Thyroid hormone directly activates mitochondrial fission process 1 (Mtfp1) gene transcription during adult intestinal stem cell development and proliferation in Xenopus tropicalis.

Thyroid hormone (T3) regulates vertebrate development via T3 receptors (TRs). T3 level peaks during postembryonic development, a period around birth in mammals or metamorphosis in anurans. Anuran metamorphosis offers many advantages for studying T3 and TR function in vivo largely because of its total dependent on T3 and the dramatic changes affecting essentially all organs/tissues that can be easily manipulated. Earlier studies have shown that TRs are both necessary and sufficient for mediating the metamorphic effects of T3. Many candidate TR target genes have been identified during Xenopus tropicalis intestinal metamorphosis, a process that involves apoptotic degeneration of most of the larval epithelial cells and de novo development of adult epithelial stem cells. Among these putative TR target genes is mitochondrial fission process 1 (Mtfp1), a nuclear-encoded mitochondrial gene. Here, we report that Mtfp1gene expression peaks in the intestine during both natural and T3-induced metamorphosis when adult epithelial stem cell development and proliferation take place. Furthermore, we show that Mtfp1 contains a T3-response element within the first intron that is bound by TR to mediate T3-induced local histone H3K79 methylation and RNA polymerase recruitment in the intestine during metamorphosis. Additionally, we demonstrate that the Mtfp1 promoter can be activated by T3 in a reconstituted frog oocyte system in vivo and that this activation is dependent on the intronic TRE. These findings suggest that T3 activates Mtfp1 gene directly via the intronic TRE and that Mtfp1 in turn facilitate adult intestinal stem cell development/proliferation by affecting mitochondrial fission process.