Diet and the epigenome: Investigating the impact of the environment on cell biology

人类细胞的功能是由遗传密码和非遗传因素决定的，这些因素被称为表观遗传学，包括人体内发现的酶。人类DNA是一种储存遗传信息的分子，它经历了特定的表观遗传修饰。表观遗传学影响细胞功能而不改变潜在的遗传密码。表观遗传修饰是动态的，易受各种内外因素（如营养不良、衰老、久坐不动的生活方式、荷尔蒙失衡、毒素、污染、过度饮酒和日晒）的影响。异常表观遗传模式在不同疾病中得到了广泛的研究，重点是预防、检测和治疗。例如，包括我们的工作在内的许多研究都提供了证据，证明饮食中的生物活性化合物可以逆转异常的表观遗传模式，调节疾病状态和疾病风险。然而，大多数表观遗传学研究在很大程度上忽略了环境（如饮食生物活性）对正常细胞生物学的作用。重要的是，我们最近的工作表明，环境通过表观遗传学在细胞生物学的调节中发挥作用。我的“发现”研究项目的长期愿景是研究环境（如饮食）如何通过表观遗传机制影响细胞生物学。在接下来的五年里，我的短期目标将集中在表观遗传酶和染色质修饰蛋白在植物雌激素中两种具有不同化学结构的膳食多酚对细胞生物学的影响中的功能作用。从毒理学的角度来看，研究植物雌激素对细胞生物学的影响尤为重要。也就是说，许多环境污染物，包括双酚、壬基酚、对羟基苯甲酸酯和邻苯二甲酸酯，具有雌激素样作用，是有效的内分泌干扰物，影响人类、动物和植物的生命。通过NSERC的发现研究计划所产生的发现，将提出可能与其他环境雌激素作用有关的机制。意义：在NSERC Discovery研究计划中描述的研究将探索表观遗传机制如何介导环境对细胞生物学的影响。这将进一步加深我们对基因转录的表观遗传调控与对环境因素（如饮食）的表型反应之间的联系的理解。考虑到几乎所有的生物过程都有表观遗传调控成分，我们的发现将广泛影响自然科学的许多学科，包括化学和生物学。最后，建议的项目将使我实验室的高素质人才在基因组学，表观基因组学，基因编辑和计算分析方面发展新的高水平技能，这将使他们在未来的就业中具有很强的竞争力。

Human cell functioning is determined by the genetic code as well as non-genetic factors called epigenetics that include enzymes found in the human body. Human DNA, a molecule that stores genetic information, undergoes specific epigenetic modifications. Epigenetics influences cellular functions without changing the underlying genetic code. The epigenetic modifications are dynamic and susceptible to changes upon various internal and external factors (e.g., malnutrition, aging, sedentary lifestyle, hormonal imbalance, toxins, pollutions, excessive alcohol and sun exposure). Aberrant epigenetic patterns have been extensively studied in different disorders with focus on prevention, detection and treatment. For instance, a number of studies, including our work, provide evidence that dietary bioactive compounds can act to reverse aberrant epigenetic patterns and modulate the disease state and disease risk. However, most epigenetic studies have largely ignored the role of the environment (e.g., dietary bioactives) on normal cell biology. Importantly, our recent work argues that the environment plays a role in regulation of cell biology through epigenetics. The long-term vision of my Discovery research program is to study how the environment (e.g., diet) impacts cell biology through epigenetic mechanisms. In the next five years, my short-term goals will focus on the functional roles of epigenetic enzymes and chromatin-modifying proteins in effects on cell biology exerted by two dietary polyphenols from phytoestrogens, that have distinct chemical structures. Studying phytoestrogens' impact on cell biology is especially important from a toxicology point of view. Namely, numerous environmental contaminants, including bisphenol, nonylphenols, parabens, and phthalates, have estrogen-like effects and are potent endocrine disruptors, which impact human, animal and plant life. Findings generated through the proposed NSERC Discovery research program will propose mechanisms that could well be involved in the action of other environmental estrogens. Significance: Studies described in the proposed NSERC Discovery research program will explore how epigenetic mechanisms mediate the impact of the environment on cell biology. This will further our understanding of the connection between epigenetic regulation of gene transcription and the phenotype in response to environmental cues (e.g., diet). Taking into account that nearly all biological processes have an epigenetically regulated component, our findings will broadly impact numerous disciplines in natural sciences, including chemistry and biology. Lastly, the proposed program will enable highly qualified personnel in my laboratory to develop new high-level skills in genomics, epigenomics, gene editing, and computational analyses which will make them highly competitive in future employment.