Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism

Совершенствование системы мотивации и стимулирования труда работников на примере ПАО "Ростелеком"

Объект ВКР - система мотивации и стимулирования персонала. Цель ВКР – изучение особенностей системы мотивации и стимулирования труда работников ПАО "Ростелеком" ,анализ применяемых методов мотивации и стимулирования и разработка рекомендаций. В результате исследования был разработан ряд мероприятий по совершенствованию системы мотивации и стимулирования персоналом.Object of WKR is a system of motivation and incentives for staff. The purpose of WKR is to study the features of the system of motivation and motivation of the work of PAO "Rostelecom" employees, analyze the methods of motivation and incentives used and develop recommendations. As a result of the research, a number of measures were developed to improve the system of motivation and incentives for staff

Role of CYP27A in cholesterol and bile acid metabolism

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being gen

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Fulminant hepatic failure in children

Fulminant hepatic failure is a clinical syndrome resulting from massive necrosis or severe func-tional impairment of hepatocytes. This paper reviews the etiology, pathogenesis and management of this condition. Orthotopic liver transplantation may achieve very high survival rates (50-70&#x0025;)

Extrahepatic biliary atresia

Extrahepatic biliary atresia is a disease of unknown cause, leading to profound cholestasis and progres-sive biliary cirrhosis. This paper discusses the diagnosis and management of this condition. It is stressed that bile flow can be established in 80-90&#x0025; of infants referred to surgery within 60 days after birth. Liver transplantation is essential for infants who are referred late (120 days of age or later); those whose initial portoenterostomy was not successful, and those who develop end-stage liver disease in spite of bile drain-age

Cloning and Molecular Characterization of the Ontogeny of a Rat Ileal Sodium-dependent Bile Acid Transporter

Sodium-dependent bile acid transport in the rat ileum is abruptly expressed at weaning. Degenerate oligonucleotides, based on amino acid sequence identities between the rat liver and hamster ileal transporters, were used to amplify a rat ileal probe. A 1.2-kb cDNA clone, which contains the full coding region (348 amino acids, 38 kD), was isolated by hybridization screening. In vitro translation yielded a 38kD protein which glycosylated to 48 kD. Sodium-dependent uptake of taurocholate was observed in oocytes injected with cRNA. Northern blot analysis revealed a 5.0-kb mRNA in ileum, kidney, and cecum. A 48-kD protein was detected in ileal brush border membranes and localized to the apical border of villus ileal enterocytes. mRNA and protein expression, which were negligible before weaning, increased dramatically at weaning. Nuclear transcription rates for the transporter increased 15-fold between postnatal days 7 and 28. The apparent molecular weight of the transporter also increased between days 19 and 28. In summary, the developmental regulation of the rat ileal sodium-dependent bile acid cotransporter is characterized by transcriptionally regulated increases in mRNA and protein levels at the time of weaning with changes in apparent molecular weight of the protein after weaning. (J. Clin. Invest. 1995. 95:745-754.) Key words: ileum- development- bile salt * transport transcriptio