The focus of the Disteche lab is the study of the regulation of the mammalian sex chromosomes. Males have one X and a Y chromosome while females have two X chromosomes. This has resulted in the evolution of mechanisms of dosage compensation. The best known form of regulation of the X chromosome is X inactivation, which silences one X chromosome in females. Using next-generation sequencing we recently discovered that the X chromosome is subject to another form of dosage compensation, which consists in a doubling of transcriptional output from the single active X to equalize expression with the autosomes present in two copies. This novel form of dosage compensation maintains a balanced expression of the genome. Our studies are relevant to the understanding of birth defects caused by dosage imbalance such as trisomy.
Mechanisms of dosage compensation are based on epigenetic modifications that take place during embryonic development. Using genome-wide approaches we have found specific chromatin modifications associated with increased expression of the active X chromosome. We have also developed unique resources based on sequencing to follow allele-specific expression of genes and to investigate their chromatin organization. Our current goals are to continue our studies of the molecular mechanisms of X upregulation and to characterize genes that escape X inactivation (i.e. expressed from both X chromosomes in females). We have found that these genes, some of which produce non-coding RNAs, have different expression levels between males and females, which may contribute to sex-specific differences.
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Fred Hutchison Cancer Research Center | University of Washington
Institute for Systems Biology | Seattle Biomed