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

一种动物所拥有的一组确切的特征和特征(表型)是由母体和父体对基因组的贡献所提供的遗传因素决定的。表型还受到所谓的“表观遗传”变化的影响，这些变化会影响基因表达，但不会改变DNA的序列。这一奖项支持了一个为期两年的热切项目，该项目专注于高阶生理过程的修饰表型的未探索表观遗传、心血管表现，以及机械变化如何导致生理变化。在拟议的实验中，关键的新奇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。这个项目将集中在潜在分子机制的个体间和个体内的差异上。这一提议的重大影响更广泛，包括对一批美国学生和墨西哥研究生进行交叉培训(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的关系方面的培训，以及对国际研究协调的丰富视角。在这个项目的过程中，将检验三个假设：H1：跨代表观遗传效应。成年斑马鱼在开始繁殖前暴露在水中缺氧(P0)会改变其后代的心血管表型(F1和可能的F2及以后)；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，又表现出在世代之间缓慢消失(逐渐消失)；以及H3：表观遗传机制。P0代胚系经历了不同程度的DNA甲基化和/或组蛋白修饰，这种甲基化和/或组蛋白修饰在随后的受精和发育过程中一直存在，这可能与基因表达的可变变化有关，从而导致F1代修改后的生理表型的变化。这项研究的数据可能会强调一个正在出现但仍未明确的理由，即为什么表观遗传被选为一种机制，以求在跨越几代人的环境变化中幸存下来。结果将通过在同行评议的期刊上发表和在科学会议上介绍来传播。

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.