MOUSE X-CHROMOSOME INACTIVATION

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DESCRIPTION (Adapted from the Investigator's Abstract): The study is aimed at defining evolutionary pathways of the sex chromosomes in mouse and human and at understanding mechanisms of gene regulation specifically related to evolutionary features of the sex chromosomes. Evolution of the mammalian sex chromosomes is characterized by degeneration of the Y chromosome, once sex was determined by a gene on the Y chromosome and recombination was inhibited. Complex regulation of X-and Y-gene expression evolved to accommodate dramatic differences in gene content between the sex chromosomes. X inactivation, which is likely to constitute a hierarchy of control mechanisms, evolved in females to restore equal expression between males and females. Along with X inactivation, upregulation of genes on the single active X chromosome evolved to restore balance of expression with disomic autosomal genes. X/Y gene pairs with functional Y genes and X genes that escape from X inactivation have persisted but differ between species, providing evidence of the evolutionary pathways of genes on the sex chromosomes. The investigators plan: (Aim 1) to systematically compare compensation by expression of Y partners of X/Y gene pairs in males and by escape from X inactivation in females. Such compensation is important since individuals with a single X chromosome have Turner syndrome, likely because of haploinsufficiency of X/Y genes. Expression from the Y gene and the inactive X gene could vary between species, tissues or cell types, modifying the impact of haploinsufficiency. Thus, the investigators will measure expression of X/Y genes in mouse and human individual cells and tissues and during mouse development; (Aim 2) to follow and manipulate epigenetic changes in relation to X/Y gene expression and escape from X inactivation. Stochastic loss of such controls during development may result in reactivation, as suggested by the investigators' previous studies. They will follow DNA methylation and association with histone acetylation of X/Y genes during female and male mouse development. DNA methylation and histone acetylation will be modified in cell lines to investigate the hierarchy of expression controls; (Aim 3) to perform large scale genomic sequencing around the CLC4 genes and compare activity of the promoters in two mouse species which either have an X-linked copy of the gene or an autosomal copy. The doubling of CLC4 expression on the single active X chromosome that they previously discovered, may result from adaptive evolutionary changes to maintain balance with autosomal gene dosage or represent a process of active X upregulation. By inserting CLC4 into an autosome and into the X chromosome in transgenic mice, they will recapitulate the evolutionary chromosomal rearrangement.