Chromatin organization as a predictor of stress induced immune dysregulation

 描述(由申请人提供)：环境是不断变化的，压力源很常见。个体对压力源的反应可能是适应性的，也可能是适应性差的。在细胞水平上，大部分反应是通过调节基因组的结构和可及性在转录上协调的。人类基因组被包装和浓缩成比染色体DNA长度小六个数量级的核。缩合是通过将DNA包裹在核心核小体结构周围而完成的，核小体结构浓缩成染色质。染色质浓缩的程度和性质决定了哪些基因被抑制，哪些基因被转录。我们已经证明了组蛋白表观遗传翻译后修饰(表观遗传标记)可以标记受到心理压力不利影响的免疫反应基因。这种表观遗传标记决定了局部和全球染色质的可及性。这个项目的重要目的是评估表观遗传标记和核结构蛋白作为与乳腺癌诊断相关的心理应激所导致的免疫失调的指标。由于这些表观遗传标记和结构蛋白通过调节DNA结构域之间和单个基因调控元件之间的相互作用来促进基因表达，因此它们是此类评估的理想候选者。表观遗传标记和核结构蛋白将基因定位于转录活跃的部位(如转录工厂)或基因失活或抑制素的部位(如异染色质)。因此，它们可能是理解一个人对心理应激源的反应导致免疫失调的细胞基础的关键，因为与应激相关的核染色质修饰可能直接与免疫细胞执行必要免疫功能的能力有关。通过测量这些表观遗传标记和结构蛋白来检测与应激相关的染色质组织，不仅可以从机制上了解应激对染色质结构的影响，而且还将为检测因心理应激而处于免疫危险中的个体提供细胞学手段的基础。对处于免疫风险中的个人进行识别对于 被诊断出患有乳腺癌的女性。上皮性恶性肿瘤，如乳腺癌，对免疫监视和免疫系统的抗肿瘤作用有反应。因此，影响这些免疫监测形式的心理压力将危及癌症控制，特别是在脆弱时期，例如手术后和辅助治疗后立即。迅速和适当地识别由于心理压力而面临免疫风险的个人，不仅可以在治疗后立即对这些个人进行更密切和仔细的监测，而且还可以深入到他们的癌症轨迹，为早期心理社会干预提供机会。我们小组和其他人已经证明，这种干预措施可以减少乳腺癌诊断对心理、生理和免疫学的影响。

 DESCRIPTION (provided by applicant): 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.