Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study

Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = −0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.     

KSHV latent protein LANA2 inhibits sumo2 modification of p53

Tumor suppressor p53 plays a crucial antiviral role and targeting of p53 by viral proteins is a common mechanism involved in virus oncogenesis. The activity of p53 is tightly regulated at the post-translational levels through a myriad of modifications. Among them, modification of p53 by SUMO has been associated with the onset of cellular senescence. Kaposi´s sarcoma-associated herpesvirus (KSHV) expresses several proteins targeting p53, including the latent protein LANA2 that regulates polyubiquitylation and phosphorylation of p53. Here we show that LANA2 also inhibits the modification of p53 by SUMO2. Furthermore, we show that the reduction of p53-SUMO2 conjugation by LANA2, as well as the p53-LANA2 interaction, both require the SUMOylation of the viral protein and its interaction with SUMO or SUMOylated proteins in a non-covalent manner. Finally, we show that the control of p53-SUMO2 conjugation by LANA2 correlates with its ability to inhibit SUMO2- and type I interferon-induced senescence. These results highlight the importance of p53 SUMOylation in the control of virus infection and suggest that viral oncoproteins could contribute to viral infection and cell transformation by abrogating p53 SUMOylation.     

Reorganization of the nuclear lamina and cytoskeleton in adipogenesis

A thorough understanding of fat cell biology is necessary to counter the epidemic of obesity. Although molecular pathways governing adipogenesis are well delineated, the structure of the nuclear lamina and nuclear-cytoskeleton junction in this process are not. The identification of the ‘linker of nucleus and cytoskeleton’ (LINC) complex made us consider a role for the nuclear lamina in adipose conversion. We herein focused on the structure of the nuclear lamina and its coupling to the vimentin network, which forms a cage-like structure surrounding individual lipid droplets in mature adipocytes. Analysis of a mouse and human model system for fat cell differentiation showed fragmentation of the nuclear lamina and subsequent loss of lamins A, C, B1 and emerin at the nuclear rim, which coincides with reorganization of the nesprin-3/plectin/vimentin complex into a network lining lipid droplets. Upon 18 days of fat cell differentiation, the fraction of adipocytes expressing lamins A, C and B1 at the nuclear rim increased, though overall lamin A/C protein levels were low. Lamin B2 remained at the nuclear rim throughout fat cell differentiation. Light and electron microscopy of a subcutaneous adipose tissue specimen showed striking indentations of the nucleus by lipid droplets, suggestive for an increased plasticity of the nucleus due to profound reorganization of the cellular infrastructure. This dynamic reorganization of the nuclear lamina in adipogenesis is an important finding that may open up new venues for research in and treatment of obesity and nuclear lamina-associated lipodystrophy.     

synMuv B proteins antagonize germline fate in the intestine and ensure C. elegans survival

Previous studies demonstrated that a subset of synMuv B mutants ectopically misexpress germline-specific P-granule proteins in their somatic cells, suggesting a failure to properly orchestrate a soma/germline fate decision. Surprisingly, this fate confusion does not affect viability at low to ambient temperatures. Here, we show that, when grown at high temperature, a majority of synMuv B mutants irreversibly arrest at the L1 stage. High temperature arrest (HTA) is accompanied by upregulation of many genes characteristic of germ line, including genes encoding components of the synaptonemal complex and other meiosis proteins. HTA is suppressed by loss of global regulators of germline chromatin, including MES-4, MRG-1, ISW-1 and the MES-2/3/6 complex, revealing that arrest is caused by somatic cells possessing a germline-like chromatin state. Germline genes are preferentially misregulated in the intestine, and necessity and sufficiency tests demonstrate that the intestine is the tissue responsible for HTA. We propose that synMuv B mutants fail to erase or antagonize an inherited germline chromatin state in somatic cells during embryonic and early larval development. As a consequence, somatic cells gain a germline program of gene expression in addition to their somatic program, leading to a mixed fate. Somatic expression of germline genes is enhanced at elevated temperature, leading to developmentally compromised somatic cells and arrest of newly hatched larvae.     

Geminin escapes degradation in G1 of mouse pluripotent cells and mediates the expression of Oct4, Sox2, and Nanog

Geminin is an essential cell-cycle protein that is only present from S phase to early mitosis in metazoan somatic cells. Genetic ablation of geminin in the mouse results in preimplantation embryonic lethality because pluripotent cells fail to form and all cells differentiate to trophoblast. Here we show that geminin is present in G1 phase of mouse pluripotent cells in contrast to somatic cells, where anaphase-promoting complex/cyclosome (APC/C)-mediated proteasomal destruction removes geminin in G1. Silencing geminin directly or by depleting the APC/C inhibitor Emi1 causes loss of stem cell identity and trophoblast differentiation of mouse embryonal carcinoma and embryonic stem cells. Depletion of cyclins A2 or B1 does not induce this effect, even though both of these APC/C substrates are also present during G1 of pluripotent cells. Crucially, geminin antagonizes the chromatin-remodeling protein Brg1 to maintain expression of Oct4, Sox2, and Nanog. Our results define a pluripotency pathway by which suppressed APC/C activity protects geminin from degradation in G1, allowing sustained expression of core pluripotency factors. Collectively, these findings link the cell cycle to the pluripotent state but also raise an unexplained paradox: How is cell-cycle progression possible in pluripotent cells when oscillations of key regulatory proteins are lost?     

Hemorrhagic Fever with Renal Syndrome Complicated by Orchitis

Hemorrhagic fever with renal syndrome (HFRS) is a disease caused by viruses of the family Bunyaviridae,genus Hantavirus.HFRS from Dobrava virus (DOBV) is a seldom reported disease in Albania.Clinically HFRS is manifested as mild,moderate,or severe.Therefore,the number of cases of Hantavirus' infection may be underestimated,and should be included in the differential diagnosis of many acute infections,hematologic diseases,acute abdominal diseases and renal diseases complicated by acute renal failure.We report...     

Binding immunoglobulin protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice

Introduction  

Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies.     

Coelomogenesis during the abbreviated development of the echinoid Heliocidaris erythrogramma and the developmental origin of the echinoderm pentameral body plan

The development of the coeloms is described in an echinoid with an abbreviated larval development and shows the early morphogenesis of the coeloms of the adult stage. The development is described from images obtained by laser scanning confocal microscopy. The development in Heliocidaris erythrogramma is asymmetric with a larger left coelom forming on the larval-left side and a smaller right coelom forming on the larval-right side. The right coelom forms after the development of the left coelom is well advanced. The hydrocoele forms from the anterior part of the left coelom. The five lobes of the hydrocoele from which the pentamery of the adult derives take shape on the outer, distal wall of the anterior part of the left coelom. The hydrocoele separates from the more posterior part of the left coelom, which becomes the left posterior coelom. The lobes of the hydrocoele are named, based on the site of the connexion of the stone canal to the hydrocoele. The mouth is assumed to form by penetration through only the outer, distal wall of the hydrocoele and the ectoderm. Both larval and adult polarities are evident in this larva. A comparison with coelomogenesis in the asteroid Parvulastra exigua, which also has an abbreviated development, leads to predictions of homology between the echinoderm and chordate phyla that do not require the hypothesis of a dorsoventral inversion event in chordates.     

Structural components and morphogenetic mechanics of the zebrafish yolk extension, a developmental module

The yolk extension (YE) appears to be a novel developmental module that has been inserted into the phylotypic period of teleostean development, specifically in the order Cypriniformes. The zebrafish YE informs the study of morphogenetic movements reshaping ventral tissues because (1) this trait is easily visible, so disruptions are easy to score; (2) its ontogenesis occurs quickly; and (3) the yolk cell isolates the tissues elongating the ventrum from the rest of the embryo, serving as a three-dimensional in vivo "tissue culture." We determined that three histological compartments comprise the structural components of the YE: (1) the internal yolk cell; (2) the mesendodermal mantle external to the yolk cell; and (3) the external embryonic integument, consisting of an embryonic epidermis plus enveloping layer cells. These structural components interact with one another in a hierarchical manner, resulting in the morphogenesis of the elongated and tubular embryonic zebrafish ventrum as the cylindrical YE forms. Time-lapse videomicroscopy and experimental manipulation show that the yolk mass is a cohesive, viscoelastic foam, which resists compression. Moreover, as the mesodermal mantle participates in tubulation of the posterior trunk, Kupffer's Vesicle, the organ of laterality in teleosts, separates from the posterior pole of the yolk syncytial layer. Additionally, the embryonic integument becomes contractile over the posterior yolk cell, constricting the yolk mass to form the YE. These findings constitute an initial assessment of the morphogenetic mechanics underlying formation of the YE developmental module in zebrafish.