Metabolic and xenobiotic control of thyroid hormone metabolism

摘要 甲状腺激素（TH）在发育中起着关键作用。在胚胎中，血浆T3相对较低， TH信号传导可以通过Dio 2的表达来增强，Dio 2是介导局部T3产生的脱碘酶。的 D2-T3激活的时间因组织而异，例如棕色脂肪组织中的胚胎第17天（E17） (BAT)或出生后15天（P15）。在上一个资助期间，我们发现了一个D2-T3高峰， 肝脏发育期（P1-P2），与C/EBPa诱导的肝母细胞向肝细胞的成熟相一致; 此后，肝脏中的Dio 2表达沉默。通过创建肝脏特异性Dio 2KO小鼠（Alb-D2 KO），我们 D2-T3峰的失活改变了成年人的肝脏转录组， 小鼠，与脂质代谢有关的基因表达减少。成年Alb-D2 KO小鼠表现出 显著降低了对肥胖、肝脂肪变性和高脂血症的易感性。一份简报怎么可能 围产期D2-T3高峰激活TH受体（TR）而产生这些变化？肝细胞经历大量 出生后的表观遗传重编程，包括DNA甲基化状态的变化，其中一些我们现在 知道取决于D2-T3。我们在成人白蛋白中鉴定了1,508个CpG位点的DNA超甲基化（H位点）， D2 KO肝脏基因组。因此，围产期D2-T3峰最终影响染色质堆积状态， 成年肝细胞的转录活性，减少1，525个基因的表达（RNA-seq）。拟议 研究的目的是确定由围产期肝脏中的D2-T3峰引发的表观遗传机制。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信号传导如何影响肝脏发育， 塑造成人器官中的基因表达。

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.