Global analysis of DNA methylation in early-stage liver fibrosis

<p>Abstract</p> <p>Background</p> <p>Liver fibrosis is caused by chemicals or viral infection. The progression of liver fibrosis results in hepatocellular carcinogenesis in later stages. Recent studies have revealed the importance of DNA hypermethylation in the progression of liver fibrosis to hepatocellular carcinoma (HCC). However, the importance of DNA methylation in the early-stage liver fibrosis remains unclear.</p> <p>Methods</p> <p>To address this issue, we used a pathological mouse model of early-stage liver fibrosis that was induced by treatment with carbon tetrachloride (CCl₄) for 2 weeks and performed a genome-wide analysis of DNA methylation status. This global analysis of DNA methylation was performed using a combination of methyl-binding protein (MBP)-based high throughput sequencing (MBP-seq) and bioinformatic tools, IPA and Oncomine. To confirm functional aspect of MBP-seq data, we complementary used biochemical methods, such as bisulfite modification and <it>in-vitro</it>-methylation assays.</p> <p>Results</p> <p>The genome-wide analysis revealed that DNA methylation status was reduced throughout the genome because of CCl₄treatment in the early-stage liver fibrosis. Bioinformatic and biochemical analyses revealed that a gene associated with fibrosis, <it>secreted phosphoprotein 1 </it>(<it>Spp1</it>), which induces inflammation, was hypomethylated and its expression was up-regulated. These results suggest that DNA hypomethylation of the genes responsible for fibrosis may precede the onset of liver fibrosis. Moreover, <it>Spp1 </it>is also known to enhance tumor development. Using the web-based database, we revealed that <it>Spp1 </it>expression is increased in HCC.</p> <p>Conclusions</p> <p>Our study suggests that hypomethylation is crucial for the onset of and in the progression of liver fibrosis to HCC. The elucidation of this change in methylation status from the onset of fibrosis and subsequent progression to HCC may lead to a new clinical diagnosis.</p

Arcuate Fasciculus Abnormalities and Their Relationship with Psychotic Symptoms in Schizophrenia

Disruption of fronto-temporal connections involving the arcuate fasciculus (AF) may underlie language processing anomalies and psychotic features such as auditory hallucinations in schizophrenia. No study to date has specifically investigated abnormalities of white matter integrity at particular loci along the AF as well as its regional lateralization in schizophrenia. We examined white matter changes (fractional anisotropy (FA), axial diffusivity (AD), asymmetry indices) along the whole extent of the AF and their relationship with psychotic symptoms in 32 males with schizophrenia and 44 healthy males. Large deformation diffeomorphic metric mapping and Fiber Assignment Continuous Tracking were employed to characterize FA and AD along the geometric curve of the AF. Our results showed that patients with schizophrenia had lower FA in the frontal aspects of the left AF compared with healthy controls. Greater left FA and AD lateralization in the temporal segment of AF were associated with more severe positive psychotic symptoms such as delusions and hallucinations in patients with schizophrenia. Disruption of white matter integrity of the left frontal AF and accentuation of normal left greater than right asymmetry of FA/AD in the temporal AF further support the notion of aberrant fronto-temporal connectivity in schizophrenia. AF pathology can affect corollary discharge of neural signals from frontal speech/motor initiation areas to suppress activity of auditory cortex that may influence psychotic phenomena such as auditory hallucinations and facilitate elaboration of delusional content

2018年度読書運動プロジェクト活動報告書

活動資料 p.(1)～p.(5)はじめに : 藤本 朝巳 p.1読書会 : 小根山 桃子、立原 優菜、三雲 紫恩 p.2-p.4コンテスト・コンクール : 森園 佳子 p.5-p.7展示 : 山下 萌 p.8-p.11コラボランチ : 社本 衣舞紀 p.12文学散歩 : 中村 好花 p.13選書ツアー : 津田 優里香、鈴木 綾紗 p.14-p.15泉区読書推進イベント : 森園 佳子、伊豆 美保、小林 すずな p.16-p.18絵本講座・読み聞かせ講座 : 森園 佳子 p.19大学祭 : 花房 若奈、林 陽子 p.20-p.22朗読会 : 小野 紘子、関口 恵奈、穂積 優香、三雲 紫恩、児玉 玲奈、平山 真由子、宇野 菜々春、小林 すずな p.23-p.29プロフィール : p.30-39おわりに : 森園 佳子 p.40写真あり表あ

MYBBP1A suppresses breast cancer tumorigenesis by enhancing the p53 dependent anoikis

Abstract Background Tumor suppressor p53 is mutated in a wide variety of human cancers and plays a critical role in anoikis, which is essential for preventing tumorigenesis. Recently, we found that a nucleolar protein, Myb-binding protein 1a (MYBBP1A), was involved in p53 activation. However, the function of MYBBP1A in cancer prevention has not been elucidated. Methods Relationships between MYBBP1A expression levels and breast cancer progression were examined using patient microarray databases and tissue microarrays. Colony formation, xenograft, and anoikis assays were conducted using cells in which MYBBP1A was either knocked down or overexpressed. p53 activation and interactions between p53 and MYBBP1A were assessed by immunoprecipitation and western blot. Results MYBBP1A expression was negatively correlated with breast cancer tumorigenesis. In vivo and in vitro experiments using the breast cancer cell lines MCF-7 and ZR-75-1, which expresses wild type p53, showed that tumorigenesis, colony formation, and anoikis resistance were significantly enhanced by MYBBP1A knockdown. We also found that MYBBP1A binds to p53 and enhances p53 target gene transcription under anoikis conditions. Conclusions These results suggest that MYBBP1A is required for p53 activation during anoikis; therefore, it is involved in suppressing colony formation and the tumorigenesis of breast cancer cells. Collectively, our results suggest that MYBBP1A plays a role in tumor prevention in the context of p53 activation.</p

Cognitive Function Related to the <i>Sirh11/Zcchc16</i> Gene Acquired from an LTR Retrotransposon in Eutherians

<div><p>Gene targeting of mouse <u><i>S</i></u><i>ushi-</i><u><i>i</i></u><i>chi-related</i><u><i>r</i></u><i>etrotransposon</i><u><i>h</i></u><i>omologue</i><u><i>11</i></u><i>/</i><u><i>Z</i></u><i>inc finger</i><u><i>CCHC</i></u><i>domain-containing</i><u><i>16</i></u> (<i>Sirh11/Zcchc16</i>) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. <i>Sirh11/Zcchc16</i> encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that <i>Sirh11/Zcchc16</i> is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. <i>Sirh11/Zcchc16</i> is the first <i>SIRH</i> gene to be involved in brain function, instead of just the placenta, as seen in the case of <i>Peg10</i>, <i>Peg11/Rtl1</i> and <i>Sirh7/Ldoc1</i>.</p></div

The dN/dS ratio between the mouse and the seven other eutherian species expect xenarthral.

<p>Pairwise dN/dS analysis was performed using PAML [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005521#pgen.1005521.ref031" target="_blank">31</a>].</p><p>The dN/dS ratio between the mouse and the seven other eutherian species expect xenarthral.</p

Abnormal behavior in the <i>Sirh11/Zcchc16</i> KO mice.

<p><b>(</b>A) Light/Dark transition test. The left panel shows the latency time before entering into the light chamber. The right panel shows the number of transitions. The white and black bars represent WT and KO, respectively. Each data point represents the mean ± S. E. M. (N = 7 each). The asterisks indicate significant differences between the male WT and KO mice (*: p < 0.05). <b>(</b>B) Home-cage activity test. Upper: The plots show the activity counts every hour over 5 days. The white and grey areas indicate the light and dark phases, respectively. Middle: The white and black bars represent the activity counts in the WT and KO, respectively (mean ± S. D. (N = 7 each)). Zeitgeiber time (ZT) is shown on the x-axis. The asterisks indicate significant differences between the male WT and KO mice (**: p < 0.01, *: p < 0.05). Lower: the table shows the p-values of the two-way ANOVA at each ZT. The yellow columns indicate a significant difference in genotype (p < 0.05). (C) Y-maze test. Left: each plot shows the percentage of alternation behavior. Right: each plot shows the number of total arm entries. The white and black plots represent the WT and KO, respectively. The asterisk indicates a significant difference between the male WT (N = 6) and KO (N = 8) mice (*: p < 0.05).</p