Adiposis is reputed as a twin disease of type 2 diabetes and
greatly harmful to human health. In order to understand the
molecular mechanisms of adiposis, the changes of physiological,
pathological, epigenetic and correlative gene expression were
investigated during the adiposis development of C57BL/6J mice
induced by long time (9 months) high-fat and high-sucrose diet
(HFSD) sustainably. The results showed that mRNA transcription
level of the Leptin, Glut4 and Glut2 genes have been obviously
changed, which exhibit a negative correlation with methylation
on their promoter DNA. The results also revealed that HFSD
induced higher level of DNA methyltransferase 1 (DNMT1) in fat
tissue might play important role in regulating the changes of
methylation pattern on Glut4 and Leptin genes, and which might
be one of the molecular mechanisms for the adiposis
development.
Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5’ UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies., S. Biswas, B. Feng, A. Thomas, S. Chen, E. Aref-Eshghi, B. Sadikovic, S. Chakrabarti., and Seznam literatury
IFN-γ is a pleiotropic cytokine crucial for both innate and adaptive immunity, which also plays a critical role in immunological surveillance of cancer. Genetic defects or gene silencing in the IFN-γ signal transduction pathways as well as in the expression of IFN-γ-regulated genes represent frequent mechanisms by which tumour cells can escape from immune responses. Epigenetic control of the IFN-γ signalling pathway activation associated with epigenetic changes in the corresponding regulatory gene regions, such as chromatin remodelling, histone acetylation and methylation, and DNA demethylation is frequently dysregulated in tumour cells. Epigenetic silencing of the IFN-γ regulatory pathway components, as well as of the IFN-γ-regulated genes crucial for tumour cell recognition or induction of anti-tumour immune responses, has been documented in various cancer models. Expression of both IFN-γ signalling pathway components and selected IFN-γ-regulated genes can be influenced by epigenetic modifiers, namely DNA methyltransferase and histone deacetylase inhibitors. These agents thus can mimic, restore, or boost the immunomodulatory effects of IFN-γ in tumour cells, which can contribute to their anti-tumour therapeutic efficacies and justifies their potential use in combined epigenetic therapy with immunotherapeutic approaches. and Corresponding author: Milan Reiniš
Increased plasma cholesterol levels are listed between the major
atherosclerosis risk factors. The final plasma cholesterol levels
result from the interplay between the genetic and environmental
(diet, physical activity) factors. Little is known, how dietary
factors influence epigenetics. We have analyzed, if an overgeneration feeding of rat with cholesterol influences total liverDNA methylation, and if total liver-DNA methylation differ
between the different rat strains (Prague hereditary
hypercholesterolemic rats, Prague hereditary hypertriglyceridemic
rats and Wistar Kyoto rats). The animals were feed with high fat
(additional 5 % over normal capacity) high cholesterol (2 %) diet
for 14 days. DNA methylation in the liver tissue in different
generations was analyzed using the liquid chromatography
coupled with tandem mass spectrometry. We have not observed
any significant changes in total liver-DNA methylation over the
9 generations of animals feed by fat/cholesterol enriched diet.
Additionally, there were no differences in DNA methylation
between different rat strains. In animal model, the dietary
changes (hypercholesterolemic diet) not significantly influence
the total DNA methylation status within the liver.
The fundamental biochemical processes of 5-methylcytosine (5-mC) synthesis, maintenance, conversion and removal determine the time and spatial pattern of DNA methylation. This has a strong effect on a plethora of physiological aspects of cellular metabolism. While the presence of 5-mC within the promoter region can silence gene expression, its derivative - 5-hydroxymethylcytosine exerts an opposite effect. Dysregulations in the metabolism of 5-mC lead to an altered DNA methylation pattern which is linked with a disrupted epigenome, and are considered to play a significant part in the etiology of several human diseases. A summary of recent knowledge about the molecular processes participating in DNA methylation pattern shaping is provided here., R. Murín, M. Abdalla, N. Murínová, J. Hatok, D. Dobrota., and Obsahuje bibliografii