Transgenerational epigenetic programming of the thyroid axis

甲状腺轴的跨代表观遗传编程

• 批准号: 10200021
• 负责人: Arturo Hernandez
• 金额: $ 43万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200021
• 关键词: Adipose tissue; Adult; Affect; Area; Award; Awareness; Characteristics; Code; Data; Development; Developmental Gene; Disease; Eating; Endocrine Disruptors; Endocrine system; Ensure; Enzymes; Epigenetic Process; Exposure to; Feedback; Functional disorder; Gene Expression; Generations; Genes; Genetic; Germ Lines; Growth; Health; Heritability; Hormonal; Hormones; Human; Human Development; Hypothalamic structure; Individual; Inheritance Patterns; Inherited; Intervention; Iodide Peroxidase; Leptin; Life; Link; Maintenance; Mental Health; Metabolic; Metabolic Diseases; Methylation; Mus; Neurosecretory Systems; Obesity; Organism; Outcome; Phenotype; Physiological; Physiological Processes; Physiology; Pituitary Gland; Play; Predisposition; Process; Regulation; Research; Role; Serum; Signal Transduction; System; Testing; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyroxine; Tissues; Triiodothyronine; base; biological systems; energy balance; experimental study; fetal; genomic locus; hypothalamic-pituitary-thyroid axis; imprint; improved; insight; metabolic phenotype; metabolic rate; mouse model; neonate; neuroendocrine phenotype; non-genetic; novel; reproductive function; response; transgenerational epigenetic inheritance

Intrinsic to the hypothalamic-pituitary-thyroid axis (HPTA) and the leptin-melanocortin system (LMS) are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4), 3,3',5- triiodothyronine (T3) and Leptin (LEP) within strict limits. These endocrine systems in turn influence a host of physiological processes critical to the metabolic health and adaptability of the organism. The type 3 deiodinase (DIO3) functions to inactivate T4 and T3 in tissues and is coded by a gene that is imprinted in mice and humans. DIO3 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 the programming of the HPTA and the LMS. Thus, mice deficient in DIO3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands and adipose tissue. Our preliminary data suggest that a developmental excess of T3 modifies the epigenetic information of the germ line, including the Dio3 locus and that of other developmental genes. This leads in subsequent generations to alterations in the ontogeny and set points of the HPTA and the LMS, with consequences for the susceptibility to metabolic disease. Thus, this proposal seeks to investigate the hypothesis that developmental overexposure to T3 elicits changes in the transgenerational epigenetic inheritance at the Dio3 locus and at other relevant loci and influences in descendants the programming of the HPTA and LMS and the regulation of TH action and energy balance throughout life. Specifically, and based on our data concerning the alterations in the epigenetic information of germ line caused by a developmental excess of T3, we propose herein experiments to: (1) Define the patterns of inheritance of altered epigenetic marks at the Dio3 locus and at other gene loci of relevance to the development of the HPTA and the LMS that are caused by an ancestral developmental overexposure to T3; (2) Delineate the phenotypic consequences of such altered epigenetic inheritance for the ontogeny, function and physiological adaptability of the HPTA and the LMS. Notably, this heritable process may represent a novel transgenerational mechanism that impacts the degree of plasticity by which the HPTA and the LMS adapt to homeostatic challenges, reducing or exacerbating the propensity to develop obesity. In addition, given the importance of the DIO3 in modulating the intracellular levels of TH and the breadth of epigenetic alterations caused by an excess of T3, this new paradigm implies an additional, heritable component that may be of significance to other disease states affecting mental health or reproductive function.

下丘脑-垂体-甲状腺轴（HPTA）和瘦素-黑皮质素系统（LMS）固有的是将甲状腺素（T4）、3，3 '，5-三碘甲状腺原氨酸（T3）和瘦素（LEP）的循环和组织水平维持在严格限度内的稳态和反馈机制。这些内分泌系统反过来又影响着一系列对生物体的代谢健康和适应性至关重要的生理过程。3型脱碘酶（DIO 3）的功能是使组织中的T4和T3脱碘，并由小鼠和人类中印记的基因编码。DIO 3在母胎单位和新生儿中高度表达，在新生儿中它在确保TH的浓度对于发育以及HPTA和LMS的编程是最佳的方面起关键作用。因此，DIO 3缺乏的小鼠具有改变的血清TH水平，下丘脑、垂体和甲状腺以及脂肪组织的显著功能障碍。我们的初步数据表明，发育过量的T3修改生殖系的表观遗传信息，包括Dio 3基因座和其他发育基因。这导致后代个体发育和HPTA和LMS设定点的改变，从而导致对代谢疾病的易感性。 因此，该建议旨在研究这样的假设，即发育过度刺激T3会导致Dio 3基因座和其他相关基因座的跨代表观遗传发生变化，并影响后代HPTA和LMS的编程以及TH作用的调节和整个生命的能量平衡。具体地说，基于我们关于由T3的发育过度引起的生殖系表观遗传信息改变的数据，我们在此提出实验：（1）确定在D10 3基因座和在与由祖先发育过度向T3引起的HPTA和LMS的发育相关的其它基因座处改变的表观遗传标记的遗传模式;（2）阐明这种改变的表观遗传对HPTA和LMS的个体发育、功能和生理适应性的表型影响。 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，其影响HPTA和LMS适应稳态挑战的可塑性程度，从而减少或加剧发展肥胖的倾向。此外，鉴于DIO 3在调节TH的细胞内水平和由过量T3引起的表观遗传改变的广度中的重要性，这种新的范例意味着可能对影响精神健康或生殖功能的其他疾病状态具有重要意义的额外的可遗传成分。