Topoisomerase II beta targets DNA crossovers formed between distant homologous sites to induce chromatin opening

Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T- segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be derived from distant sites on the same chromosome. Due to lack of proper methodology, however, no direct evidence has been described so far. The beta isoform of topo II (topo II beta) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. Here we devise a genome-wide mapping technique (eTIP-seq) for topo II beta target sites that can measure the genomic distance between G- and T-segments. It revealed that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that topo II beta acts on crossovers to unknot the intertwined DSP sites, leading to chromatin decondensation

Evolution in an oncogenic bacterial species with extreme genome plasticity: Helicobacter pylori East Asian genomes

<p>Abstract</p> <p>Background</p> <p>The genome of <it>Helicobacter pylori</it>, an oncogenic bacterium in the human stomach, rapidly evolves and shows wide geographical divergence. The high incidence of stomach cancer in East Asia might be related to bacterial genotype. We used newly developed comparative methods to follow the evolution of East Asian <it>H. pylori </it>genomes using 20 complete genome sequences from Japanese, Korean, Amerind, European, and West African strains.</p> <p>Results</p> <p>A phylogenetic tree of concatenated well-defined core genes supported divergence of the East Asian lineage (hspEAsia; Japanese and Korean) from the European lineage ancestor, and then from the Amerind lineage ancestor. Phylogenetic profiling revealed a large difference in the repertoire of outer membrane proteins (including <it>oipA</it>, <it>hopMN</it>, <it>babABC</it>, <it>sabAB </it>and <it>vacA-2</it>) through gene loss, gain, and mutation. All known functions associated with molybdenum, a rare element essential to nearly all organisms that catalyzes two-electron-transfer oxidation-reduction reactions, appeared to be inactivated. Two pathways linking acetyl~CoA and acetate appeared intact in some Japanese strains. Phylogenetic analysis revealed greater divergence between the East Asian (hspEAsia) and the European (hpEurope) genomes in proteins in host interaction, specifically virulence factors (<it>tipα</it>), outer membrane proteins, and lipopolysaccharide synthesis (human Lewis antigen mimicry) enzymes. Divergence was also seen in proteins in electron transfer and translation fidelity (<it>miaA, tilS</it>), a DNA recombinase/exonuclease that recognizes genome identity (<it>addA</it>), and DNA/RNA hybrid nucleases (<it>rnhAB</it>). Positively selected amino acid changes between hspEAsia and hpEurope were mapped to products of <it>cagA</it>, <it>vacA</it>, <it>homC </it>(outer membrane protein), <it>sotB </it>(sugar transport), and a translation fidelity factor (<it>miaA</it>). Large divergence was seen in genes related to antibiotics: <it>frxA </it>(metronidazole resistance), <it>def </it>(peptide deformylase, drug target), and <it>ftsA </it>(actin-like, drug target).</p> <p>Conclusions</p> <p>These results demonstrate dramatic genome evolution within a species, especially in likely host interaction genes. The East Asian strains appear to differ greatly from the European strains in electron transfer and redox reactions. These findings also suggest a model of adaptive evolution through proteome diversification and selection through modulation of translational fidelity. The results define <it>H. pylori </it>East Asian lineages and provide essential information for understanding their pathogenesis and designing drugs and therapies that target them.</p

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million personyears of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eG FR values 105 mL.min(-1).1.73 m(-2), compared with those with eG FR between 60 and 105 mL.min(-1).1.73 m(-2). Mendelian randomization analyses for CHD showed an association among participants with eGFR 105 mL.min(-1).1.73 m(-2). Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin Alc, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function

Japanese Television Advertisements of Cigarettes and Image of Schoolchildren

We surveyed cigarette advertising at 4 Television (TV) stations in the Nagoya-city area in Japan. The advertising was videotaped all day for one week in August of 1988 (before it was under self-imposed regulation) as well as in January of 1989 (after regulation went into effect). These videotapes were shown to 140 schoolchildren in an attempt to determine the image of which youngsters think as cigarette advertising. Cigarette advertising TV spots totaled up to 134 (3435 sec) before self-restraints went into effect as against 93 spots (2430 sec) following imposition of the restraints. The frequency and time of the spots devoted to cigarette advertising showed a 30 % decrease after the restraints went into effect. The advertising of Japanese cigarettes decreased, whereas the proportion of American cigarette advertising increased. The advertising content showed a clear change after the restraints came off. Boys had a better impression of cigarette advertising than girls. As to the schoolchildren\u27s image of cigarette commercials, "grown-up" was the most common followed by interesting, "cheerful" and "happy". Many schoolchildren watch TV nightly, so we strongly recommend that cigarette TV advertising should be banned