Influence of sex chromosome complement and hormones on heterochromatin silencing in mice

Abstract

Gender differences are accounted for by sex hormones, autosomal genes, sex-chromosome genes. Previously, the use of sex-reversed mice -hence producing XY females and XX males - revealed that a heterochromatic transgene and 369 autosomal genes in the thymus were differentially expressed dependent on the sex chromosome complement (SCC). These genes were enriched for sensitivity to HP1β dosage. Pericentromeric repeats were also less expressed in XY males when compared to XY gonadectomised/XX males and XY/XX females, suggesting a connection between testosterone, Sry and the Y chromosome. Stemming from the above findings, it was sought to determine: i. if the Y chromosome could enable testosterone to silence heterochromatic repeats ii. whether removal of testosterone affected heterochromatin structure and integrity. Since proximity to heterochromatin had been shown to influence expression of translocated genes and transgenes, the distance of the SCC genes to the nearest annotated major satellite sequence was determined. Twelve predicted protein encoding genes were found embedded in major satellites located near the centromere of chromosome 9. These genes were found to be repressed by testosterone on the XY male, which suggested a potential heterochromatin position effect operating on these endogenous genes which was regulated by sex hormones, tending to equalise their expression between the sexes. Moreover, a trend of increasing number of heterochromatic foci per cell in circulating lymphocytes after gonadectomy of male mice was observed. Together with the upregulation of heterochromatic repeats in the thymus from gonadectomised male mice, suggests that absence of testosterone in males could affect genome stability. Lymphocytes derived from lymph nodes and thymus, showed tissue specificity and dependency on age in the expression of heterochromatic repeats and number of heterochromatic foci per cell. This data has implications for understanding how heterochromatin silencing is regulated between genders and has implications for understanding sex bias genome stability.