ABSTRACT
Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP-PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP-PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Centromere/genetics , Centromere/metabolism , Chromosomal Instability , Heterochromatin/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Cell Line, Tumor , Chromosomes, Human, Pair 5/genetics , Female , Histones/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/metabolism , Kinetochores/metabolism , Neoplasm InvasivenessABSTRACT
The original aim of this report was to present a series of theoretical and technical doubts relating to 'children and their dreams' and the answers I have found. 'From a theoretical viewpoint' shows that although Freud did not investigate repetition compulsion in children's dreams, we can deduce that even children's dreams could not be an exception to repetition. In other words, not all dreams in children are accomplishments of wishes. 'From a technical viewpoint' discusses: (a) the importance psychoanalysts give to children's dreams; (b) ways of bringing and not bringing their dreams to analysis; (c) notes on theory and technique in view of these dreams.
Subject(s)
Dreams , Personality Development , Psychoanalytic Interpretation , Anxiety/psychology , Child , Freudian Theory , Humans , Life Change Events , Parent-Child Relations , Psychoanalytic TherapyABSTRACT
This study has demonstrated that the ability of BeAn 8386 virus to persist in the central nervous system of mice declines with the increasing age of the host at the time of inoculation. Although persistent infection was established in 1-, 3-, 9-, and 40-week-old mice, there was a significant reduction in both the frequency of virus isolations and the mean virus titers in mice inoculated after 3 weeks of age. The incidence of clinical demyelinating disease (late disease) also decreased in animals infected after 3 weeks of age in parallel with the decline in virus persistence.
