X inactivation results in silencing of genes on one X chromosome in females. However, a number of genes escape from X inactivation. Persistence of escape genes in humans is largely unexplained, but is important for a normal phenotype. Indeed, women with a single X chromosome have Turner syndrome, due to haplo-insufficiency for escape genes. Thus, tissue-specific expression of sex-chromosomal genes is likely to be determined by a combination of gene copy number and dosage regulation in addition to hormonal influences. The role of escape genes in sex-specific differences and in sex chromosome aneuploidy is poorly understood. In this proposal we address the sex-specific expression and the role of escape genes in different tissues using genome-wide approaches. Based on our previous studies supported by this grant we will construct a new mouse model to evaluate escape from X inactivation in vivo. To determine expression from each X allele we will generate this model from two mouse species in which X inactivation is skewed, and use RNA-sequencing together with SNP identification to quantify allele-specific expression. The extent of X inactivation and escape for protein-coding genes and for non-coding RNA genes will be evaluated in different tissues and developmental stages. Escape genes are devoid of repressive histone modifications associated with X inactivation, such as tri-methylation of histone H3 lysine 27. Our preliminary evidence indicates that the histone demethylase KDM6A is associated with escape genes in early ES cell differentiation. Thus, we will manipulate the dose of this gene to determine how expression influences X-linked gene expression. The higher expression of escape genes in females suggests that these genes have roles in female-specific functions or processes. One example is Xist, an escape gene that produces a non-coding RNA essential for the onset of X inactivation during early development. An important factor in silencing by repressive chromatin modifications is the position of the inactive X in nuclei. We discovered two regions that bind CTCF only on the inactive X and produce non-coding RNAs that escape X inactivation. In fact, one of these genes is more highly expressed from the inactive than the active X. Both regions are associated with the nucleolus, a nuclear compartment that plays a role in maintenance of heterochromatin. We will examine the role of these regions by knockdown of the long non-coding RNAs in ES cells and in a mouse knockout. Our study will help understanding the role of escape genes in normal development, and in diseases associated with sex chromosome aneuploidy.
X inactivation is an important process required to balance gene dosage between males and females. Equally important are those genes that escape X inactivation, which causes sex- specific differences in gene expression levels and play a role in sex chromosome disorders. Our proposal aims at a better understanding of the function of escape genes in relation to female- specific processes such as X inactivation.
|Disteche, Christine M (2016) Dosage compensation of the sex chromosomes and autosomes. Semin Cell Dev Biol 56:9-18|
|Berletch, Joel B; Ma, Wenxiu; Yang, Fan et al. (2015) Identification of genes escaping X inactivation by allelic expression analysis in a novel hybrid mouse model. Data Brief 5:761-9|
|Yang, Fan; Deng, Xinxian; Ma, Wenxiu et al. (2015) The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol 16:52|
|Deng, Xinxian; Ma, Wenxiu; Ramani, Vijay et al. (2015) Bipartite structure of the inactive mouse X chromosome. Genome Biol 16:152|
|Berletch, Joel B; Ma, Wenxiu; Yang, Fan et al. (2015) Escape from X inactivation varies in mouse tissues. PLoS Genet 11:e1005079|
|Ma, Wenxiu; Ay, Ferhat; Lee, Choli et al. (2015) Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. Nat Methods 12:71-8|
|Disteche, Christine M; Berletch, Joel B (2015) X-chromosome inactivation and escape. J Genet 94:591-9|
|Deng, Xinxian; Berletch, Joel B; Nguyen, Di K et al. (2014) X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet 15:367-78|
|Disteche, Christine M (2013) How to correct chromosomal trisomy. Cell Res 23:1345-6|
|Deng, Xinxian; Berletch, Joel B; Ma, Wenxiu et al. (2013) Mammalian X upregulation is associated with enhanced transcription initiation, RNA half-life, and MOF-mediated H4K16 acetylation. Dev Cell 25:55-68|
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