Abstract
BackgroundThyroid 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 Xenopus tropicalis is known to be mediated by TRs. Many putative TR target genes have been identified previously. Among them is the tRNA methyltransferase Mettl1.ResultsWe 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.ConclusionsOur 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.
Highlights
Thyroid hormone (T3) plays important roles for organ development and regulates homeostasis and physiological function of many adult organs/tissues in vertebrates [1,2,3,4,5,6,7,8]
Our findings suggest that methyltransferase-like 1 (Mettl1) is activated early during intestinal remodeling to facilitate adult intestinal stem cell development and/or proliferation
Xenopus tropicalis Mettl1 is upregulated in the intestine during natural and T3‐induced metamorphosis Because of the causative role of T3 on amphibian metamorphosis, the identification of Mettl1 as a putative target of T3 receptors (TRs) from our earlier Chromatin immunoprecipitation (ChIP)-on-chip analysis of the tadpole intestine [40] suggests that Mettl1 is regulated by T3 during intestinal remodeling
Summary
Xenopus tropicalis Mettl is upregulated in the intestine during natural and T3‐induced metamorphosis Because of the causative role of T3 on amphibian metamorphosis, the identification of Mettl as a putative target of TR from our earlier ChIP-on-chip analysis of the tadpole intestine [40] suggests that Mettl is regulated by T3 during intestinal remodeling. ChIP assay using normal IgG as a negative control showed the expected background signal both in the presence or absence of T3 (Fig. 4d) These results indicate that liganded TR is bound to Mettl TRE in tadpole intestine and enhances local histone modification and RNA polymerase II recruitment to activate the Mettl promoter during T3-induced metamorphosis. TR binding, histone H3K79 methylation, and RNA polymerase II recruitment all peak at the climax of metamorphosis when drastic intestinal remodeling, larval epithelial cell death and adult epithelial stem cell formation/proliferation take place These data suggest that the endogenous TRs bind to Mettl TRE region to regulate local histone modifications and recruit RNA polymerase II in the presence of T3, leading to the activation of Mettl expression to facilitate intestinal remodeling. It would be of interest in the future to test this by adopting gene editing approaches [64, 65] to knock out Mettl and study its effect on Xenopus tropicalis metamorphosis
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