads to hematologic malignancies (40) and genomic instability of the X chromosome (41). One hypothesis would be that true BRCA1-loss-driven cancers require (a sequence of) events or multiple functions of BRCA1 that results in losing the inactive X chromosome.…”

Disruption of Topoisomerase II Perturbs Pairing in Drosophila Cell Culture

“…Importantly, nonmeiotic pairing can influence gene regulation and DNA repair through the processes of transvection (reviewed by Pirrotta 1999;Wu and Morris 1999;Duncan 2002;Kassis 2002;Kennison and Southworth 2002) and recombination (reviewed by Gloor 2002;Wyman et al 2004; also see Rong and Golic 2003), respectively. Pairing of homologous chromosomal regions has also been implicated in mammalian X-inactivation (Marahrens 1999;Bacher et al 2006;Diaz-Perez et al 2006;Xu et al 2006) and imprinting (Lasalle and Lalande 1996;Riesselmann and Haaf 1999). Intriguingly, a reduced level of pairing at imprinted regions may be associated with syndromes such as autism and the Prader-Willi and Angelman syndromes (Lasalle and Lalande 1996;Thatcher et al 2005).…”

The role of long noncoding RNAs in cancer metastasis

“…The precise mechanism by which XIST recruits PRC1/2 to the X-chromosome is still unclear, as X-inactivation requires an evenly distributed presence of PRC1/2 across the Xi so as to ensure the proper silencing of both coding and noncoding transcripts [ Figure 2B]. Some have indicated that the silencing of Xi is accompanied by phosphorylation events on p53, indicating XIST cooperates with the p53 DNA-repair machinery during X-inactivation [78] . Given other ncRNAs such as miR-34 are known regulators of TP53 expression in cancer cell lines as well as during development [79] , this raises the notion that lincRNAs cooperate with ncRNAs to carry out specific cellular programs.…”