Epigenetic Inheritance of Physiological Phenotypes: Occurrence, Mechanism and Inter-and Intra-individual Variation

动物所拥有的确切的性状和特征（表型）是由母亲和父亲对基因组的贡献所提供的遗传因素形成的。表型也由所谓的“表观遗传”变化塑造，这种变化影响基因表达，但不改变DNA序列。该奖项支持一个为期两年的EAGER项目，该项目重点研究高阶生理过程、心血管性能的修饰表型的未探索表观遗传，以及生理变异如何由机制变异引起。在提出的实验的关键新颖方面是关注非胎盘动物的“真正的”跨代表观遗传，而不是子宫或母体的影响。本项目将重点研究潜在分子机制中的个体间和个体内变异。这项提议的更广泛的重要影响包括对美国学生和墨西哥研究生的交叉培训（涉及UNT与墨西哥CONACyT资助机构的新协议）。这些学生将接受生理学和表观遗传学联系方面的培训，并丰富国际研究协调的观点。在这个项目的过程中，将测试三个假设：H1：跨代表观遗传效应。成年斑马鱼（P0）在开始繁殖前暴露于水中缺氧会改变其后代（F1和可能的F2及以后）的心血管表型；H2：表观遗传动力学。表观遗传的心血管表型是高度动态的，既表现出个体之间的差异，也表现出在几代人中缓慢消失（淡出）；H3：表观遗传机制。P0代的种系经历了不同程度的DNA甲基化和/或组蛋白修饰，并在随后的受精和发育中持续存在，这可能与基因表达的不同改变有关，从而导致F1代修饰生理表型的变化。这项研究的数据很可能强调了一个正在出现但仍然模糊定义的基本原理，即为什么表观遗传被选择为一种跨越几代的环境变化的生存机制。研究结果将通过在同行评议的期刊上发表和在科学会议上发表来传播。

The exact set of traits and features possessed by an animal (phenotypes) is shaped by genetic factors provided by maternal and paternal contributions to the genome. The phenotypes are also shaped by so-called "epi-genetic" changes that impact gene expression but do not change the sequence of the DNA. This award supports a two year EAGER project that focuses on the unexplored epigenetic inheritance of modified phenotypes of a higher-order physiological process, cardiovascular performance, and how physiological variation might result from mechanistic variation. Among key novel aspects of the proposed experiments is the focus on "true" transgenerational epigenetic inheritance in non-placental animals, rather than in utero or maternal effects. This project will focus on inter- and intra-individual variation in the underlying molecular mechanisms. The significant Broader Impacts of this proposal include the cross-training of a cohort of both US students and Mexican graduate students (involving UNT's new agreement with Mexico's CONACyT funding agency). These students will receive training in the nexus of physiology and epigenetics as well as an enriched perspective on international research coordination.Three hypotheses will be tested in the course of this project: H1: The Transgenerational Epigenetic Effect. Exposure to aquatic hypoxia in mature adult zebrafish (P0) before they begin reproduction will modify cardiovascular phenotype in their offspring (F1 and possibly F2 and beyond); H2: Epigenetic Dynamics. Epigenetically-inherited cardiovascular phenotypes are highly dynamic, showing both variation between individuals and slowly disappearing (fading out) across generations; and H3: Epigenetic Mechanisms. The germ-line of the P0 generation experiences variable degrees of DNA methylation and/or histone modification that lingers through subsequent fertilization and development, which may be correlated with variably altered gene expression and hence variation in the modified physiological phenotypes in the F1 generation. Data from this study are likely to underscore an emerging yet still vaguely defined rationale for why epigenetic inheritance has been selected for as a mechanism for surviving environmental changes that span several generations. Results will be disseminated through publication in peer-reviewed journals and through presentation at scientific meetings.