Endometriosis is characterized by the presence of endometrial-like tissue located outside the uterine cavity. Recent evidence suggests that endometriosis may be an epigenetic disease, as well as an estrogen-dependent disease. Based on the unique steroid hormone receptor expression profile observed in endometriotic lesions as compared to eutopic endometrium, the present study aimed to gain further insight into the DNA methylation patterns of alternative promoters of the steroid receptor genes ESR1, ESR2 and PGR in intestinal deep endometriosis, one of the most aggressive forms of endometriosis. The DNA methylation patterns were evaluated by methylation-specific polymerase chain reaction (MS-PCR) after bisulfite modification in 44 endometriotic tissues as well as in 7 matched eutopic endometrium. No differences in the DNA methylation were observed for the ESR1 and ESR2 genes. Methylation of the PGR gene was observed in 39% (17 out of 44) and 19% (7 out of 37) of the cases in the promoter regions B (PGRB) and A (PGRA), respectively. Both PGR promoter regions were methylated in 3 cases. PGRB methylated alleles were detected exclusively in the endometriotic lesions when compared to the eutopic endometrium obtained from the same patient. The effect of DNA methylation in inhibiting the PGR gene expression was corroborated by immuno-staining for PgR protein in a subset of tissue samples. The present study demonstrated that epigenetic changes occur in both promoter regions of the PGR gene in intestinal endometriosis. Since eutopic and ectopic tissues do not respond sufficiently to progesterone in women with endometriosis, further study is necessary to evaluate the effect of epigenetic alterations in progesterone-resistance in this enigmatic disease.
and 3 The Jackson Laboratory, Bar Harbor, ME Pseudoxanthoma elasticum (PXE) is characterized by systemic connective tissue mineralization caused by loss-of-function mutations in the ABCC6 gene. The currently available Abcc6 -/mice represent a useful model system to study PXE pathophysiology and to explore potential treatment modalities. Abcc6 -/rats would, however, provide a more suitable model for metabolic studies and specifically unravel the role of PPi and Pi homeostasis in PXE. We have therefore generated Abcc6 -/rats using zinc finger nuclease (ZFN), targeting the first coding exon of Abcc6. Five germline transmission competent rats were identified that harbored deletions ranging from 10 to 23 bp surrounding the ZFN target site. These mutations were predicted to cause out-of-frame translation and induce a premature stop codon. Immunostaining of liver sections using a rat ABCC6 specific antibody showed plasma membrane expression in basolateral surface of hepatocytes in wild type rats and complete absence in the homozygous mutant rats. As a consequence of ABCC6 deficiency, complete necropsy of three mutant lines demonstrated ectopic mineralization in the muzzle skin, eyes, and arterial blood vessels in the knockout rats, features mimicking human PXE. Mineralization in the dermal sheath of vibrissae was also monitored by small animal CT scanning, which allows noninvasive evaluation of the mineralization process. Similar to human PXE patients, clinical chemistry did not reveal differences in serum calcium and phosphorus levels between wild type and Abcc6 -/rats. However, plasma PPi level was significantly reduced (<60%) in the Abcc6 -/rats as compared to wild type rats, leading to a significantly lower PPi/Pi ratio. Since PPi is physiologically a potent antimineralization factor, the results highlight the role of PPi in the context of the PPi/Pi ratio in the novel Abcc6 -/rat model due to loss-of-function of ABCC6, leading to ectopic mineralization in PXE.
Skin microbiome has an important role as host guardian, contributing to several physiological functions including skin barrier maintenance and protection against pathogenic microorganisms. Skin microbiome varies according to geography, cultural and ethnic conditions and all these parameters interfere in skin-microorganism communication. In this study, we identified the skin microbiome of a South American group and studied its behavior when associated with a 3D skin model. Both metagenomic and transcriptomic evaluations were performed to understand the interaction between the microbiome and the skin in vitro. Altogether, our results suggest that although it is feasible to cultivate a wild type microbiome with a 3D skin model, it generates some artifacts. Curiously, these artifacts mimic some in vitro models found in the literature and raises the debate about the biological relevance of some conclusions that have been made in a fast growing field.
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