Transgenerational Epigenetic Programming of the Thyroid Axis

甲状腺轴的跨代表观遗传编程

• 批准号: 8666641
• 负责人: Arturo Hernandez
• 金额: $ 33.06万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666641
• 关键词: Adult; Animals; Brain; Brain Part; Characteristics; Code; CpG Islands; DNA; Data; Development; Disease; Elderly; Endocrine; Endocrine system; Ensure; Enzymes; Epigenetic Process; Feedback; Fetus; Functional disorder; Generations; Genes; Gonadal structure; Growth; Health; Hormones; Human; Human Development; Hyperthyroidism; Hypothalamic structure; Hypothyroidism; Inheritance Patterns; Inherited; Iodide Peroxidase; Left; Life; Mental Health; Metabolic; Methylation; Mus; Mutation; Neonatal; Neurologic; Organism; Partner in relationship; Pattern; Perinatal; Physiological; Physiological Processes; Pituitary Gland; Play; Process; Program Development; Promoter Regions; Regulation; Reproduction; Role; Sampling; Serum; System; Testis; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroxine; Tissues; Triiodothyronine; Wild Type Mouse; Work; base; fetal; genome-wide; grandparent; hormone metabolism; imprint; mature animal; mouse model; neonate; novel; offspring; pituitary thyroid axis; programs; reproductive; reproductive function; research study; response; sperm cell

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, this 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.

下丘脑-垂体-甲状腺（HPT）轴的内在平衡和反馈机制， 维持甲状腺素（T4）和3，3-，5-三碘甲状腺原氨酸（T3）的循环和组织水平在严格的限度内。这些 激素水平反过来又影响许多对人体健康和适应性至关重要的生理过程。 有机体3型脱碘酶（D3）在组织中起着抑制T4和T3的作用， 甲状腺激素（TH）作用的决定因素。D3是由一个基因编码的，该基因在小鼠（Dio 3）中留下印记， 人（DIO 3）。在这两个物种中，D3在母胎单位和新生儿中高度表达， 它在确保TH的浓度对发展和环境保护是最佳的方面发挥着关键作用。 HPT轴的编程。因此，缺乏D3的小鼠具有改变的血清TH水平， 下丘脑、垂体和甲状腺，生长受损和其他表型异常。我们 来自小鼠模型的初步数据强烈表明，TH状态的改变可以通过 表观遗传机制，诱导下丘脑中D3表达模式的显著变化， 其他组织在后代的后代。 因此，这项建议试图调查的假设，跨代表观遗传在 Dio 3基因座影响HPT轴的编程以及TH代谢和作用的调节 在生活中。此外，我们推测TH本身以及动物的甲状腺状态起着关键作用， 在设定表观遗传标记中的作用，表观遗传标记部分地决定了D3在后代中的表达模式。 具体地，我们在此提出实验以： (1)定义Dio 3跨代遗传模式的表型后果 在HPT轴改变的动物的后代中观察到; (2)确定负责Dio 3跨代的不同模式的表观遗传变化 传承 (3)确定TH在诱导改变的跨代表观遗传中的作用， 在发育和成年动物中的Dio 3基因座。 值得注意的是，这种遗传过程可能代表了一种新的跨代机制， HPT轴具有额外程度的可塑性，以适应稳态挑战。此外，鉴于 D3在调节TH的细胞内水平中的重要性，特别是在发育和成人脑中， 这种新的范式意味着TH的作用有一个额外的、可遗传的成分，它可能影响心理健康。 健康或易患代谢或生殖功能障碍。