Transgenerational epigenetic programming of the thyroid axis

甲状腺轴的跨代表观遗传编程

• 批准号: 10458645
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458645
• 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) 本质上是稳态和反馈机制，可将甲状腺素 (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的范围内。这些内分泌系统反过来影响对生物体的代谢健康和适应性至关重要的一系列生理过程。 3 型脱碘酶 (DIO3) 的作用是使组织中的 T4 和 T3 失活，由小鼠和人类体内印记的基因编码。 DIO3 在母胎单位和新生儿中高度表达，在确保 TH 浓度最适合发育以及 HPTA 和 LMS 编程方面发挥着关键作用。因此，缺乏 DIO3 的小鼠血清 TH 水平发生改变，下丘脑、垂体、甲状腺和脂肪组织明显功能障碍。我们的初步数据表明，T3 的发育过量会改变种系的表观遗传信息，包括 Dio3 基因座和其他发育基因的表观遗传信息。这导致后代个体发育以及 HPTA 和 LMS 设定点的改变，从而导致对代谢疾病的易感性。 因此，本提案旨在研究以下假设：发育过度暴露于 T3 会引起 Dio3 基因座和其他相关基因座的跨代表观遗传变化，并影响后代 HPTA 和 LMS 的编程以及整个生命过程中 TH 作用和能量平衡的调节。具体来说，基于我们关于由 T3 发育过量引起的种系表观遗传信息改变的数据，我们在此提出实验：（1）定义 Dio3 基因座和与 HPTA 和 LMS 发育相关的其他基因位点改变的表观遗传标记的遗传模式，这些基因座是由祖先发育过度暴露于 T3 引起的； (2) 描述这种表观遗传改变对 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，这种遗传过程可能代表了一种新的跨代机制，该机制影响 HPTA 和 LMS 适应稳态挑战的可塑性程度，从而减少或加剧肥胖的倾向。此外，鉴于 DIO3 在调节细胞内 TH 水平方面的重要性以及 T3 过量引起的表观遗传改变的广度，这种新范式意味着一个额外的、可遗传的成分，可能对影响心理健康或生殖功能的其他疾病状态具有重要意义。

项目成果

Deletion of the Thyroid Hormone-Activating Type 2 Deiodinase Rescues Cone Photoreceptor Degeneration but Not Deafness in Mice Lacking Type 3 Deiodinase.

删除甲状腺激素激活 2 型脱碘酶可挽救缺乏 3 型脱碘酶的小鼠视锥细胞变性，但不能挽救耳聋。

• DOI: 10.1210/en.2017-00055
• 发表时间: 2017
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Ng,Lily;Liu,Hong;StGermain,DonaldL;Hernandez,Arturo;Forrest,Douglas
• 通讯作者: Forrest,Douglas

The Intrinsic Activity of Thyroxine Is Critical for Survival and Growth and Regulates Gene Expression in Neonatal Liver.

甲状腺素的内在活性对于新生儿肝脏的生存和生长至关重要，并调节基因表达。

• DOI: 10.1089/thy.2020.0508
• 发表时间: 2021
• 期刊: Thyroid : official journal of the American Thyroid Association
• 作者: Galton,ValerieAnne;Martinez,MariaElena;Dragon,JulieA;StGermain,DonaldL;Hernandez,Arturo
• 通讯作者: Hernandez,Arturo

Developmental thyroid hormone action on pro-opiomelanocortin-expressing cells programs hypothalamic BMPR1A depletion and brown fat activation.

• DOI: 10.1093/jmcb/mjac078
• 发表时间: 2023-02-07
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5