Na Wonho, Fu Liezhen, Luu Nga, Shi Yun-Bo
Section on Molecular Morphogenesis, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 USA.
Cell Biosci. 2020 May 4;10:60. doi: 10.1186/s13578-020-00423-1. eCollection 2020.
Thyroid hormone (T3) plays an important role in vertebrate development. Compared to the postembryonic development of uterus-enclosed mammalian embryos, T3-dependent amphibian metamorphosis is advantageous for studying the function of T3 and T3 receptors (TRs) during vertebrate development. The effects of T3 on the metamorphosis of anurans such as is known to be mediated by TRs. Many putative TR target genes have been identified previously. Among them is the tRNA methyltransferase Mettl1.
We studied the regulation of Mettl1 gene by T3 during intestinal metamorphosis, a process involves near complete degeneration of the larval epithelial cells via apoptosis and de novo formation of adult epithelial stem cells and their subsequent proliferation and differentiation. We observed that Mettl1 was activated by T3 in the intestine during both natural and T3-induced metamorphosis and that its mRNA level peaks at the climax of intestinal remodeling. We further showed that Mettl1 promoter could be activated by liganded TR via a T3 response element upstream of the transcription start site in vivo. More importantly, we found that TR binding to the TRE region correlated with the increase in the level of H3K79 methylation, a transcription activation histone mark, and the recruitment of RNA polymerase II by T3 during metamorphosis.
Our findings suggest that Mettl1 is activated by liganded TR directly at the transcriptional level via the TRE in the promoter region in the intestine during metamorphosis. Mettl1 in turn regulate target tRNAs to affect translation, thus facilitating stem cell formation and/or proliferation during intestinal remodeling.
甲状腺激素（T3）在脊椎动物发育中起重要作用。与子宫内发育的哺乳动物胚胎的胚后发育相比，依赖T3的两栖动物变态对于研究脊椎动物发育过程中T3和T3受体（TRs）的功能具有优势。已知T3对诸如无尾两栖类动物变态的影响是由TRs介导的。先前已经鉴定出许多假定的TR靶基因。其中包括tRNA甲基转移酶Mettl1。
我们研究了在肠道变态过程中T3对Mettl1基因的调控，该过程涉及幼虫上皮细胞通过凋亡几乎完全退化以及成体上皮干细胞的重新形成及其随后的增殖和分化。我们观察到，在自然变态和T3诱导的变态过程中，Mettl1在肠道中均被T3激活，并且其mRNA水平在肠道重塑的高潮时达到峰值。我们进一步表明，在体内，配体化的TR可以通过转录起始位点上游的T3反应元件激活Mettl1启动子。更重要的是，我们发现TR与TRE区域的结合与H3K79甲基化水平的增加相关，H3K79甲基化是一种转录激活组蛋白标记，并且在变态过程中T3会募集RNA聚合酶II。
我们的研究结果表明，在变态过程中，Mettl1在肠道中通过启动子区域的TRE被配体化的TR直接在转录水平上激活。Mettl1进而调节靶tRNA以影响翻译，从而在肠道重塑过程中促进干细胞的形成和/或增殖。
