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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
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PMID:Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. 1758 7

Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.
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PMID:NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. 1769 90

Sir2 protein deacetylases (or sirtuins) catalyze NAD+-dependent conversion of epsilon-amino-acetylated lysine residues to deacetylated lysine, nicotinamide, and 2'-O-acetyl-ADP-ribose. Small-molecule modulation of sirtuin activity might treat age-associated diseases, such as type II diabetes, obesity, and neurodegenerative disorders. Here, we have evaluated the mechanisms of sirtuin inhibition of histone peptides containing thioacetyl or mono-, di-, and trifluoroacetyl groups at the epsilon-amino of lysine. Although all substituted peptides yielded inhibition of the deacetylation reaction, the thioacetyl-lysine peptide exhibited exceptionally potent inhibition of sirtuins Sirt1, Sirt2, Sirt3, and Hst2. Using Hst2 as a representative sirtuin, the trifluoroacetyl-lysine peptide displayed competitive inhibition with acetyl-lysine substrate and yielded an inhibition constant (Kis) of 4.8 microM, similar to its Kd value of 3.3 microM. In contrast, inhibition by thioacetyl-lysine peptide yielded an inhibition constant (Kis) of 0.017 microM, 280-fold lower than its Kd value of 4.7 microM. Examination of thioacetyl-lysine peptide as an alternative sirtuin substrate revealed conserved production of deacetylated peptide and 1'-SH-2'-O-acetyl-ADP-ribose. Pre-steady-state and steady-state analysis of the thioacetyl-lysine peptide showed rapid nicotinamide formation (4.5 s-1) but slow overall turnover (0.0024 s-1), indicating that the reaction stalled at an intermediate after nicotinamide formation. Mass spectral analysis yielded a novel species (m/z 1754.3) that is consistent with an ADP-ribose-peptidyl adduct (1'-S-alkylamidate) as the stalled intermediate. Additional experiments involving solvent isotope effects, general base mutational analysis, and density functional calculations are consistent with impaired 2'-hydroxyl attack on the ADP-ribose-peptidyl intermediate. These results have implications for the development of mechanism-based inhibitors of Sir2 deacetylases.
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PMID:Mechanism-based inhibition of Sir2 deacetylases by thioacetyl-lysine peptide. 1802 80

The advent of the epigenetic era has sparked a new frontier in molecular research and the understanding of how development can be regulated beyond direct alterations of the genome. Thus far, the focal point of epigenetic regulation during development has been chromatin modifications that control differential gene expression by DNA methylation and histone alterations. But what of events that alter gene expression without direct influence on the DNA itself? The present review focuses on epigenetic pathways regulating development from oogenesis to organogenesis and back that do not involve methylation of cytosine in DNA. We discuss target components of epigenetic modification such as organelle development, compartmentalisation of maternal factors and molecular mediators in the oocyte and how these factors acting during oogenesis impact on later development. Epigenetic regulation of development, be it via cytosine methylation or not, has wide-ranging effects on the subsequent success of a pregnancy and the intrinsic health of offspring. Perturbations in epigenetic regulation have been clearly associated with disease states in adult offspring, including Type II diabetes, hypertension, cancers and infertility. A clear understanding of all epigenetic mechanisms is paramount when considering the increased use of assisted reproductive techniques and the risks associated with their use.
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PMID:Epigenetic regulation during mammalian oogenesis. 1815 1

Intrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type 2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications of developmental genes. To determine whether epigenetic modifications may play a role in the development of adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a pancreatic and duodenal homeobox 1 transcription factor critical for beta cell function and development, which develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR beta cells and underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by loss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and the corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4) was demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic changes and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes in adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we believe they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset of disease in adulthood.
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PMID:Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. 1846 33

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary beta-cells and hepatocytes freshly isolated from mice lacking Hnf1alpha, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a-/- cells inactive endogenous Hnf1alpha-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1alpha-targets in Hnf1a-/- cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease.
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PMID:Targeted deficiency of the transcriptional activator Hnf1alpha alters subnuclear positioning of its genomic targets. 1849 63

Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link between epigenetic changes such as chromatin histone lysine methylation and gene expression. We hypothesized that H3 lysine-9 tri-methylation (H3K9me3), a key repressive and relatively stable epigenetic chromatin mark, may be involved in metabolic memory. This was tested in vascular smooth muscle cells (VSMC) derived from type 2 diabetic db/db mice. These cells exhibit a persistent atherogenic and inflammatory phenotype even after culture in vitro. ChIP assays showed that H3K9me3 levels were significantly decreased at the promoters of key inflammatory genes in cultured db/db VSMC relative to control db/+ cells. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase Suv39h1 were also reduced in db/db VSMC. Furthermore, db/db VSMC were hypersensitive to TNF-alpha inflammatory stimulus, which induced dramatic and sustained decreases in promoter H3K9me3 and Suv39h1 occupancy. Recruitment of corepressor HP1alpha was also reduced under these conditions in db/db cells. Overexpression of SUV39H1 in db/db VSMC reversed this diabetic phenotype. Conversely, gene silencing of SUV39H1 with shRNAs in normal human VSMC (HVSMC) increased inflammatory genes. HVSMC cultured in high glucose also showed increased inflammatory gene expression and decreased H3K9me3 at their promoters. These results demonstrate protective roles for H3K9me3 and Suv39h1 against the preactivated state of diabetic VSMC. Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype of diabetic cells.
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PMID:Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. 1857 79

Both intrauterine and postnatal environments contribute to diabetes risk. A recent paper highlights epigenetic mechanisms underlying beta cell dysfunction associated with intrauterine growth retardation, including repressive histone modification and DNA methylation during postnatal life. Thus, intrauterine stress can initiate a disturbing epigenetic cascade of progressive transcriptional repression linked to beta cell failure.
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PMID:Diabetes risk begins in utero. 1859 Jun 86

Histone lysine and arginine residues are subject to a wide array of post-translational modifications including methylation, citrullination, acetylation, ubiquitination, and sumoylation. The combinatorial action of these modifications regulates critical DNA processes including replication, repair, and transcription. In addition, enzymes that modify histone lysine and arginine residues have been correlated with a variety of human diseases including arthritis, cancer, heart disease, diabetes, and neurodegenerative disorders. Thus, it is important to fully understand the detailed kinetic and chemical mechanisms of these enzymes. Here, we review recent progress towards determining the mechanisms of histone lysine and arginine modifying enzymes. In particular, the mechanisms of S-adenosyl-methionine (AdoMet) dependent methyltransferases, FAD-dependent demethylases, iron dependent demethylases, acetyl-CoA dependent acetyltransferases, zinc dependent deacetylases, NAD(+) dependent deacetylases, and protein arginine deiminases are covered. Particular attention is paid to the conserved active-site residues necessary for catalysis and the individual chemical steps along the catalytic pathway. When appropriate, areas requiring further work are discussed.
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PMID:Chemical mechanisms of histone lysine and arginine modifications. 1860 28

Diabetic cardiomyopathy is characterized by structural alterations such as cardiomyocyte hypertrophy, necrosis and focal fibrosis. Hyperglycemia-induced oxidative damage may play an important role in this pathogenetic process. Recent studies have shown that poly (ADP-ribose) polymerase (PARP) is activated in response to oxidative stress and cellular damage as well, plays a role in gene expression. This study investigated mechanisms of diabetes-induced, PARP-mediated development of structural alterations in the heart. Two models of diabetic complications were used to determine the role of PARP in oxidative stress, cardiac hypertrophy and fibrosis in the heart. PARP-1 knockout (PARP(-/-)) mice and their respective controls were fed a 30% galactose diet while male Sprague-Dawley rats were injected with streptozotocin and subsequently treated with PARP inhibitor 3-aminobenzamide (ABA). The in vivo experiments were verified in in vitro models which utilized both neonatal cardiomyocytes and endothelial cells. Our results indicate that hyperhexosemia caused upregulation of extracellular matrix proteins in association with increased transcriptional co-activator p300 levels, cardiomyocyte hypertrophy and increased oxidative stress. These pathogenetic changes were not observed in the PARP(-/-) mice and diabetic rats treated with ABA. Furthermore, these changes appear to be influenced by histone deacetylases. Similar results were obtained in isolated cardiomyocytes and endothelial cells. This study has elucidated for the first time a PARP-dependent, p300-associated pathway mediating the development of structural alterations in the diabetic heart.
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PMID:PARP mediates structural alterations in diabetic cardiomyopathy. 1865 44


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