Mammalian females have two X chromosomes and males have only one. This fundamental difference has lead to the evolution of dosage compensation mechanisms. An important problem that males face is a deficiency in X-linked gene expression. A well-known mechanism of dosage compensation is X inactivation, which equalizes gene expression dosage between the sexes. We recently obtained evidence of another form of dosage compensation, which doubles the global transcriptional output from the active X chromosome in males and females to achieve a similar expression level to that of autosomes. A crucial role of X up- regulation, the focus of the present proposal, is to avoid deleterious effects of haplo-insufficiency. This is similar to the situation in Drosophila where the male X is up-regulated. We used microarray analyses in several mammalian species to demonstrate that X up-regulation is established in early embryos, and is maintained in somatic tissues. We also found higher expression of X-linked genes in brain. The goal of the proposed research is to determine the molecular mechanisms of mammalian X up- regulation. We speculate that X up-regulation may result either from epigenetic modifications of the active X and/or from evolutionary modifications of the DMA sequence to increase gene expression.
Our Aims are (1) to determine when and where X up-regulation is established during development, (2) to study global epigenetic modifications potentially associated with X up-regulation, including histone modifications and candidate proteins known to be involved in Drosophila dosage compensation, (3) to investigate the mechanisms of high expression of X-linked genes in specific regions of the brain, and (4) to perform functional studies of X up-regulation using a mouse model in which we have previously shown a doubling of expression from the chloride channel gene, Clcr>4, when it is located on the X compared to an autosome. Our research has implications for understanding the developmental and evolutionary biology of the X chromosome and the role of X-linked gene expression in sex chromosome disorders and mental retardation. The proposed research is relevant to the role of the X chromosome in human diseases. Particularly significant are our findings of overall increased X expression in specific regions of the brain as the prevalence of X-linked mental retardation is well documented. Maintenance of the balance of gene expression is critical for normal development, as can be seen from the presence of multiple congenital abnormalities in individuals with chromosomal imbalance due to autosomal monosomy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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University of Washington
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Disteche, Christine M (2016) Dosage compensation of the sex chromosomes and autosomes. Semin Cell Dev Biol 56:9-18
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
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
Disteche, Christine M (2012) Dosage compensation of the sex chromosomes. Annu Rev Genet 46:537-60
Deng, Xinxian; Hiatt, Joseph B; Nguyen, Di Kim et al. (2011) Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat Genet 43:1179-85
Nguyen, Di Kim; Yang, Fan; Kaul, Rajinder et al. (2011) Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X. Genome Res 21:402-9
Berletch, Joel B; Yang, Fan; Xu, Jun et al. (2011) Genes that escape from X inactivation. Hum Genet 130:237-45
Yang, Fan; Babak, Tomas; Shendure, Jay et al. (2010) Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 20:614-22
Deng, Xinxian; Disteche, Christine M (2010) Genomic responses to abnormal gene dosage: the X chromosome improved on a common strategy. PLoS Biol 8:e1000318
Berletch, Joel B; Yang, Fan; Disteche, Christine M (2010) Escape from X inactivation in mice and humans. Genome Biol 11:213

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