Adult organ-specific stem cells are essential for organ homeostasis and repair in adult vertebrates. The intestine is one of the best-studied organs in this regard. The intestinal epithelium undergoes constant self-renewal throughout adult life across vertebrates through the proliferation and subsequent differentiation of the adult stem cells. This self-renewal system is established late during development, around birth, in mammals when endogenous thyroid hormone (T3) levels are high. Amphibian metamorphosis resembles mammalian postembryonic development around birth and is totally dependent upon the presence of high levels of T3. During this process, the tadpole intestine, predominantly a monolayer of larval epithelial cells, undergoes drastic transformation. The larval epithelial cells undergo apoptosis and concurrently, adult epithelial stem/progenitor cells develop de novo, rapidly proliferate, and then differentiate to establish a trough-crest axis of the epithelial fold, resembling the crypt-villus axis in the adult mammalian intestine. We and others have studied the T3-dependent remodeling of the intestine in Xenopus laevis. Here we will highlight some of the recent findings on the origin of the adult intestinal stem cells. We will discuss observations suggesting that liganded T3 receptor (TR) regulates cell autonomous formation of adult intestinal progenitor cells and that T3 action in the connective tissue is important for the establishment of the stem cell niche. We will further review evidence suggesting similar T3-dependent formation of adult intestinal stem cells in other vertebrates.

The drastic morphological changes of the tadpole are induced during the climax of anuran metamorphosis, when the concentration of endogenous thyroid hormone is maximal. The tadpole tail, which is twice as long as the body, shortens rapidly and disappears completely in several days. We isolated a cDNA clone, designated as Xl MMP-9TH, similar to the previously reported Xenopus laevis MMP-9 gene, and showed that their Xenopus tropicalis counterparts are located tandemly about 9 kb apart from each other in the genome. The Xenopus MMP-9TH gene was expressed in the regressing tail and gills and the remodeling intestine and central nervous system, and induced in thyroid hormone-treated tail-derived myoblastic cultured cells, while MMP-9 mRNA was detected in embryos. Three thyroid hormone response elements in the distal promoter and the first intron were involved in the upregulation of the Xl MMP-9TH gene by thyroid hormone in transient expression assays, and their relative positions are conserved between X. laevis and X. tropicalis promoters. These data strongly suggest that the MMP-9 gene was duplicated, and differentiated into two genes, one of which was specialized in a common ancestor of X. laevis and X. tropicalis to be expressed in degenerating and remodeling organs as a response to thyroid hormone during metamorphosis.

Objective. Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.Methods. MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6.Results. The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs.Conclusion. Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that results in progressive joint destruction and is difficult to treat effectively (1). Several lines of evidence suggest that synovial fibroblasts (SFs) are characterized by an activated and aggressive phenotype with a tumor-like appearance and play a major role in the pathogenesis of RA (2). RASFs produce a variety of proteolytic enzymes, such as matrix metalloproteinases (MMPs) and cathepsins. These enzymes degrade articular cartilage, which is mainly composed of an extracellular matrix (ECM) that consists of proteoglycans and type II collagen (3).The MMPs are a family of zinc-dependent endopeptidases that have the catalytic extracellular activity of degrading the ECM components in a neutral pH environment (4). Twenty-three human MMPs have been identified and grouped into different subfamilies, including the collagenases, gelatinases, stromelysins, matrilysins, and membrane-type MMPs, according to

Several matrix metalloproteinases (MMP) are induced by thyroid hormone (TH) during the climax of amphibian metamorphosis and play a pivotal role in the remodeling of the intestine and the regressing tail and gills by degrading the extracellular matrix (ECM). We compared MMP gene expression levels precisely by quantitative real-time reverse transcription-polymerase chain reaction. The expression of MMP genes increases prominently at Nieuwkoop and Faber (NF) stages 60, 60-61 and 62 in the intestine, gills and tail, respectively, when the drastic morphological changes start in each organ. Gene expression analysis in the TH-treated tadpoles and cell line revealed that MMP mRNAs are upregulated in response to TH quickly within several hours to low levels and then increase in a day to high levels. All TH-induced MMP genes have TH response elements (TREs). The presence of high affinity TREs in MMP genes correlates with early THinduction. Based on these results, we propose that TH stimulates the transcription of MMP genes through TREs within several hours to low levels and then brings about the main increase of mRNAs by TH-induced transcriptional factors, including TH receptor β , in a cell type-specific transcriptional environment.

Thyroid hormone (T(3)) plays an important role in regulating multiple cellular and metabolic processes, including cell proliferation, cell death, and energy metabolism, in vertebrates. Dysregulation of T(3) signaling results in developmental abnormalities, metabolic defects, and even cancer. We used T(3)-dependent Xenopus metamorphosis as a model to study how T(3) regulates transcription during vertebrate development. T(3) exerts its metamorphic effects through T(3) receptors (TR). TR recruits, in a T(3)-dependent manner, cofactor complexes that can carry out chromatin remodeling/histone modifications. Whether and how histone modifications change upon gene regulation by TR during vertebrate development is largely unknown. Here we analyzed histone modifications at T(3) target genes during intestinal metamorphosis, a process that involves essentially total apoptotic degeneration of the simple larval epithelium and de novo development of the adult epithelial stem cells, followed by their proliferation and differentiation into the complex adult epithelium. We demonstrated for the first time in vivo during vertebrate development that TR induces the removal of core histones at the promoter region and the recruitment of RNA polymerase. Furthermore, a number of histone activation and repression marks have been defined based on correlations with mRNA levels in cell cultures. Most but not all correlate with gene expression induced by liganded TR during development, suggesting that tissue and developmental context influences the roles of histone modifications in gene regulation. Our findings provide important mechanistic insights on how chromatin remodeling affects developmental gene regulation in vivo.

BackgroundThyroid hormone (T3) is important for adult organ function and vertebrate development. Amphibian metamorphosis is totally dependent on T3 and offers a unique opportunity to study how T3 controls postembryonic development in vertebrates. Earlier studies have demonstrated that TR mediates the metamorphic effects of T3 in Xenopus laevis. Liganded TR recruits histone modifying coactivator complexes to target genes during metamorphosis. This leads to nucleosomal removal and histone modifications, including methylation of histone H3 lysine (K) 79, in the promoter regions, and the activation of T3-inducible genes.ResultsWe 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.ConclusionsOur 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.

The authors present a case in which dysembryoplastic neuroepithelial tumors (DNETs) occurred in the cerebellum and brainstem of a 44-year-old woman. A magnetic resonance image of the brain revealed multiple cystic lesions in the right cerebellar hemisphere, vermis, tonsil, and brainstem. Partial removal of the tumors was performed. There were gray multinodular gelatinous lesions on the cerebellar hemisphere. Histologically, the tumors exhibited areas of multiple microcystic nodules in the cerebellar white matter, which were composed of oligodendroglia-like cells (OLCs), astrocytes, and neurons. There were multiple, variable nodules in the lesions, lined by OLCs. The adjacent cerebellar cortex displayed dysplastic features. Reduction of granule neurons and dislocation of Purkinje cells into the molecular layer were observed. The pathological profile of this patient agrees with that described by Daumas-Duport, et al., as a "dysembryoplastic neuroepithelial tumor."

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