Fu L , Yin J , Shi YB .

ZIA HD001901-23 Intramural NIH HHS, ZIA HD008858-10 Intramural NIH HHS, ZIA HD008858-11 Intramural NIH HHS

	Fig. 1. Xenopus intestinal metamorphosis serves as a model for studying adult organ-specific stem cell development in vertebrates. In premetamorphic tadpoles (e.g., at stage 51), the intestine has only a single fold, the typhlosole, where connective tissue is abundant, and is structurally similar to the mammalian embryonic intestine. At the metamorphic climax around stage 61, the vast majority of the larval epithelial cells undergo apoptosis (the open circles). A small fraction of the larval epithelial cells undergo dedifferentiation into cells that rapidly proliferate (EdU positive) and express the adult stem cell marker Lgr5 (black dots in the stage 61 diagram). By stage 66 (the end of metamorphosis), these cells differentiate to form a multiply folded epithelium surrounded by elaborate connective tissue and thick muscle layers. See (Okada et al., 2015) for EdU labeling and Lgr5 in situ hybridization.
	Fig. 2. Regulation of T3-inducible genes by TR during Xenopus development. In premetamorphic tadpoles, there is little T3 and TR is unliganded. The unliganded TR/RXR heterodimer binds to TREs in the target genes and recruits corepressor complexes such as the N-CoR-HDAC3 complex, resulting in the reduction in the levels of activation histone marks and increase of repression marks, and consequently gene repression. During metamorphosis, high levels of T3 leads to T3-binding to TR. Liganded TR/RXR recruits coactivator complexes such as SRC complexes as shown to disrupt chromatin and modify histones, leading to increased levels of activation histone marks and gene activation. N-CoR: nuclear corepressor, HDAC: histone deacetylase, SRC3: steroid receptor coactivator 3 (a histone acetyltransferase), p300: a histone acetyltransferase, PRMT1: protein arginine methyltransferase 1.
	Fig. 3. A positive feedback mechanism to enhance T3 activation of gene transcription through histone methylation. T3 induces the expression of Dot1L directly at the transcription level (Matsuura et al., 2012a) and PRMT1 indirectly via transcriptional activation of cMyc by TR in the developing stem cells (Fujimoto et al., 2012, Okada et al., 2017). Dot1L and PRMT1 in turn function as TR coactivators to increase local histone methylations to enhance transcription (Fujimoto et al., 2012, Wen et al., 2017a). It is worth pointing out that there has been no direct evidence for the recruitment of Dot1L to TREs, although PRMT1 has been shown to be recruited by TR to TREs in the presence of T3 during metamorphosis (Matsuda et al., 2009).

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