Basic Biology of Aging at the University of Washington

Christine Disteche, Ph.D.

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Email: cdistech@u.washington.edu

 

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Our main interest is the study of the structure, evolution, and functions of the sex chromosomes in mammals. Our long-term goal is to study the mechanisms of X inactivation and escape. These studies are relevant to the understanding of aging because it has been shown that genes subject to X inactivation can become reactivated with age, which would potentially cause aberrant gene expression in relation to aging. This suggests that epigenetic modifications at X-linked loci, similar to the ones we have observed during development, occur during aging.

Our recent work has focused on the analysis of epigenetic changes at the 5' end of a gene that escapes X inactivation during mouse development. Our studies have shown that specific epigenetic modifications, including DNA methylation and chromatin modifications, take place in relation to the escape.

Currently the major goals of the mouse X-chromosome inactivation project are to: determine the level of dosage compensation from the Y chromosome and from the inactive X chromosome in cases of X/Y gene pairs during mouse development and adulthood; follow epigenetic changes such as loss of DNA methylation and acquisition of histone acetylation associated with escape from X inactivation and expression levels of X/Y genes; and determine whether there is an active process of upregulation of the single active X chromosome of males and females or whether upregulation occured as a slow evolutionary process of adaptation.

Marsupial X inactivation differs from eutherian mammal X inactivation in several aspects, including the fact that marsupial inactivation affects the paternal X chromosome only, that marsupial X inactivation is variable between tissues and that inctivated marsupial genes do not appear to be methylated when inactive. The goals of this project are to isolate the marsupial XIST gene and to investigate the stability and modalities of X inactivation in marsupials in comparison to mouse.

Dr. Disteche is Professor of Pathology and Adjunct Professor of Medical Genetics. She was a recent member, Working Group of the Human Genetic Mutant Cell Repository, NIH, and is a current member, Mammalian Genetics Study Section, NIH. Dr. Disteche is the PI of two individual NIH grants, Mouse X-chromosome inactivation and Marsupial X inactivation.


Selected Relevant Publications

  • Disteche CM, Dinulos MB, Bassi MT, Elliott RW, Rugarli EI. Mapping of the murine tbl1 gene reveals a new rearrangement between mouse and human X chromosomes. Mamm Genome 9:1062-1064, 1998.
  • Disteche CM. Escapees on the X chromosome. Proc Natl Acad Sci USA 96:14180-14182, 1999.
  • Marshall AJ, Niiro H, Lerner CG, Yun TJ, Thomas S, Disteche CM, Clark EA. A novel B lymphocyte- associated adaptor protein, Bam32, regulates antigen receptor signaling downstream of phosphatidylinositol 3-kinase. J Exp Med 191:1319-1332, 2000.
  • Miano JM, Thomas S, Disteche CM. Expression and chromosomal mapping of the mouse smooth muscle calponin gene. Mamm Genome12:187-191, 2001.
  • Lingenfelter PA, Delbridge ML, Thomas S, Hoekstra HE, Mitchell MJ, Graves JA, Disteche CM. Expression and conservation of processed copies of the RBMX gene. Mamm Genome 12:538-545, 2001.
  • Leppig KA, Disteche CM. Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin Reprod Med 19:147-157, 2001.
  • Brannan CI, Disteche CM, Park LS, Copeland NG, Jenkins NA. Autosomal telomere exchange results in the rapid amplification and dispersion of Csf2ra genes in wild-derived mice. Mamm Genome 12:882-886, 2001.