Assessing the Effect of Epigenetic Dysregulation on Oncogenesis and Immunocompetence in a Mouse Model

Abstract

While there is a clear link between increasing mammalian age and alteration in baseline gene expression in somatic cells, the causality of these changes, how they affect the aging process itself, and their effect on age-related morbidity and mortality remain unclear. Part of the challenge lies in a lack of preclinical models that can isolate specific factors of the aging phenomenon for rigorous study. This in turn makes studying complex relationships between aging and fundamental disease processes such as cancer difficult. In this study, we isolated a single aspect of aging, epigenetic dysregulation via relocalization of chromatin modifiers (RCM), and hypothesized a causal relationship between it and decreased immunocompetence and increasing oncogenesis found in older mammals. To test this hypothesis, a unique transgenic C57BL/6 inducible RCM mouse model was studied before and after exposure to sublethal irradiation. Adaptive immunity was analyzed using in vitro cellular profiling, while oncogenesis was assessed via multi-organ histopathology. We found that the adaptive immunity of RCM mice, at a younger chronological age, paralleled that of older control mice by producing a progeroid immune system characterized by weaker T-cell response to TH1-biasing stimuli, decreased memory B-cell populations, and compromised bone marrow and thymic production. Moreover, irradiated RCM mice went on over the course of 150 days to develop progressive and persistent bone marrow failure and multi-organ oncogenesis that again paralleled chronologically older mice. Therefore, we conclude that the epigenetic “scarring” of the RCM phenomenon is a crucial aspect of age-associated immunosenescence, oncogenesis, and the pathophysiological interplay between the two.