XB-ART-55494Gen Comp Endocrinol January 1, 2019; 271 91-96.
Involvement of epigenetic modifications in thyroid hormone-dependent formation of adult intestinal stem cells during amphibian metamorphosis.
Amphibian metamorphosis has long been used as model to study postembryonic development in vertebrates, a period around birth in mammals when many organs/tissues mature into their adult forms and is characterized by peak levels of plasma thyroid hormone (T3). Of particular interest is the remodeling of the intestine during metamorphosis. In the highly-related anurans Xenopus laevis and Xenopus tropicalis, this remodeling process involves larval epithelial cell death and de novo formation of adult stem cells via dedifferentiation of some larval cells under the induction of T3, making it a valuable system to investigate how adult organ-specific stem cells are formed during vertebrate development. Here, we will review some studies by us and others on how T3 regulates the formation of the intestinal stem cells during metamorphosis. We will highlight the involvement of nucleosome removal and a positive feedback mechanism involving the histone methyltransferases in gene regulation by T3 receptor (TR) during this process.
PubMed ID: 30472386
PMC ID: PMC6322911
Article link: Gen Comp Endocrinol
Genes referenced: bmp1 dot1l ep300 hdac3 lgr5 myc ncoa3 nodal prmt1
Article Images: [+] show captions
|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).|
References [+] :
Amano, Isolation of genes involved in intestinal remodeling during anuran metamorphosis. 1999, Pubmed, Xenbase