Histone H3K79 methyltransferase Dot1L is directly activated by thyroid hormone receptor during Xenopus metamorphosis

We show that Dot1L, the only histone methyltransferase capable of methylating H3K79, is directly regulated by TR via binding to a T3 response element in the promoter region during metamorphosis in Xenopus tropicalis, a highly related species of Xenopus laevis. We further show that Dot1L expression in both the intestine and tail correlates with the transformation of the organs.Our findings suggest that TR activates Dot1L, which in turn participates in metamorphosis through a positive feedback to enhance H3K79 methylation and gene activation by liganded TR.Thyroid hormone (T3) is important for proper development and normal physiology of many adult organs/tissues in vertebrates [1,2]. Sever T3 deficiency during human development leads to the formation of human cretins, who are short in stature and severely mentally retarded [3]. The most critical period of T3 action appears to be the several months around birth, the so-called postembryonic period, when T3 levels are high [1]. It has been difficult to study how T3 affects mammalian postembryonic development due to the lack of easily manipulatable models.Metamorphosis in anurans such as Xenopus laevis or tropicalis mimics mammalian postembryonic development [1,4]. This process involves distinct changes in different organs and tissues [4,5]. The larval specific organs, such as the tail and gills, are totally resorbed during metamorphosis, while the adult specific ones, such as the limbs, develop de novo. Most of the organs/tissues are present in both tadpoles and frogs but are drastically remodeled during metamorphosis. For example, the animal intestine involves apoptotic degeneration of larval epithelial cells and concurrent de novo formation of adult stem cells to eventually develop the adult epithelium resembling that in mammals [6,7]. Interestingly, all such diverse changes during amphibian metamorphosis are totally dependent on T3 [5]. T3 can regulate transcription through T3 receptor (TR). TRs can form heterodimers