University of Washington
C-526 Health Sciences Building
Pathology, Box 357470
Seattle, WA 98195
Phone: (206) 543-0716
FAX: (206) 543-3644
The focus of the Disteche lab is the study of the regulation of the mammalian sex chromosomes. The difference in sex chromosome make up between males (XY) and females (XX) has led to the evolution of two dosage compensation mechanisms: X up-regulation or doubling of gene expression on the active X chromosome in both sexes to balance X expression with the autosomes and X inactivation or silencing of one X chromosome in females to avoid X hyperexpression and correct for the gene dosage difference between the sexes. We recently discovered X up-regulation based on global analyses of gene expression by RNA-sequencing and microarrays. We also found higher expression of X-linked genes in brain versus other tissues, which is relevant to the high frequency of X-linked intellectual disability. Our current goals are to characterize the molecular mechanisms of X up-regulation and X inactivation in mammals in terms of developmental aspects and chromatin structure in relation to sex differences. We have found specific changes associated with X upregulation in terms of histone modifications using ChIP-sequencing. In addition, we are studying the role of genes that escape X inactivation and have higher expression in females versus males. Using allele-specific RNA-sequencing approaches we have mapped the extent of escape from X inactivation in multiple mouse tissues. We demonstrated that a specific gene that escapes X inactivation, KDM6A regulates a set of reproduction-related genes in early development and in ovary, thereby demonstrating for the first time a link between escape from X inactivation and a female-specific function.
Investigator: Christine Disteche is a Professor in the Department of Pathology and Adjunct Professor in Medicine
Berletch JB, Deng X, Nguyen DK, Disteche CM. Female bias in Rhox6 and 9 regulation by the histone demethylase KDM6A. PLoS Genet. 2013 May;9(5):e1003489.
Deng X, Berletch JB, Ma W, Nguyen DK, Hiatt JB, Noble WS, Shendure J, Disteche CM. Mammalian X upregulation is associated with enhanced transcription initiation, RNA half-life, and MOF-mediated H4K16 acetylation. Dev Cell. 2013 Apr 15;25(1):55-68.
Disteche CM. Dosage compensation of the sex chromosomes. Annu Rev Genet. 2012;46:537-60.
Deng X, Hiatt JB, Nguyen DK, Ercan S, Sturgill D, Hillier LW, Schlesinger F, Davis CA, Reinke VJ, Gingeras TR, Shendure J, Waterston RH, Oliver B, Lieb JD, Disteche CM. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat Genet. 2011 Oct 23;43(12):1179-85.
Berletch JB, Yang F, Xu J, Carrel L, Disteche CM. Genes that escape from X inactivation. Hum Genet. 2011 Aug;130(2):237-45.
Nguyen DK, Yang F, Kaul R, Alkan C, Antonellis A, Friery KF, Zhu B, de Jong PJ, Disteche CM. 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. 2011 Mar;21(3):402-9.
Berletch JB, Yang F, Disteche CM. Escape from X inactivation in mice and humans. Genome Biol. 2010;11(6):213.
Yang F, Babak T, Shendure J, Disteche CM. Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res. 2010 May;20(5):614-22.
Deng X, Disteche CM. Genomic responses to abnormal gene dosage: the X chromosome improved on a common strategy. PLoS Biol. 2010 Feb 23;8(2):e1000318.
Deng X, Nguyen DK, Hansen RS, Van Dyke DL, Gartler SM, Disteche CM. Dosage regulation of the active X chromosome in human triploid cells. PLoS Genet. 2009 Dec;5(12):e1000751.
Xu J, Disteche CM. Sex differences in brain expression of X- and Y-linked genes. Brain Res. 2006 Dec 18;1126(1):50-5.
Heard E, Disteche CM. Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev. 2006 Jul 15;20(14):1848-67.
Nguyen DK, Disteche CM. Dosage compensation of the active X chromosome in mammals. Nat Genet. 2006 Jan;38(1):47-53.