Dynamic Nucleosome Signatures in Epigenetic Memory and Cancer Development

$273,049U54FY2010CANIH

Northwestern University At Chicago, Evanston IL

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Abstract

Increasing evidence indicates that cancer results not only from changes in genetic information;in the form of point mutations, chromosomal rearrangements, gene segment amplification and deletion, but also from changes in epigenetic information. Recent theoretical analyses of epigenetic regulation in a model organism (yeast) show that ideas from the dynamical systems field may explain the stability of epigenetic states and the dynamics of spontaneous changes between them. This project will experimentally define the epigenetic changes resulting from the action of (1) a mutant kinase JAK2V617F, a causative factor in myeloproliferative disease;(2) a defined set of oncogenes that transform normal human cells to cancer cells (T antigen, ras, shRNA PP2a, telomerase);and (3) the changes in state of the MLH1 promoter that accompany gene silencing associated with promoter methylation, and reactivation that is induced by 5-aza-2'-deoxycytidine and is associated with DNA demethylation. We will use this information to develop quantitative predictive models of epigenetic inheritance and switching in these systems, based on a dynamical systems framework.

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