Section on Molecular Morphogenesis; National Institutes of Health (NIH), Bethesda, Maryland, USA.
Bioinformatics and Scientific Programming Core; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Thyroid. 2023 Apr;33(4):511-522. doi: 10.1089/thy.2022.0469. Epub 2023 Jan 24.
Thyroid hormone (triiodothyronine [T3]) is essential for development and organ metabolism in all vertebrates. T3 has both genomic and nongenomic effects on target cells. While much has been learnt on its genomic effects via T3 receptors (TRs) in vertebrate development, mostly through TR-knockout and TR-knockin studies, little is known about the effects of T3 on gene expression in animals in the absence of TR. We have been studying metamorphosis as a model for mammalian postembryonic development, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult forms. We have recently generated TR double knockout (TRDKO) animals. This offers an opportunity to compare the effects of T3 on global gene expression in tadpole tissues in the presence or absence of TR. We analyzed the effects of T3 on gene expression in tadpole tail and intestine by using RNA-seq analysis on wild-type and TRDKO tadpoles with or without T3 treatment. We observed that removing TRs reduced the number of genes regulated by T3 in both organs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that T3 affected distinct biological processes and pathways in wild-type and TRDKO tadpoles. Many GO terms and KEGG pathways that were enriched among genes regulated in wild-type tissues are likely involved in mediating the effects of T3 on metamorphosis, for example, those related to development, stem cells, apoptosis, and cell cycle/cell proliferation. However, such GO terms and pathways were not enriched among T3-regulated genes in TRDKO tadpoles. Instead, in TRDKO tadpoles, GO terms and pathways related to "metabolism" and "immune response" were highly enriched among T3-regulated genes. We further observed strong divergence in the TR-independent nongenomic effects of T3 in the intestine and tail. Our data suggest that T3 has distinct and organ-dependent effects on gene expression in developing tadpoles. The TR-mediated effects are consistent with the metamorphic changes, in agreement with the fact that TR is necessary and sufficient to mediate the effects of T3 on metamorphosis. T3 appears to have a major effect on metabolism and immune response via TR-independent nongenomic processes.
甲状腺激素（三碘甲状腺原氨酸[T3]）是所有脊椎动物发育和器官代谢所必需的。T3 对靶细胞具有基因组和非基因组效应。虽然通过脊椎动物发育过程中的 T3 受体（TR）在很大程度上了解了其基因组效应，主要是通过 TR 敲除和 TR 敲入研究，但对于没有 TR 的情况下 T3 对动物基因表达的影响知之甚少。我们一直在研究变态作为哺乳动物胚胎后发育的模型，这是出生前后的一个时期，此时血浆 T3 水平达到峰值，许多器官/组织成熟为成人形式。我们最近生成了 TR 双敲除（TRDKO）动物。这为比较 TR 存在或不存在时 T3 对蝌蚪组织中全局基因表达的影响提供了机会。我们通过 RNA-seq 分析，比较了有或没有 T3 处理的野生型和 TRDKO 蝌蚪尾巴和肠道中 T3 对基因表达的影响。我们观察到，去除 TR 减少了这两种器官中受 T3 调节的基因数量。基因本体论（GO）和京都基因与基因组百科全书（KEGG）途径分析表明，T3 影响了野生型和 TRDKO 蝌蚪中不同的生物学过程和途径。在野生型组织中受调控的基因中富集的许多 GO 术语和 KEGG 途径可能参与介导 T3 对变态的影响，例如与发育、干细胞、细胞凋亡和细胞周期/细胞增殖相关的途径。然而，在 TRDKO 蝌蚪中，受 T3 调节的基因中没有富集这些 GO 术语和途径。相反，在 TRDKO 蝌蚪中，受 T3 调节的基因中高度富集了与“代谢”和“免疫反应”相关的 GO 术语和途径。我们还观察到 T3 在肠道和尾巴中的非基因组作用具有明显的器官依赖性和 TR 独立性。我们的数据表明，T3 对发育中的蝌蚪的基因表达具有独特的、器官依赖性的影响。TR 介导的效应与变态变化一致，这与 TR 是介导 T3 对变态作用所必需和充分的事实一致。T3 似乎通过 TR 非基因组过程对代谢和免疫反应产生重大影响。
