Transgenerational Epigenetic Programming of the Thyroid Axis

描述(申请人提供)：下丘脑-垂体-甲状腺(HPT)轴固有的动态平衡和反馈机制，将循环和组织中的甲状腺素(T4)和3，3‘，5-三碘甲状腺原氨酸(T3)水平保持在严格的限制内。这些荷尔蒙水平反过来影响对生物体的健康和适应性至关重要的一系列生理过程。3型脱碘酶(D3)是甲状腺激素(TH)作用的关键决定因素，其功能是使组织中的T4和T3失活。D3是由在老鼠(Dio3)和人类(Dio3)身上印记的基因编码的。在这两个物种中，D3在母胎单位和新生儿中都高度表达，在确保 对于HPT轴的开发和编程是最佳的。因此，缺乏D3的小鼠血清TH水平发生改变，下丘脑、垂体和甲状腺明显功能障碍，生长受损和其他表型异常。我们从小鼠模型中获得的初步数据有力地表明，TH状态的变化可以通过表观遗传机制在后代后代的下丘脑和其他组织中诱导D3表达模式的显著变化。因此，这一建议试图调查这一假说，即dio3基因座的跨代表观遗传影响HPT轴的编程以及一生中TH代谢和行为的调节。此外，我们推测，TH本身以及动物的甲状腺状况，在设定表观遗传标记方面发挥了关键作用，表观遗传标记部分地决定了D3在后续世代中的表达模式。具体地说，我们在这里提出的实验是：(1)确定在HPT轴改变的动物的后代中观察到的dio3跨代遗传模式的表型后果；(2)确定导致dio3跨代遗传模式变化的表观遗传变化。(3)确定TH在诱导发育过程中和成年动物dio3基因座改变的跨代表观遗传中的作用。值得注意的是，这种可遗传的过程可能代表了一种新的跨代机制，为HPT轴提供了额外程度的可塑性，以适应内环境平衡的挑战。此外，鉴于D3在调节TH的细胞内水平方面的重要性，特别是在发育中的和成人的大脑中，这个新的范例意味着TH的活动中有一个额外的、可遗传的成分，可能会影响心理健康，或者可能容易导致代谢或生殖功能障碍。

DESCRIPTION (provided by applicant): Intrinsic to the hypothalamic-pituitary-thyroid (HPT) axis are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4) and 3,3',5-triiodothyronine (T3) within strict limits. These hormone levels in turn influence a host of physiological processes critical to the health and adaptability of the organism. The type 3 deiodinase (D3), which functions to inactivate T4 and T3 in tissues, is a critical determinant of thyroid hormone (TH) action. The D3 is coded by a gene that is imprinted in mice (Dio3) and humans (DIO3). In both species, the D3 is highly expressed in the maternal-fetal unit and in the neonate, where it plays a critical role in ensuring that concentrations of TH are optimal for development and for programming of the HPT axis. Thus, mice deficient in D3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands, impaired growth and other phenotypic abnormalities. Our preliminary data derived from mouse models strongly suggest that alterations in TH status, can, through epigenetic mechanisms, induce marked changes in the expression patterns of the D3 in the hypothalamus and other tissues in subsequent generations of offspring. Thus, this proposal seeks to investigate the hypothesis that transgenerational epigenetic inheritance at the Dio3 locus influences the programming of the HPT axis and the regulation of TH metabolism and action throughout life. Furthermore, we speculate that TH itself, and thus the thyroid status of the animal, plays a key role in setting the epigenetic marks that determine, in part, D3 expression patterns in subsequent generations. Specifically, we propose herein experiments to: (1) Define the phenotypic consequences of the transgenerational inheritance patterns of the Dio3 observed in the descendants of an animal with an altered HPT axis; (2) Identify the epigenetic changes responsible for the varied patterns of Dio3 transgenerational inheritance. (3) Determine the role of TH in the induction of altered transgenerational epigenetic inheritance at the Dio3 locus during development and in adult animals. Notably, this heritable process may represent a novel transgenerational mechanism that provides the HPT axis with an additional degree of plasticity to adapt to homeostatic challenges. In addition, given the importance of the D3 in modulating the intracellular levels of TH, particularly in the developing and adult brain, ths new paradigm implies an additional, heritable component to the action of TH that may impact mental health or conceivably predispose to metabolic or reproductive dysfunction.