Histone modifications and chromatin dynamics of the mammalian inactive sex chromosomes

Epigenetics is the study of heritable modifications that affect the regulation of gene function without a change in the underlying DNA sequence itself. The field of epigenetics has significant implications for numerous human genetic diseases, birth defects and cancers. The best known (and studied) examples of epigenetic processes are mammalian X chromosome inactivation (Xi) in female somatic cells and genomic imprinting. However, very little is known about the mechanism of the transient inactivation of the X and Y chromosomes (XYi) during mammalian spermatogenesis.; Research described in this dissertation show that both the X and Y chromosomes undergo sequential changes in their histone modifications beginning at the pachytene stage of meiosis. These changes are usually associated with transcriptional inactivation in somatic cells, and they coincide with the exclusion of the phosphorylated form of RNA polymerase II from the XY body. Both sex chromosomes undergo extensive deacetylation at histone H3 and H4, and (di)methylation of lysine 9 on histone H3; however, there are no changes in H3-K4 methylation. These changes persist even when the XY body disappears in late pachytene, and the X and Y segregate from one another after the first meiotic division. By the spermatid stage, histone modifications of the X and Y revert back to those of active chromatin and RNA polymerase II reengages with both chromosomes. Our observations indicate that XYi is extensive and persists even when the X and Y are separated in secondary spermatocytes.; We also show here that there are several regions that escape X inactivation in male meiosis. Further, our data suggest that similar regions escape Xi during male meiosis and Xi in female somatic cells. Trimethylation of histone H3 at lysine 4 appears to serve as an epigenetic mark for regions escaping the chromosome-wide silencing in both males and females. Xi in female somatic cells and XYi during spermatogenesis are potentially powerful experimental systems to elucidate epigenetic mechanisms of gene regulation, an understanding that will provide novel insights into the molecular events leading to many human diseases.