Abstract
Epigenetic modifications of histones are emerging as key factors in gene regulation by diverse transcription factors. Their roles during vertebrate development and pathogenesis are less clear. The causative effect of thyroid hormone (T3) on amphibian metamorphosis and the ability to manipulate this process for molecular and genetic studies have led to the demonstration that T3 receptor (TR) is necessary and sufficient for Xenopus metamorphosis, a process that resembles the postembryonic development (around birth) in mammals. Importantly, analyses during metamorphosis have provided some of the first in vivo evidence for the involvement of histone modifications in gene regulation by TR during vertebrate development. Furthermore, expression and functional studies suggest that various histone modifying epigenetic enzymes likely participate in multiple steps during the formation of adult intestinal stem cells during metamorphosis. The similarity between intestinal remodeling and the maturation of the mammalian intestine around birth when T3 levels are high suggests conserved roles for the epigenetic enzymes in mammalian adult intestinal stem cell development and/or proliferation.Electronic supplementary materialThe online version of this article (doi:10.1186/2045-3701-4-73) contains supplementary material, which is available to authorized users.
Highlights
The adult mammalian intestine has long been served as a model system to study the property and function of adult organ-specific stem cells due to the constant selfrenewal of the intestinal epithelium throughout adult life [1,2]
By using recombinant organ-cultures made of wild type and transgenic animals expressing GPF, we have shown that adult epithelial stem cells formed upon T3 treatment of the organ cultures of premetamorphic intestine originate from the larval epithelium [8]
Expression of dominant positive TR (dpTR) in the larval epithelium alone is able to induce the dedifferentiation of larval epithelial cells to upregulate sonic hedgehog gene, which is highly expressed in the proliferating adult epithelial progenitor/stem cells. Such cells fail to upregulate the expression of two well-known markers of the adult mammalian intestinal stem cells and the formation of the stem cells expressing such markers requires the expression of dpTR in the rest of the intestinal organ culture, i.e., the nonepithelium [10], consistent with earlier studies showing an requirement for cell-cell interaction during the formation of the adult intestine [28,32]. These findings suggest that T3 receptor (TR)-mediated gene regulation in both the epithelium and the non-epithelium are required for stem cell development, with the T3-induced gene expression changes in the non-epithelium likely contribute to the formation of the stem cell niche for the developing adult stem cells
Summary
The adult mammalian intestine has long been served as a model system to study the property and function of adult organ-specific stem cells due to the constant selfrenewal of the intestinal epithelium throughout adult life [1,2]. To investigate the role of TR in adult intestinal stem cell development, we have made use of recombinant organ-cultures consisting of tissues from wild type and transgenic animals expressing a dominant positive TR (dpTR) under the control of a heat shock-inducible promoter [10,22].
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