Environments are ever-changing and stressors commonplace. Individual response to a stressor can be adaptive or maladaptive. At the cellular level, much of the response is coordinated transcriptionally by modulating the structure and accessibility of the genome. The human genome is packaged and condensed into nuclei six orders of magnitude smaller than the length of chromosomal DNA. Condensation is accomplished by packaging DNA around core nucleosome structures that are condensed into chromatin. The degree and nature of chromatin condensation determines which genes are repressed and which genes are transcribed. We have demonstrated histone epigenetic post-translational modifications (epigenetic marks) to mark immune response genes that are adversely affected by psychological stress. Such epigenetic marks determine local and global chromatin accessibility. It is the significant purpose of this project to evaluate both epigenetic marks and nuclear architectural proteins as indices of the immune dysregulation resultant from the psychological stress associated with a diagnosis of breast cancer. Because these epigenetic marks and architectural proteins contribute to gene expression by regulating interactions among DNA domains and among individual gene regulatory elements, they are ideal candidates for such an evaluation. Epigenetic marks and nuclear architectural proteins localize genes to sites of active transcription (e.g. transcription factories) or to sites of gene inactivation or repressin (e.g. heterochromatin). As such they may hold the key to understanding the cellular basis by which one's response to a psychological stressor leads to immune dysregulation, in that stress related modification of nuclear chromatin may directly relate to the capacity of immune cells to carry out necessary immune functions. Detection of stress related chromatin organization by measurement of these epigenetic marks and architectural proteins will provide not only for a mechanistic understanding of the effects of stress upon chromatin structure but will also provide the basis for a cytometric means by which to detect individuals at immunological risk due to psychological stress. Identification of individuals at immunologic risk is especially important for women diagnosed with breast cancer. Epithelial malignancies, like breast cancer, are responsive to immune surveillance and to the anti- tumor effects of the immune system. As such, psychological stress that impacts these forms of immune surveillance would jeopardize cancer control, especially during vulnerable periods, e.g. after surgery and immediately post adjuvant therapy. Quick and appropriate identification of individuals at immunologic risk, due to psychological stress, would allow for more intense and careful monitoring of those individuals not just during the immediate post-treatment period but well into their cancer trajectory, providing the opportunity for early psycho-social intervention. Such interventions have been demonstrated by our group and others to reduce the psychological, physiological and immunological impact of a diagnosis of breast cancer.
Many women diagnosed with breast cancer report intense and enduring levels of psychological stress, which is associated with impaired immune function critical for cancer control. High thru-put imaging will be used investigate molecular biomarkers as indicators of impaired immune function in breast cancer patients. Findings have future potential to identify which cancer patients are at higher risk for stress-related immune dysfunction, allowing early targeting of stress-reducing interventions, which can improve or restore immune function.
| Misale, Michael S; Witek Janusek, Linda; Tell, Dina et al. (2018) Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction. Brain Behav Immun 67:279-289 |
