Abstract 5128: Changes in mitochondrial background affect nuclear DNA methylation

Abstract

Abstract There is emerging evidence demonstrating that mitochondrial DNA (mtDNA) contributes to complex genetic diseases such as cancer. To test directly the role of mtDNA in tumorigenicity and metastasis, a new genetically engineered mouse model was created that contains nuclear DNA from one mouse strain and mtDNA contribution from different mouse strain(s). Taking advantage of maternal inheritance, Mitochondrial Nuclear Exchange (MNX) mice can be bred to mice sharing the same nuclear DNA background. As a result, MNX serves as an important tool to determine if and how mitochondrial genetic background contributes to cancer, negating the concern for mixing maternal and paternal nuclear DNA polymorphisms. MNX mice are healthy, breed normally, show no overt differences in cell cycle or apoptosis and are genetically stable for multiple (>10) generations. Nonetheless, they are distinct strains based upon behaviors and gene expression patterns. The mechanisms controlling gene expression in different MNX strains are not yet known; however, retrograde and anterograde cross-talk exists between the nuclear and mitochondrial genomes. Our hypothesis is that important epigenetic changes occur in the nuclear genome depending upon mitochondrial genetics. To test this hypothesis, we performed Meth-Seq using the Agilent Mouse SureSelect platform and Affymetrix gene expression arrays on four mouse brains (8 wk) that were pooled from different litters and cages of wild-type and MNX to minimize age, developmental, inter-individual and generational heterogeneity. Both differential DNA methylation and gene expression patterns were observed but analyses are ongoing to better define the observed differences. Together these observations provide novel insights into how mtDNA could be altering epigenetic regulation and thereby contribute to cancer pathogenesis. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res., Kansas Bioscience Authority, Steiner Family Fund. Citation Format: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Bodour Salhia, Danny R. Welch. Changes in mitochondrial background affect nuclear DNA methylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5128. doi:10.1158/1538-7445.AM2015-5128