Metabolic and xenobiotic control of thyroid hormone metabolism

摘要 甲状腺激素(TH)在发育过程中起着关键作用。在胚胎中，血浆T3相对较低，但 TH信号可以通过表达Dio2来增强，Dio2是一种介导局部T3产生的脱碘酶。这个 D2-T3激活的时间因组织而异，例如棕色脂肪组织中胚胎第17天(E17) (BAT)，或在耳蜗生后第15天(P15)。在上一次资助期间，我们发现D2-T3峰值出现在 发育中的肝脏(P1-P2)，与C/EBPA诱导的肝母细胞成熟为肝细胞相一致； 此后，Dio2在肝脏中的表达被沉默。通过创建肝脏特异性Dio2KO小鼠(Alb-D2KO)，我们制作了 令人着迷的发现是D2-T3峰的失活会改变成人的肝脏转录组 小鼠，参与脂类代谢的基因表达减少。成年Alb-D2KO小鼠表现出 对肥胖、肝脏脂肪变性和高脂血症易感性降低的显著表型。怎么会有一个简短的 围产期D2-T3高峰期激活TH受体并产生这些变化？肝细胞经历了大量的 出生后的表观遗传重新编程，包括DNA甲基化状态的变化，我们现在 知道依赖于D2-T3。我们在成人白蛋白中发现了1,508个DNA高甲基化的CpG位点(H-位点)。 D2KO肝基因组。因此，围产期D2-T3峰值最终影响染色质堆积状态和 成人肝细胞的转录活性，减少1,525个基因的表达(RNA-seq)。建议数 研究旨在确定围产期肝脏D2-T3峰值启动的表观遗传学机制。这是 绝对新颖和令人兴奋，因为我们将了解脱碘酶介导的TH信号如何影响肝脏发育， 在成人器官中塑造基因表达。

ABSTRACT Thyroid hormones (TH) play a critical role in development. In the embryo, plasma T3 is relatively low but TH signaling can be enhanced by expression of Dio2, the deiodinase that mediates local T3 production. The timing of the D2-T3 activation varies among tissues, e.g. embryonic day 17 (E17) in brown adipose tissue (BAT), or post-natal day 15 in the cochlea (P15). During the last funding period we discovered a D2-T3 peak in the developing liver (P1-P2), coincidental with the C/EBPa-induced maturation of hepatoblasts to hepatocytes; Dio2 expression in liver is silenced thereafter. By creating a liver-specific Dio2KO mouse (Alb-D2KO) we made the fascinating discovery that inactivation of the D2-T3 peak modifies the liver transcriptome of the adult mouse, with reduced expression of genes involved in lipid metabolism. The adult Alb-D2KO mouse exhibits a dramatic phenotype of reduced susceptibility to obesity, liver steatosis and hyperlipidemia. How could a brief perinatal peak of D2-T3 activate TH receptors (TR) and produce these changes? Hepatocytes undergo massive postnatal epigenetic reprogramming, including changes in the DNA methylation status, some of which we now know depend on D2-T3. We identified 1,508 CpG sites of DNA hypermethylation (H-sites) in the adult Alb- D2KO liver genome. Thus, the perinatal D2-T3 peak ultimately affects the chromatin packing status and transcriptional activity of adult hepatocytes, reducing the expression of 1,525 genes (RNA-seq). The proposed studies are to identify the epigenetic mechanisms initiated by the perinatal D2-T3 peak in the liver. This is absolutely novel and exciting as we will learn how deiodinase-mediated TH signaling affects liver development, shaping gene expression in the adult organ.